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Sample records for suppressing uncontrolled growth

  1. Physical Growth and Body Composition of Controlled Versus Uncontrolled Type 1 Egyptian Diabetic Children

    Directory of Open Access Journals (Sweden)

    Nayera E. Hassan

    2014-12-01

    CONCLUSION: Growth was compromised in uncontrolled T1DM children. This is of utmost importance since most of the clinical features are reversible with better glycemic control and appropriate insulin management.

  2. Abnormal Grain Growth Suppression in Aluminum Alloys

    Science.gov (United States)

    Hales, Stephen J. (Inventor); Claytor, Harold Dale (Inventor); Alexa, Joel A. (Inventor)

    2015-01-01

    The present invention provides a process for suppressing abnormal grain growth in friction stir welded aluminum alloys by inserting an intermediate annealing treatment ("IAT") after the welding step on the article. The IAT may be followed by a solution heat treatment (SHT) on the article under effectively high solution heat treatment conditions. In at least some embodiments, a deformation step is conducted on the article under effective spin-forming deformation conditions or under effective superplastic deformation conditions. The invention further provides a welded article having suppressed abnormal grain growth, prepared by the process above. Preferably the article is characterized with greater than about 90% reduction in area fraction abnormal grain growth in any friction-stir-welded nugget.

  3. Void growth suppression by dislocation impurity atmospheres

    International Nuclear Information System (INIS)

    Weertman, J.; Green, W.V.

    1976-01-01

    A detailed calculation is given of the effect of an impurity atmosphere on void growth under irradiation damage conditions. Norris has proposed that such an atmosphere can suppress void growth. The hydrostatic stress field of a dislocation that is surrounded by an impurity atmosphere was found and used to calculate the change in the effective radius of a dislocation line as a sink for interstitials and vacancies. The calculation of the impurity concentration in a Cottrell cloud takes into account the change in hydrostatic pressure produced by the presence of the cloud itself. It is found that void growth is eliminated whenever dislocations are surrounded by a condensed atmosphere of either oversized substitutional impurity atoms or interstitial impurity atoms. A condensed atmosphere will form whenever the average impurity concentration is larger than a critical concentration

  4. Movement - uncontrolled or slow

    Science.gov (United States)

    Dystonia; Involuntary slow and twisting movements; Choreoathetosis; Leg and arm movements - uncontrollable; Arm and leg movements - uncontrollable; Slow involuntary movements of large muscle groups; Athetoid movements

  5. Suppressing magnetic island growth by resonant magnetic perturbation

    Science.gov (United States)

    Yu, Q.; Günter, S.; Lackner, K.

    2018-05-01

    The effect of externally applied resonant magnetic perturbations (RMPs) on the growth of magnetic islands is investigated based on two-fluid equations. It is found that if the local bi-normal electron fluid velocity at the resonant surface is sufficiently large, static RMPs of the same helicity and of moderate amplitude can suppress the growth of magnetic islands in high-temperature plasmas. These islands will otherwise grow, driven by an unfavorable plasma current density profile and bootstrap current perturbation. These results indicate that the error field can stabilize island growth, if the error field amplitude is not too large and the local bi-normal electron fluid velocity is not too low. They also indicate that applied rotating RMPs with an appropriate frequency can be utilized to suppress island growth in high-temperature plasmas, even for a low bi-normal electron fluid velocity. A significant change in the local equilibrium plasma current density gradient by small amplitude RMPs is found for realistic plasma parameters, which are important for the island stability and are expected to be more important for fusion reactors with low plasma resistivity.

  6. "Cold" X5 Hairlaser™ used to treat male androgenic alopecia and hair growth: an uncontrolled pilot study.

    Science.gov (United States)

    Blum, Kenneth; Han, David; Madigan, Margaret A; Lohmann, Raquel; Braverman, Eric R

    2014-02-24

    Various trials have been conducted on the management and treatment of androgenic alopecia (AGA) or male pattern hair loss using a variety of laser and light sources. For this feasibility study, the population was composed of males between the ages of 20 and 60 years who have been experiencing active hair loss within the last 12 months and the diagnosis of AGA. They also had a Norwood-Hamilton classification of 3, 3A, 3 V, 4, 4A, or 5 for the hair thinning patterns and skin type I, II, III, or IV on the Fitzpatrick skin type scale. This two-arm randomized, parallel group study design employed stratifying randomization to balance treatment assignment within three investigational centers with at least 2 subjects enrolled in each Fitzpatrick skin type. A statistically significant positive trend in hair growth was observed from this pilot study, to evaluate the efficacy of the novel cold X5 hairlaser device for treating male androgenic alopecia. From the repeated measures analysis of variance, difference in mean hair counts over time was statistically significant (F = 7.70; p-value laser hair devices requires intensive further investigation. NCT02067260.

  7. “Cold” X5 Hairlaser™ used to treat male androgenic alopecia and hair growth: an uncontrolled pilot study

    Science.gov (United States)

    2014-01-01

    Background Various trials have been conducted on the management and treatment of androgenic alopecia (AGA) or male pattern hair loss using a variety of laser and light sources. Methods For this feasibility study, the population was composed of males between the ages of 20 and 60 years who have been experiencing active hair loss within the last 12 months and the diagnosis of AGA. They also had a Norwood-Hamilton classification of 3, 3A, 3 V, 4, 4A, or 5 for the hair thinning patterns and skin type I, II, III, or IV on the Fitzpatrick skin type scale. This two-arm randomized, parallel group study design employed stratifying randomization to balance treatment assignment within three investigational centers with at least 2 subjects enrolled in each Fitzpatrick skin type. Results A statistically significant positive trend in hair growth was observed from this pilot study, to evaluate the efficacy of the novel cold X5 hairlaser device for treating male androgenic alopecia. From the repeated measures analysis of variance, difference in mean hair counts over time was statistically significant (F = 7.70; p-value laser hair devices requires intensive further investigation. Trial registration NCT02067260 PMID:24559020

  8. Uncovering growth-suppressive MicroRNAs in lung cancer

    DEFF Research Database (Denmark)

    Liu, Xi; Sempere, Lorenzo F; Galimberti, Fabrizio

    2009-01-01

    PURPOSE: MicroRNA (miRNA) expression profiles improve classification, diagnosis, and prognostic information of malignancies, including lung cancer. This study uncovered unique growth-suppressive miRNAs in lung cancer. EXPERIMENTAL DESIGN: miRNA arrays were done on normal lung tissues...... and adenocarcinomas from wild-type and proteasome degradation-resistant cyclin E transgenic mice to reveal repressed miRNAs in lung cancer. Real-time and semiquantitative reverse transcription-PCR as well as in situ hybridization assays validated these findings. Lung cancer cell lines were derived from each......-malignant human lung tissue bank. RESULTS: miR-34c, miR-145, and miR-142-5p were repressed in transgenic lung cancers. Findings were confirmed by real-time and semiquantitative reverse transcription-PCR as well as in situ hybridization assays. Similar miRNA profiles occurred in human normal versus malignant lung...

  9. Water relations, gas exchange and growth of dominant and suppressed shoots of Arbutus unedo L.

    Science.gov (United States)

    Castell, C; Terradas, J

    1995-06-01

    Basal shoots produced by Arbutus unedo L. after cutting at ground level vary in size and growth rate, and are classified accordingly as dominant or suppressed. The suppressed shoots eventually cease growth and die. In this study, we investigated the role of light and water in the competition among shoots of A. unedo. Dominant and suppressed shoots of A. unedo showed similar leaf water potentials and tissue water relations over the year, suggesting that water status is not responsible for the lack of flushing in suppressed shoots. Although suppressed shoots did not flush under low light, they showed many characteristics of shade-tolerant plants. Leaves of suppressed shoots had lower leaf conductance and light-saturated photosynthetic rate, and higher specific leaf area than leaves of dominant shoots. We conclude that light was the main resource determining competition among shoots and the death of suppressed shoots.

  10. Withaferin A Suppresses Liver Tumor Growth in a Nude Mouse ...

    African Journals Online (AJOL)

    Purpose: To investigate the effect of withaferin A on tumor growth and metastasis in liver in a nude mouse model. Methods: Withaferin A was injected through a portal vein to the orthotopic liver tumor in a nude mice model. Xenogen in vivo imaging system was used to monitor tumor growth and metastasis. The effect of ...

  11. Bergenin suppresses the growth of colorectal cancer cells by ...

    African Journals Online (AJOL)

    anticancer drugs as well as new chemotherapy adjuvants that enhance efficacy and diminish side effects of chemotherapeutic agent. In this study, bergenin showed significant inhibitory effect on the growth of HCT116 cells. Bergenin induced ROS-mediated DNA damage, which resulted in G1 phase arrest and inhibited the.

  12. Pyridine 2,4-dicarboxylic acid suppresses tomato seedling growth

    Science.gov (United States)

    Fragkostefanakis, Sotirios; Kaloudas, Dimitrios; Kalaitzis, Panagiotis

    2018-01-01

    Pyridine 2,4-dicarboxylic acid is a structural analogue of 2-oxoglutarate and is known to inhibit 2-oxoglutare-dependent dioxygenases. The effect of this inhibitor in tomato seedlings grown in MS media supplied with various concentrations of PDCA was investigated, resulting in shorter roots and hypocotyls in a dose-dependent manner. The partial inhibition of growth in roots was more drastic compared to hypocotyls and was attributed to a decrease in the elongation of root and hypocotyl cells. Concentrations of 100 and 250 μΜ of PDCA decreased hydroxyproline content in roots while only the 250 μΜ treatment reduced the hydroxyproline content in shoots. Seedlings treated with 100 μΜ PDCA exhibited enhanced growth of hypocotyl and cotyledon cells and higher hydroxyproline content resulting in cotyledons with greater surface area. However, no alterations in hypocotyl length were observed. Prolyl 4 hydroxylases (P4Hs) are involved in the O-glycosylation of AGPs and were also highly expressed during seedling growth. Moreover PDCA induced a decrease in the accumulation of HRGPs and particularly in AGPs-bound epitopes in a dose dependent-manner while more drastic reduction were observed in roots compared to shoots. In addition, bulged root epidermal cells were observed at the high concentration of 250 μΜ which is characteristic of root tissues with glycosylation defects. These results indicate that PDCA induced pleiotropic effects during seedling growth while further studies are required to better investigate the physiological significance of this 2-oxoglutarate analogue. This pharmacological approach might be used as a tool to better understand the physiological significance of HRGPs and probably P4Hs in various growth and developmental programs in plants.

  13. Pyridine 2,4-Dicarboxylic Acid Suppresses Tomato Seedling Growth

    Directory of Open Access Journals (Sweden)

    Sotirios Fragkostefanakis

    2018-01-01

    Full Text Available Pyridine 2,4-dicarboxylic acid is a structural analog of 2-oxoglutarate and is known to inhibit 2-oxoglutare-dependent dioxygenases. The effect of this inhibitor in tomato seedlings grown in MS media supplied with various concentrations of PDCA was investigated, resulting in shorter roots and hypocotyls in a dose-dependent manner. The partial inhibition of growth in roots was more drastic compared to hypocotyls and was attributed to a decrease in the elongation of root and hypocotyl cells. Concentrations of 100 and 250 μM of PDCA decreased hydroxyproline content in roots while only the 250 μM treatment reduced the hydroxyproline content in shoots. Seedlings treated with 100 μM PDCA exhibited enhanced growth of hypocotyl and cotyledon cells and higher hydroxyproline content resulting in cotyledons with greater surface area. However, no alterations in hypocotyl length were observed. Prolyl 4 hydroxylases (P4Hs are involved in the O-glycosylation of AGPs and were also highly expressed during seedling growth. Moreover PDCA induced a decrease in the accumulation of HRGPs and particularly in AGPs-bound epitopes in a dose dependent-manner while more drastic reduction were observed in roots compared to shoots. In addition, bulged root epidermal cells were observed at the high concentration of 250 μM which is characteristic of root tissues with glycosylation defects. These results indicate that PDCA induced pleiotropic effects during seedling growth while further studies are required to better investigate the physiological significance of this 2-oxoglutarate analog. This pharmacological approach might be used as a tool to better understand the physiological significance of HRGPs and probably P4Hs in various growth and developmental programs in plants.

  14. Triparanol suppresses human tumor growth in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Bi, Xinyu [Department of Abdominal Surgical Oncology, Lab of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021 (China); Han, Xingpeng [Department of Pathology, Tianjin Chest Hospital, Tianjin 300051 (China); Zhang, Fang [Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, Zhejiang (China); He, Miao [Life Sciences School, Sun Yat-sen University, Guangzhou 510275 (China); Zhang, Yi [Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Zhi, Xiu-Yi, E-mail: xiuyizhi@yahoo.com.cn [Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Zhao, Hong, E-mail: zhaohong9@sina.com [Department of Abdominal Surgical Oncology, Lab of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021 (China)

    2012-08-31

    Highlights: Black-Right-Pointing-Pointer Demonstrate Triparanol can block proliferation in multiple cancer cells. Black-Right-Pointing-Pointer Demonstrate Triparanol can induce apoptosis in multiple cancer cells. Black-Right-Pointing-Pointer Proved Triparanol can inhibit Hedgehog signaling in multiple cancer cells. Black-Right-Pointing-Pointer Demonstrated Triparanol can impede tumor growth in vivo in mouse xenograft model. -- Abstract: Despite the improved contemporary multidisciplinary regimens treating cancer, majority of cancer patients still suffer from adverse effects and relapse, therefore posing a significant challenge to uncover more efficacious molecular therapeutics targeting signaling pathways central to tumorigenesis. Here, our study have demonstrated that Triparanol, a cholesterol synthesis inhibitor, can block proliferation and induce apoptosis in multiple human cancer cells including lung, breast, liver, pancreatic, prostate cancer and melanoma cells, and growth inhibition can be rescued by exogenous addition of cholesterol. Remarkably, we have proved Triparanol can significantly repress Hedgehog pathway signaling in these human cancer cells. Furthermore, study in a mouse xenograft model of human lung cancer has validated that Triparanol can impede tumor growth in vivo. We have therefore uncovered Triparanol as potential new cancer therapeutic in treating multiple types of human cancers with deregulated Hedgehog signaling.

  15. Triparanol suppresses human tumor growth in vitro and in vivo

    International Nuclear Information System (INIS)

    Bi, Xinyu; Han, Xingpeng; Zhang, Fang; He, Miao; Zhang, Yi; Zhi, Xiu-Yi; Zhao, Hong

    2012-01-01

    Highlights: ► Demonstrate Triparanol can block proliferation in multiple cancer cells. ► Demonstrate Triparanol can induce apoptosis in multiple cancer cells. ► Proved Triparanol can inhibit Hedgehog signaling in multiple cancer cells. ► Demonstrated Triparanol can impede tumor growth in vivo in mouse xenograft model. -- Abstract: Despite the improved contemporary multidisciplinary regimens treating cancer, majority of cancer patients still suffer from adverse effects and relapse, therefore posing a significant challenge to uncover more efficacious molecular therapeutics targeting signaling pathways central to tumorigenesis. Here, our study have demonstrated that Triparanol, a cholesterol synthesis inhibitor, can block proliferation and induce apoptosis in multiple human cancer cells including lung, breast, liver, pancreatic, prostate cancer and melanoma cells, and growth inhibition can be rescued by exogenous addition of cholesterol. Remarkably, we have proved Triparanol can significantly repress Hedgehog pathway signaling in these human cancer cells. Furthermore, study in a mouse xenograft model of human lung cancer has validated that Triparanol can impede tumor growth in vivo. We have therefore uncovered Triparanol as potential new cancer therapeutic in treating multiple types of human cancers with deregulated Hedgehog signaling.

  16. Fagopyrum esculentum Alters Its Root Exudation after Amaranthus retroflexus Recognition and Suppresses Weed Growth.

    Science.gov (United States)

    Gfeller, Aurélie; Glauser, Gaétan; Etter, Clément; Signarbieux, Constant; Wirth, Judith

    2018-01-01

    Weed control by crops through growth suppressive root exudates is a promising alternative to herbicides. Buckwheat ( Fagopyrum esculentum ) is known for its weed suppression and redroot pigweed ( Amaranthus retroflexus ) control is probably partly due to allelopathic root exudates. This work studies whether other weeds are also suppressed by buckwheat and if the presence of weeds is necessary to induce growth repression. Buckwheat and different weeds were co-cultivated in soil, separating roots by a mesh allowing to study effects due to diffusion. Buckwheat suppressed growth of pigweed, goosefoot and barnyard grass by 53, 42, and 77% respectively without physical root interactions, probably through allelopathic compounds. Root exudates were obtained from sand cultures of buckwheat (BK), pigweed (P), and a buckwheat/pigweed mixed culture (BK-P). BK-P root exudates inhibited pigweed root growth by 49%. Characterization of root exudates by UHPLC-HRMS and principal component analysis revealed that BK and BK-P had a different metabolic profile suggesting that buckwheat changes its root exudation in the presence of pigweed indicating heterospecific recognition. Among the 15 different markers, which were more abundant in BK-P, tryptophan was identified and four others were tentatively identified. Our findings might contribute to the selection of crops with weed suppressive effects.

  17. Procyanidins Mitigate Osteoarthritis Pathogenesis by, at Least in Part, Suppressing Vascular Endothelial Growth Factor Signaling

    Directory of Open Access Journals (Sweden)

    Angela Wang

    2016-12-01

    Full Text Available Procyanidins are a family of plant metabolites that have been suggested to mitigate osteoarthritis pathogenesis in mice. However, the underlying mechanism is largely unknown. This study aimed to determine whether procyanidins mitigate traumatic injury-induced osteoarthritis (OA disease progression, and whether procyanidins exert a chondroprotective effect by, at least in part, suppressing vascular endothelial growth factor signaling. Procyanidins (extracts from pine bark, orally administered to mice subjected to surgery for destabilization of the medial meniscus, significantly slowed OA disease progression. Real-time polymerase chain reaction revealed that procyanidin treatment reduced expression of vascular endothelial growth factor and effectors in OA pathogenesis that are regulated by vascular endothelial growth factor. Procyanidin-suppressed vascular endothelial growth factor expression was correlated with reduced phosphorylation of vascular endothelial growth factor receptor 2 in human OA primary chondrocytes. Moreover, components of procyanidins, procyanidin B2 and procyanidin B3 exerted effects similar to those of total procyanidins in mitigating the OA-related gene expression profile in the primary culture of human OA chondrocytes in the presence of vascular endothelial growth factor. Together, these findings suggest procyanidins mitigate OA pathogenesis, which is mediated, at least in part, by suppressing vascular endothelial growth factor signaling.

  18. Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression.

    Science.gov (United States)

    Nahta, Rita; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Andrade-Vieira, Rafaela; Bay, Sarah N; Brown, Dustin G; Calaf, Gloria M; Castellino, Robert C; Cohen-Solal, Karine A; Colacci, Annamaria; Cruickshanks, Nichola; Dent, Paul; Di Fiore, Riccardo; Forte, Stefano; Goldberg, Gary S; Hamid, Roslida A; Krishnan, Harini; Laird, Dale W; Lasfar, Ahmed; Marignani, Paola A; Memeo, Lorenzo; Mondello, Chiara; Naus, Christian C; Ponce-Cusi, Richard; Raju, Jayadev; Roy, Debasish; Roy, Rabindra; Ryan, Elizabeth P; Salem, Hosni K; Scovassi, A Ivana; Singh, Neetu; Vaccari, Monica; Vento, Renza; Vondráček, Jan; Wade, Mark; Woodrick, Jordan; Bisson, William H

    2015-06-01

    As part of the Halifax Project, this review brings attention to the potential effects of environmental chemicals on important molecular and cellular regulators of the cancer hallmark of evading growth suppression. Specifically, we review the mechanisms by which cancer cells escape the growth-inhibitory signals of p53, retinoblastoma protein, transforming growth factor-beta, gap junctions and contact inhibition. We discuss the effects of selected environmental chemicals on these mechanisms of growth inhibition and cross-reference the effects of these chemicals in other classical cancer hallmarks. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Emittance growth due to noise and its suppression with the Feedback system in large hadron colliders

    International Nuclear Information System (INIS)

    Lebedev, V.; Parkhomchuk, V.; Shiltsev, V.; Stupakov, G.

    1993-03-01

    The problem of emittance growth due to random fluctuation of the magnetic field in hadron colliders is considered. Based on a simple one-dimensional linear model, a formula for an emittance growth rate as a function of the noise spectrum is derived. Different sources of the noise are analyzed and their role is estimated for the Superconducting Super Collider (SSC). A theory of feedback suppression of the emittance growth is developed which predicts the residual growth of the emittance in the accelerator with a feedback system

  20. The super collider transverse feedback system for suppression of the emittance growth and beam instabilities

    International Nuclear Information System (INIS)

    Lebedev, V.A.

    1993-01-01

    A super collider transverse feedback system designed to suppress injection errors, emittance growth due to external noises, and beam instabilities is considered. It is supposed that the feedback system should consist of two circuits: an injection damper operating just after injection and a super damper. To damp the emittance growth, the superdamper has to operate with the ultimate decrement close to the revolution frequency. The physics of such a feedback system and its main limitations are discussed. 9 refs.; 21 figs.; 1 tab

  1. Crustose coralline algae can suppress macroalgal growth and recruitment on Hawaiian coral reefs

    NARCIS (Netherlands)

    Vermeij, M.J.A.; Dailer, M.L.; Smith, C.M.

    2011-01-01

    Crustose coralline algae are important components of tropical reef communities because they promote successful settlement by corals and contribute to solidification of the reef framework. We show experimentally that crustose coralline algae are also capable of suppressing the growth and recruitment

  2. The flight of uncontrolled rockets

    CERN Document Server

    Gantmakher, F R; Dryden, H L

    1964-01-01

    International Series of Monographs on Aeronautics and Astronautics, Division VII, Volume 5: The Flight of Uncontrolled Rockets focuses on external ballistics of uncontrolled rockets. The book first discusses the equations of motion of rockets. The rocket as a system of changing composition; application of solidification principle to rockets; rotational motion of rockets; and equations of motion of the center of mass of rockets are described. The text looks at the calculation of trajectory of rockets and the fundamentals of rocket dispersion. The selection further focuses on the dispersion of f

  3. miR-137 suppresses tumor growth of malignant melanoma by targeting aurora kinase A

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Xiao; Zhang, Haiping [Department of Dermatology and Venereal Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Lian, Shi [Department of Dermatology and Venereal Disease, Capital Medical University, Beijing 100069 (China); Zhu, Wei, E-mail: zhuwei_2020@163.com [Department of Dermatology and Venereal Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China)

    2016-07-01

    As an oncogene, aurora kinase A (AURKA) is overexpressed in various types of human cancers. However, the expression and roles of AURKA in malignant melanoma are largely unknown. In this study, a miR-137-AURKA axis was revealed to regulate melanoma growth. We found a significant increase in levels of AURKA in melanoma. Both genetic knockdown and pharmacologic inhibition of AURKA decreased tumor cell growth in vitro and in vivo. Further found that miR-137 reduced AURKA expression through interaction with its 3′ untranslated region (3′UTR) and that miR-137 was negatively correlated with AURKA expression in melanoma specimens. Overexpression of miR-137 decreased cell proliferation and colony formation in vitro. Notably, re-expression of AURKA significantly rescued miR-137-mediated suppression of cell growth and clonality. In summary, these results reveal that miR-137 functions as a tumor suppressor by targeting AURKA, providing new insights into investigation of therapeutic strategies against malignant melanoma. -- Highlights: •First reported overexpression of AURKA in melanoma. •Targeting AURKA inhibits melanoma growth in vitro and in vivo. •Further found miR-137 suppressed cell growth by binding to AURKA 3′UTR. •Re-expression of AURKA rescued miR-137-mediated suppression. •miR-137-AURKA axis may be potential therapeutic targets of melanoma.

  4. Exogenous regucalcin suppresses the growth of human liver cancer HepG2 cells in vitro.

    Science.gov (United States)

    Yamaguchi, Masayoshi; Murata, Tomiyasu

    2018-04-05

    Regucalcin, which its gene is localized on the X chromosome, plays a pivotal role as a suppressor protein in signal transduction in various types of cells and tissues. Regucalcin gene expression has been demonstrated to be suppressed in various tumor tissues of animal and human subjects, suggesting a potential role of regucalcin in carcinogenesis. Regucalcin, which is produced from the tissues including liver, is found to be present in the serum of human subjects and animals. This study was undertaken to determine the effects of exogenous regucalcin on the proliferation in cloned human hepatoma HepG2 cells in vitro. Proliferation of HepG2 cells was suppressed after culture with addition of regucalcin (0.01 – 10 nM) into culture medium. Exogenous regucalcin did not reveal apoptotic cell death in HepG2 cells in vitro. Suppressive effects of regucalcin on cell proliferation were not enhanced in the presence of various signaling inhibitors including tumor necrosis factor-α (TNF-α), Bay K 8644, PD98059, staurosporine, worthomannin, 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) or gemcitabine, which were found to suppress the proliferation. In addition, exogenous regucalcin suppressed the formation of colonies of cultured hepatoma cells in vitro. These findings demonstrated that exogenous regucalcin exhibits a suppressive effect on the growth of human hepatoma HepG2 cells, proposing a strategy with the gene therapy for cancer treatment.

  5. Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis.

    Science.gov (United States)

    Wang, Ying; Rishi, Arun K; Wu, Wenjuan; Polin, Lisa; Sharma, Sunita; Levi, Edi; Albelda, Steven; Pass, Harvey I; Wali, Anil

    2011-11-01

    Malignant pleural mesothelioma (MPM) is an aggressive, asbestos-related malignancy of the thoracic pleura. Although, platinum-based agents are the first line of therapy, there is an urgent need for second-line therapies to treat the drug-resistant MPM. Cell cycle as well as apoptosis pathways are frequently altered in MPM and thus remain attractive targets for intervention strategies. Curcumin, the major component in the spice turmeric, alone or in combination with other chemotherapeutics has been under investigation for a number of cancers. In this study, we investigated the biological and molecular responses of MPM cells to curcumin treatments and the mechanisms involved. Flow-cytometric analyses coupled with western immunoblotting and gene-array analyses were conducted to determine mechanisms of curcumin-dependent growth suppression of human (H2373, H2452, H2461, and H226) and murine (AB12) MPM cells. Curcumin inhibited MPM cell growth in a dose- and time-dependent manner while pretreatment of MPM cells with curcumin enhanced cisplatin efficacy. Curcumin activated the stress-activated p38 kinase, caspases 9 and 3, caused elevated levels of proapoptotic proteins Bax, stimulated PARP cleavage, and apoptosis. In addition, curcumin treatments stimulated expression of novel transducers of cell growth suppression such as CARP-1, XAF1, and SULF1 proteins. Oral administration of curcumin inhibited growth of murine MPM cell-derived tumors in vivo in part by stimulating apoptosis. Thus, curcumin targets cell cycle and promotes apoptosis to suppress MPM growth in vitro and in vivo. Our studies provide a proof-of-principle rationale for further in-depth analysis of MPM growth suppression mechanisms and their future exploitation in effective management of resistant MPM.

  6. Virus-like particles suppress growth of the red-tide-forming marine dinoflagellate Gymnodinium mikimotoi.

    Science.gov (United States)

    Onji, Masashi; Nakano, Shin-ichi; Suzuki, Satoru

    2003-01-01

    We isolated 2 virus-like agents that suppressed growth of Gymnodinium mikimotoi from coastal waters of the Uwa Sea, Japan. The agents found in the flagellate cells, named GM6 and GM7, were filterable in a 0.22-microm-pore filter with approximately 100-nm shapes. Electron microscopic observation showed the presence of virus-like particles in severely damaged G. mikimotoi cells infected by GM6. The growth-suppression activity of the agents (GM6 or GM7) was lost by heating at 50 degrees C, with treatments of DNase and protease, and filtration through a 0.05-microm filter. Our results suggest that the agents are DNA viruses infectious to and virulent for G. mikimotoi. This is the first report of a virus-like agent specific to G. mikimotoi.

  7. Complete suppression of in vivo growth of human leukemia cells by specific immunotoxins: nude mouse models

    International Nuclear Information System (INIS)

    Hara, H.; Seon, B.K.

    1987-01-01

    In this study, immunotoxins containing monoclonal anti-human T-cell leukemia antibodies are shown to be capable of completely suppressing the tumor growth of human T-cell leukemia cells in vivo without any overt undersirable toxicity. These immunotoxins were prepared by conjugating ricin A chain (RA) with our monoclonal antibodies, SN1 and SN2, directed specifically to the human T-cell leukemia cell surface antigens TALLA and GP37, respectively. The authors have shown that these monoclonal antibodies are highly specific for human T-cell leukemia cells and do not react with various normal cells including normal T and B cells, thymocytes, and bone marrow cells. Ascitic and solid human T-cell leukemia cell tumors were generated in nude mice. The ascitic tumor was generated by transplanting Ichikawa cells (a human T-cell leukemia cell) i.p. into nude mice, whereas the solid tumor was generated by transplanting s.c. MOLT-4 cells (a human T-cell leukemia cell line) and x-irradiated human fibrosarcoma cells into x-irradiated nude mice. To investigate the efficacy of specific immunotoxins in suppression the in vivo growth of the ascitic tumor, they divided 40 nude mice that were injected with Ichikawa cells into four groups. None of the mice in group 4 that were treated with SN1-RA and SN2-RA showed any signs of a tumor or undesirable toxic effects for the 20 weeks that they were followed after the transplantation. Treatment with SN1-RA plus SN2-RA completely suppressed solid tumor growth in 4 of 10 nude mice carrying solid tumors and partially suppressed the tumor growth in the remaining 6 nude mice. These results strongly suggest that SN1-RA and SN2-RA may be useful for clinical treatment

  8. Locoregional injection of F-18 radiopharmaceuticals suppresses tumor xenograft growth in rats

    Energy Technology Data Exchange (ETDEWEB)

    Wong, C -L [The Univ. of Texas M.D. Anderson Cancer Center, Texas (United States)

    2004-07-01

    The energetic positrons (0.633 Mev) from F-18 dissipate kinetic energies before annihilation to produce two 0.511 Mev photons which also contribute to the radiation absorbed dose to the surroundings. In living organism, the contribution from the positron itself to the surrounding tissues (up to 2 mm) is larger than from the 2 photons. Apoptosis has been reported in rat tumors after systemic injection of F-18 FDG although no growth retardation was noted. This study is designed to exploit the pharmacokinetic advantages of locoregional injection of positron emitters in the suppression of tumor growth in rats. Methods: Groups of Fisher 344 adult female rats were inoculated with rat mammary tumors (100,000 cells) intramuscularly (IM) in the thigh. Locoregional injection with F-18 NaF or F-18 FDG was accomplished in days 3 or 7 with single doses of increasing strengths (0.2 to 3 mCi). Tumor growth rates were noted and compared to control (sham injection with saline). The locoregional distribution and clearance of F-18 were estimated from serial tomograms using a Concord MicroPET (R4) after intramuscular injection of 0.1-0.2 mCi of F-18 NaF or F-18 FDG in groups of triplicate rats. Results: A dose-related pattern of tumor suppression is noted with F-18 FDG, whether treatment occurs in day 3 or 7 after inoculation. Additional experiment of injection of 5 mci of F-18 FDG at day 14 also suppressed the growth of a well-formed tumor. Tumor suppression by F-18 NaF is less obvious and only occurs with high dose (2 mCi). MicroPET images demonstrate that F-18 FDG is retained in the injection site while F-18 NaF dissipates rapidly. Conclusion: Locoregional injection of positron-emitters may be sufficient to suppress tumor growth. The mechanism is likely related to the pharmacokinetic profile of the compound within the tissue. Discussion: Locoregional application of radionuclides may provide feasible alternatives to slow tumor growth or prevent tumor recurrence. The use of

  9. Rapamycin delays growth of Wnt-1 tumors in spite of suppression of host immunity

    International Nuclear Information System (INIS)

    Svirshchevskaya, Elena V; Mariotti, Jacopo; Wright, Mollie H; Viskova, Natalia Y; Telford, William; Fowler, Daniel H; Varticovski, Lyuba

    2008-01-01

    Rapamycin, an inhibitor of mammalian target of Rapamycin (mTOR), is an immunosuppressive agent that has anti-proliferative effects on some tumors. However, the role of Rapamycin-induced immune suppression on tumor progression has not been examined. We developed a transplantation model for generation of mammary tumors in syngeneic recipients that can be used to address the role of the immune system on tumor progression. We examined the effect of Rapamycin on the immune system and growth of MMTV-driven Wnt-1 mammary tumors which were transplanted into irradiated and bone marrow-reconstituted, or naïve mice. Rapamycin induced severe immunosuppression and significantly delayed the growth of Wnt-1 tumors. T cell depletion in spleen and thymus and reduction in T cell cytokine secretion were evident within 7 days of therapy. By day 20, splenic but not thymic T cell counts, and cytokine secretion recovered. We determined whether adoptive T cell therapy enhances the anti-cancer effect using ex vivo generated Rapamycin-resistant T cells. However, T cell transfer during Rapamycin therapy did not improve the outcome relative to drug therapy alone. Thus, we could not confirm that suppression of T cell immunity contributes to tumor growth in this model. Consistent with suppression of the mTOR pathway, decreased 4E-BP1, p70 S6-kinase, and S6 protein phosphorylation correlated with a decrease in Wnt-1 tumor cell proliferation. Rapamycin has a direct anti-tumor effect on Wnt-1 breast cancer in vivo that involves inhibition of the mTOR pathway at doses that also suppress host immune responses

  10. Inhibition of BRD4 suppresses tumor growth and enhances iodine uptake in thyroid cancer

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Xuemei [Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province (China); Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, Hubei Province (China); Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province (China); Wu, Xinchao [Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province (China); Zhang, Xiao; Hua, Wenjuan; Zhang, Yajing [Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province (China); Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, Hubei Province (China); Maimaiti, Yusufu [Department of Thyroid and Breast Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province (China); Gao, Zairong, E-mail: gaobonn@163.com [Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province (China); Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, Hubei Province (China); Zhang, Yongxue [Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province (China); Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, Hubei Province (China)

    2016-01-15

    Thyroid cancer is a common malignancy of the endocrine system. Although radioiodine {sup 131}I treatment on differentiated thyroid cancer is widely used, many patients still fail to benefit from {sup 131}I therapy. Therefore, exploration of novel targeted therapies to suppress tumor growth and improve radioiodine uptake remains necessary. Bromodomain-containing protein 4 (BRD4) is an important member of the bromodomain and extra terminal domain family that influences transcription of downstream genes by binding to acetylated histones. In the present study, we found that BRD4 was up-regulated in thyroid cancer tissues and cell lines. Inhibition of BRD4 in thyroid cancer cells by JQ1 resulted in cell cycle arrest at G0/G1 phase and enhanced {sup 131}I uptake in vitro and suppressed tumor growth in vivo. Moreover, JQ1 treatment suppressed C-MYC but enhanced NIS expression. We further demonstrated that BRD4 was enriched in the promoter region of C-MYC, which could be markedly blocked by JQ1 treatment. In conclusion, our findings revealed that the aberrant expression of BRD4 in thyroid cancer is possibly involved in tumor progression, and JQ1 is potentially an effective chemotherapeutic agent against human thyroid cancer. - Highlights: • BRD4 is upregulated in thyroid cancer tissues and cell lines. • Inhibition of BRD4 induced cell cycle arrest and enhanced radioiodine uptake in vitro and impaired tumor growth in vivo. • JQ1 suppressed the expression of C-MYC and promoted the expression of NIS and P21. • JQ1 attenuated the recruitment of BRD4 to MYC promoter in thyroid cancer.

  11. Inhibition of BRD4 suppresses tumor growth and enhances iodine uptake in thyroid cancer

    International Nuclear Information System (INIS)

    Gao, Xuemei; Wu, Xinchao; Zhang, Xiao; Hua, Wenjuan; Zhang, Yajing; Maimaiti, Yusufu; Gao, Zairong; Zhang, Yongxue

    2016-01-01

    Thyroid cancer is a common malignancy of the endocrine system. Although radioiodine "1"3"1I treatment on differentiated thyroid cancer is widely used, many patients still fail to benefit from "1"3"1I therapy. Therefore, exploration of novel targeted therapies to suppress tumor growth and improve radioiodine uptake remains necessary. Bromodomain-containing protein 4 (BRD4) is an important member of the bromodomain and extra terminal domain family that influences transcription of downstream genes by binding to acetylated histones. In the present study, we found that BRD4 was up-regulated in thyroid cancer tissues and cell lines. Inhibition of BRD4 in thyroid cancer cells by JQ1 resulted in cell cycle arrest at G0/G1 phase and enhanced "1"3"1I uptake in vitro and suppressed tumor growth in vivo. Moreover, JQ1 treatment suppressed C-MYC but enhanced NIS expression. We further demonstrated that BRD4 was enriched in the promoter region of C-MYC, which could be markedly blocked by JQ1 treatment. In conclusion, our findings revealed that the aberrant expression of BRD4 in thyroid cancer is possibly involved in tumor progression, and JQ1 is potentially an effective chemotherapeutic agent against human thyroid cancer. - Highlights: • BRD4 is upregulated in thyroid cancer tissues and cell lines. • Inhibition of BRD4 induced cell cycle arrest and enhanced radioiodine uptake in vitro and impaired tumor growth in vivo. • JQ1 suppressed the expression of C-MYC and promoted the expression of NIS and P21. • JQ1 attenuated the recruitment of BRD4 to MYC promoter in thyroid cancer.

  12. Pseudomonas aeruginosa biofilm hampers murine central wound healing by suppression of vascular epithelial growth factor

    DEFF Research Database (Denmark)

    Trøstrup, Hannah; Lerche, Christian J; Christophersen, Lars J

    2018-01-01

    -wounded, infection-susceptible BALB/c mice, which display delayed wound closure compared to C3H/HeN mice. Wounds were evaluated histopathologically 4, 7 or 10 days post-infection. Photoplanimetry evaluated necrotic areas. P. aeruginosa biofilm suppressed vascular endothelial growth factor levels centrally in BALB....../c wounds but increased peripheral levels 4-7 days post-infection. Central zones of the burn wound displayed lower levels of central vascular endothelial growth factor as observed 4 and 7 days post-infection in BALB/c mice compared to their C3H/HeN counterparts. Biofilm suppressed early, centrally located S......100A8/A9 in BALB/c and centrally and peripherally later on in C3H/HeN wounds as compared to uninfected mice. Peripheral polymorphonuclear-dominated inflammation and larger necrosis were observed in BALB/c wounds. In conclusion, P. aeruginosa biofilm modulates wounds by suppressing central...

  13. Opioid-dependent growth of glial cultures: Suppression of astrocyte DNA synthesis by met-enkephalin

    International Nuclear Information System (INIS)

    Stiene-Martin, A.; Hauser, K.F.

    1990-01-01

    The action of met-enkephalin on the growth of astrocytes in mixed-glial cultures was examined. Primary, mixed-glial cultures were isolated from 1 day-old mouse cerebral hemispheres and continuously treated with either basal growth media, 1 μM met-enkephalin, 1 μM met-enkephalin plus the opioid antagonist naloxone, or naloxone alone. Absolute numbers of neural cells were counted in unstained preparations, while combined [ 3 H]-thymidine autoradiography and glial fibrillary acid protein (GFAP) immunocytochemistry was performed to identify specific changes in astrocytes. When compared to control and naloxone treated cultures, met-enkephalin caused a significant decrease in both total cell numbers, and in [ 3 H]-thymidine incorporation by GFAP-positive cells with flat morphology. These results indicate that met-enkephalin suppresses astrocyte growth in culture

  14. Opioid-dependent growth of glial cultures: Suppression of astrocyte DNA synthesis by met-enkephalin

    Energy Technology Data Exchange (ETDEWEB)

    Stiene-Martin, A.; Hauser, K.F. (Univ. of Kentucky, Lexington (USA))

    1990-01-01

    The action of met-enkephalin on the growth of astrocytes in mixed-glial cultures was examined. Primary, mixed-glial cultures were isolated from 1 day-old mouse cerebral hemispheres and continuously treated with either basal growth media, 1 {mu}M met-enkephalin, 1 {mu}M met-enkephalin plus the opioid antagonist naloxone, or naloxone alone. Absolute numbers of neural cells were counted in unstained preparations, while combined ({sup 3}H)-thymidine autoradiography and glial fibrillary acid protein (GFAP) immunocytochemistry was performed to identify specific changes in astrocytes. When compared to control and naloxone treated cultures, met-enkephalin caused a significant decrease in both total cell numbers, and in ({sup 3}H)-thymidine incorporation by GFAP-positive cells with flat morphology. These results indicate that met-enkephalin suppresses astrocyte growth in culture.

  15. A nonlinear competitive model of the prostate tumor growth under intermittent androgen suppression.

    Science.gov (United States)

    Yang, Jing; Zhao, Tong-Jun; Yuan, Chang-Qing; Xie, Jing-Hui; Hao, Fang-Fang

    2016-09-07

    Hormone suppression has been the primary modality of treatment for prostate cancer. However long-term androgen deprivation may induce androgen-independent (AI) recurrence. Intermittent androgen suppression (IAS) is a potential way to delay or avoid the AI relapse. Mathematical models of tumor growth and treatment are simple while they are capable of capturing the essence of complicated interactions. Game theory models have analyzed that tumor cells can enhance their fitness by adopting genetically determined survival strategies. In this paper, we consider the survival strategies as the competitive advantage of tumor cells and propose a new model to mimic the prostate tumor growth in IAS therapy. Then we investigate the competition effect in tumor development by numerical simulations. The results indicate that successfully IAS-controlled states can be achieved even though the net growth rate of AI cells is positive for any androgen level. There is crucial difference between the previous models and the new one in the phase diagram of successful and unsuccessful tumor control by IAS administration, which means that the suggestions from the models for medication can be different. Furthermore we introduce quadratic logistic terms to the competition model to simulate the tumor growth in the environment with a finite carrying capacity considering the nutrients or inhibitors. The simulations show that the tumor growth can reach an equilibrium state or an oscillatory state with the net growth rate of AI cells being androgen independent. Our results suggest that the competition and the restraint of a limited environment can enhance the possibility of relapse prevention. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer

    International Nuclear Information System (INIS)

    Montgomery, Bruce; Nelson, Peter S; Vessella, Robert; Kalhorn, Tom; Hess, David; Corey, Eva

    2010-01-01

    Estrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), although the mechanisms are unclear. We hypothesize that estrogen inhibits CRPC in anorchid animals by suppressing tumoral androgens, an effect independent of the estrogen receptor. The human CRPC xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo, 17β-estradiol or 17β-estradiol and estrogen receptor antagonist ICI 182,780. Effects of 17β-estradiol on tumor growth were evaluated and tissue testosterone (T) and dihydrotestosterone (DHT) evaluated by mass spectrometry. Treatment of LuCaP 35V with 17β-estradiol slowed tumor growth compared to controls (tumor volume at day 21: 785 ± 81 mm 3 vs. 1195 ± 84 mm 3 , p = 0.002). Survival was also significantly improved in animals treated with 17β-estradiol (p = 0.03). The addition of the estrogen receptor antagonist ICI 182,780 did not significantly change survival or growth. 17β-estradiol in the presence and absence of ICI 182,780 suppressed tumor testosterone (T) and dihydrotestosterone (DHT) as assayed by mass spectrometry. Tissue androgens in placebo treated LuCaP 35V xenografts were; T = 0.71 ± 0.28 pg/mg and DHT = 1.73 ± 0.36 pg/mg. In 17β-estradiol treated LuCaP35V xenografts the tissue androgens were, T = 0.20 ± 0.10 pg/mg and DHT = 0.15 ± 0.15 pg/mg, (p < 0.001 vs. controls). Levels of T and DHT in control liver tissue were < 0.2 pg/mg. CRPC in anorchid animals maintains tumoral androgen levels despite castration. 17β-estradiol significantly suppressed tumor T and DHT and inhibits growth of CRPC in an estrogen receptor independent manner. The ability to manipulate tumoral androgens will be critical in the development and testing of agents targeting CRPC through tissue steroidogenesis

  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. Suppressed eye growth following diffuser removal from myopic birds is not due to increased dopamine release

    International Nuclear Information System (INIS)

    Morgan, I.; Boelen, M.; Megaw, P.; Miethke, P.

    2001-01-01

    Full text: Myopia can be induced in developing chickens by fitting a diffuser over the eye. If the diffuser is removed, the restoration of normal visual input results in rapid suppression of eye growth, with ultimate restoration of normal vision. We have investigated whether the suppression of eye growth after the removal of a diffuser from a myopic eye results from an increased rate of release of dopamine from the retina. Chickens were maintained on a 12:12 light-dark cycle, and were fitted with a diffuser from day 7 to day 21. After removal of the diffuser, the rate of dopamine release was then followed by measuring the kinetics of accumulation of DOPAC in the vitreous during the light phase. The rate of scleral glycosaminoglycan synthesis (SGS) was followed by measuring the rate of incorporation of 35 S-sulphate into scleral buttons incubated in vitro. At the end of the period of development of form-deprivation myopia,dopamine release rates were very low in the myopic eyes compared to those in the contralateral control eyes. In contrast, SGS rates were higher in the sclera from myopic eyes. After removal of the diffusers, the rate of SGS declined rapidly to below that in the control eyes within 72h. In contrast, dopamine release rates remained low for up to 10 days after removal of the occluders. These results show that there is a correlation between reduced dopamine release and increased SGS during the development of myopia, but that there is not a symmetrical relationship during the suppression of SGS following occluder removal. These results therefore suggest that dopamine is not a crucial signalling molecule in the visually mediated control of eye growth. Copyright (2001) Australian Neuroscience Society

  19. miR-216b suppresses breast cancer growth and metastasis by targeting SDCBP

    International Nuclear Information System (INIS)

    Jana, Samir; Sengupta, Suman; Biswas, Subir; Chatterjee, Annesha; Roy, Himansu; Bhattacharyya, Arindam

    2017-01-01

    Breast cancer is the most deadly cancer among women and the second leading cause of cancer death worldwide. Treatment effectiveness is complicated with tumor invasiveness/drug resistance. To tailor treatments more effectively to individual patients, it is important to define tumor growth and metastasis at molecular levels. SDCBP is highly overexpressed and associated with a strikingly poor prognosis in breast cancer. However the post transcriptional regulation of SDCBP overexpression remains to be an unexplored area. Our study reveals that miR-216b directly regulates SDCBP expression by binding to its 3′UTR region. miR-216b is a tumor suppressive miRNA and it is underexpressed during metastatic breast cancer. Consequently, overexpression of miR-216b resulted in decreased proliferation, migration and invasion in BC cell lines by modulating the expression of SDCBP. Inhibition of miR-216b divergent the tumor suppressive role by inducing the growth proliferation, migration and invasion in vitro. There is therefore a negative correlation between the expression of miR-216b and its target gene SDCBP in the BC tissue samples as well as cell lines. Simultaneous expression of miR-216b and SDCBP rescued the growth, migration and invasion effect suggesting that tumor suppressive action of miR-216b may be directly mediated by SDCBP. In summary, the study identifies miR-216b as a regulator of SDCBP expression in breast cancer which can potentially be targeted for developing newer therapies for the effective treatment of this killer disease.

  20. Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models.

    Science.gov (United States)

    Leu, Jyh-Der; Wang, Bo-Shen; Chiu, Shu-Jun; Chang, Chun-Yuan; Chen, Chien-Chih; Chen, Fu-Du; Avirmed, Shiirevnyamba; Lee, Yi-Jang

    2016-12-01

    Fisetin (3,7,3',4'-tetrahydroxyflavone), which belongs to the flavonoid group of polyphenols and is found in a wide range of plants, has been reported to exhibit a number of biological activities in human cancer cells, including antioxidant, anti-inflammatory, antiangiogenic, anti-invasive and antiproliferative effects. Although previous in vitro studies have shown that fisetin treatment increases the apoptotic rate and enhances the radiosensitivity of human colorectal cancer cells, the in vivo effects of fisetin on tumor growth remain unclear. In the present study a murine xenograft tumor model was employed to investigate the therapeutic effects of fisetin in combination with radiation on CT-26 colon cancer cells and human HCT116 colorectal cancer cells. This revealed that intratumoral injection of fisetin significantly suppressed the growth of CT-26 tumors compared with the untreated control group, but had little effect on the growth of HCT116 tumors. However, fisetin in combination with 2-Gy radiation enhanced tumor suppressor activity in murine colon and human colorectal xenograft tumors, as compared with 2-Gy fractionated radiation administered alone for 5 days and fisetin alone. Interestingly, fisetin downregulated the expression of the oncoprotein securin in a p53-independent manner. However, securin-null HCT116 tumors showed only moderate sensitivity to fisetin treatment, and the combination of fisetin and radiation did not significantly suppress securin-null HCT116 tumor growth compared with normal HCT116 tumors. Therefore, the role of securin in mediating the effect of fisetin on colorectal cancer growth warrants further investigation. In conclusion, the results of the current study provide important preclinical data for evaluating the efficacy of fisetin and radiation combination treatment as an adjuvant chemoradiotherapy for human colorectal cancers.

  1. Noise suppress or express exponential growth for hybrid Hopfield neural networks

    International Nuclear Information System (INIS)

    Zhu Song; Shen Yi; Chen Guici

    2010-01-01

    In this Letter, we will show that noise can make the given hybrid Hopfield neural networks whose solution may grows exponentially become the new stochastic hybrid Hopfield neural networks whose solution will grows at most polynomially. On the other hand, we will also show that noise can make the given hybrid Hopfield neural networks whose solution grows at most polynomially become the new stochastic hybrid Hopfield neural networks whose solution will grows at exponentially. In other words, we will reveal that the noise can suppress or express exponential growth for hybrid Hopfield neural networks.

  2. Invasive plant suppresses the growth of native tree seedlings by disrupting belowground mutualisms.

    Directory of Open Access Journals (Sweden)

    Kristina A Stinson

    2006-05-01

    Full Text Available The impact of exotic species on native organisms is widely acknowledged, but poorly understood. Very few studies have empirically investigated how invading plants may alter delicate ecological interactions among resident species in the invaded range. We present novel evidence that antifungal phytochemistry of the invasive plant, Alliaria petiolata, a European invader of North American forests, suppresses native plant growth by disrupting mutualistic associations between native canopy tree seedlings and belowground arbuscular mycorrhizal fungi. Our results elucidate an indirect mechanism by which invasive plants can impact native flora, and may help explain how this plant successfully invades relatively undisturbed forest habitat.

  3. Nematode suppression and growth stimulation in corn plants (Zea mays L.) irrigated with domestic effluent.

    Science.gov (United States)

    Barros, Kenia Kelly; do Nascimento, Clístenes Williams Araújo; Florencio, Lourdinha

    2012-01-01

    Treated wastewater has great potential for agricultural use due to its concentrations of nutrients and organic matter, which are capable of improving soil characteristics. Additionally, effluents can induce suppression of plant diseases caused by soil pathogens. This study evaluates the effect of irrigation with effluent in a UASB reactor on maize (Zea mays L.) development and on suppression of the diseases caused by nematodes of the genus Meloidogyne. Twelve lysimeters of 1 m(3) each were arranged in a completely randomized design, with four treatments and three replicates. The following treatments were used: T1 (W+I), irrigation with water and infestation with nematodes; T2 (W+I+NPK), irrigation with water, infestation with nematodes and fertilization with nitrogen (N), phosphorus (P) and potassium (K); T3 (E+I), irrigation with effluent and infestation with nematodes; and T4 (E+I+P), irrigation with effluent, infestation with nematodes and fertilization with phosphorus. The plants irrigated with the effluent plus the phosphorus fertilizer had better growth and productivity and were more resistant to the disease symptoms caused by the nematodes. The suppression levels may have been due to the higher levels of Zn and NO(3)(-) found in the leaf tissue of the plants irrigated with the effluent and phosphorus fertilizer.

  4. Genetic analysis of ectopic growth suppression during planar growth of integuments mediated by the Arabidopsis AGC protein kinase UNICORN.

    Science.gov (United States)

    Enugutti, Balaji; Schneitz, Kay

    2013-01-02

    The coordination of growth within a tissue layer is of critical importance for tissue morphogenesis. For example, cells within the epidermis undergo stereotypic cell divisions that are oriented along the plane of the layer (planar growth), thereby propagating the layered epidermal structure. Little is known about the developmental control that regulates such planar growth in plants. Recent evidence suggested that the Arabidopsis AGC VIII protein kinase UNICORN (UCN) maintains planar growth by suppressing the formation of ectopic multicellular protrusions in several floral tissues including integuments. In the current model UCN controls this process during integument development by directly interacting with the ABERRANT TESTA SHAPE (ATS) protein, a member of the KANADI (KAN) family of transcription factors, thereby repressing its activity. Here we report on the further characterization of the UCN mechanism. Phenotypic analysis of flowers of ucn-1 plants impaired in floral homeotic gene activity revealed that any of the four floral whorls could produce organs carrying ucn-1 protrusions. The ectopic outgrowths of ucn integuments did not accumulate detectable signals of the auxin and cytokinin reporters DR5rev::GFP and ARR5::GUS, respectively. Furthermore, wild-type and ucn-1 seedlings showed similarly strong callus formation upon in vitro culture on callus-inducing medium. We also show that ovules of ucn-1 plants carrying the dominant ats allele sk21-D exhibited more pronounced protrusion formation. Finally ovules of ucn-1 ett-1 double mutants and ucn-1 ett-1 arf4-1 triple mutants displayed an additive phenotype. These data deepen the molecular insight into the UCN-mediated control of planar growth during integument development. The presented evidence indicates that UCN downstream signaling does not involve the control of auxin or cytokinin homeostasis. The results also reveal that UCN interacts with ATS independently of an ATS/ETT complex required for integument

  5. Suppression of Growth by Multiplicative White Noise in a Parametric Resonant System

    Science.gov (United States)

    Ishihara, Masamichi

    2015-02-01

    The growth of the amplitude in a Mathieu-like equation with multiplicative white noise is studied. To obtain an approximate analytical expression for the exponent at the extremum on parametric resonance regions, a time-interval width is introduced. To determine the exponents numerically, the stochastic differential equations are solved by a symplectic numerical method. The Mathieu-like equation contains a parameter α determined by the intensity of noise and the strength of the coupling between the variable and noise; without loss of generality, only non-negative α can be considered. The exponent is shown to decrease with α, reach a minimum and increase after that. The minimum exponent is obtained analytically and numerically. As a function of α, the minimum at α≠0, occurs on the parametric resonance regions of α=0. This minimum indicates suppression of growth by multiplicative white noise.

  6. Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells.

    Science.gov (United States)

    Ruma, I Made Winarsa; Putranto, Endy Widya; Kondo, Eisaku; Watanabe, Risayo; Saito, Ken; Inoue, Yusuke; Yamamoto, Ken-Ichi; Nakata, Susumu; Kaihata, Masaji; Murata, Hitoshi; Sakaguchi, Masakiyo

    2014-07-01

    Angiogenesis is essential for tumor development and metastasis. Among several angiogenic factors, vascular endothelial growth factor receptor (VEGF) is important for tumor-derived angiogenesis and commonly overexpressed in solid tumors. Thus, many antitumor strategies targeting VEGF have been developed to inhibit cancer angiogenesis, offering insights into the successful treatment of solid cancers. However, there are a number of issues such as harmful effects on normal vascularity in clinical trials. Taking this into consideration, we employed Cordyceps militaris as an antitumor approach due to its biological safety in vivo. The herbal medicinal mushroom Cordyceps militaris has been reported to show potential anticancer properties including anti-angiogenic capacity; however, its concrete properties have yet to be fully demonstrated. In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and tumor growth of a human malignant melanoma cell line. We demonstrated that Cordyceps militaris extract remarkably suppressed tumor growth via induction of apoptotic cell death in culture that links to the abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3β activation, while p38α phosphorylation levels were increased. Extract treatment in mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with down-regulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti-angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be a potent antitumor herbal drug for solid tumors.

  7. Tumor-specific RNA interference targeting Pokemon suppresses tumor growth and induces apoptosis in prostate cancer.

    Science.gov (United States)

    Li, Yining; Xu, Shuxiong; Wang, Xiangwei; Shi, Hua; Sun, Zhaolin; Yang, Zhao

    2013-02-01

    To explore the exact mechanism of Pokemon in prostate cancer. Pokemon is a member of the POK family of transcriptional repressors. Its main function is suppression of the p14ARF (alternate reading frame) tumor suppressor gene. Although Pokemon expression has been found to be increased in various types of lymphoma, the exact mechanism of the gene in prostate cancer is not clear. In the present study, prostate cancer cells were transfected with the specific short hairpin ribonucleic acid (RNA) expression vector targeting Pokemon. The expression of Pokemon messenger RNA and its protein was detected by semiquantitative reverse transcriptase-polymerase chain reaction and Western blotting, respectively. The cell growth and cell apoptosis were also examined using the methyl thiazolyl tetrazolium assay and flow cytometry. The results demonstrated that specific RNA interference (RNAi) could decrease the expression levels of Pokemon gene messenger RNA and protein in prostate cancer cells. In addition, that specific RNAi significantly inhibited the cell proliferation and increased the apoptotic rate. In vivo experiments showed that specific RNAi inhibited the tumorigenicity of prostate cancer cells and significantly suppressed tumor growth. Therefore, an RNAi-targeted Pokemon gene strategy could be a potential approach to prostate cancer therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome.

    Directory of Open Access Journals (Sweden)

    Ingrid van der Pluijm

    2007-01-01

    Full Text Available Cockayne syndrome (CS is a photosensitive, DNA repair disorder associated with progeria that is caused by a defect in the transcription-coupled repair subpathway of nucleotide excision repair (NER. Here, complete inactivation of NER in Csb(m/m/Xpa(-/- mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csb(m/m/Xpa(-/- mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the growth hormone/insulin-like growth factor 1 (GH/IGF1 somatotroph axis and oxidative metabolism, increased antioxidant responses, and hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csb(m/m/Xpa(-/- and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural ageing and the DNA repair-deficient mice. Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis.

  9. Delayed Growth Suppression and Radioresistance Induced by Long-Term Continuous Gamma Irradiation.

    Science.gov (United States)

    Nakajima, Hiroo; Furukawa, Chiharu; Chang, Young-Chae; Ogata, Hiromitsu; Magae, Junji

    2017-08-01

    Biological response to ionizing radiation depends not only on the type of radiation and dose, but also on the duration and dose rate of treatment. For a given radiation dose, the biological response may differ based on duration and dose rate. We studied the properties of two human cell lines, M059K glioma and U2OS osteosarcoma, continuously exposed to γ rays for long time periods of more than five months. Growth inhibition in both cell lines was dependent on total dose when exposed to acute radiation over several minutes, whereas prolonged growth inhibition was dependent on dose rate after continuous irradiation over several months. The minimum dose rate for growth inhibition was 53.6 mGy/h. Cell cycle analysis showed G 1 phase accumulation in cell populations continuously exposed to γ rays, and G 2 phase accumulation in cells acutely exposed to high-dose-rate γ rays. Cells continuously exposed to γ rays continued to exhibit delayed growth suppression even after one month in an environment of background radiation, and maintained a high-level expression of c-Jun and its phosphorylation forms, as well as resistance to apoptosis induced by staurosporine and chemotherapeutic agents. These delayed effects were not observed in cells acutely exposed to 5 Gy of radiation. These results suggest that optimization of the irradiation schedule is crucial for risk estimation, protection and therapeutic utilization of ionizing radiation.

  10. Celecoxib suppresses fibroblast growth factor-2 expression in pancreatic ductal adenocarcinoma PANC-1 cells.

    Science.gov (United States)

    Li, Jing; Luo, Miaosha; Wang, Yan; Shang, Boxin; Dong, Lei

    2016-09-01

    The inhibition of cyclooxygenase (COX)-2 has been reported to suppress growth and induce apoptosis in human pancreatic cancer cells. Nevertheless, the precise biological mechanism of how celecoxib, a selective COX-2 inhibitor, regulates the growth and invasion of pancreatic tumors is not completely understood. It has been shown that fibroblast growth factor-2 (FGF-2) and its receptor levels correlate with the inhibition of cancer cell proliferation, migration and invasion in pancreatic ductal adenocarcinoma (PDAC). Therefore, the aim of the present study was to examine the hypothesis that the antitumor activity of celecoxib in PDAC may be exerted through modulation of FGF-2 function. In the present study, we evaluated the effects of celecoxib on the proliferation, migration, invasion and apoptosis of the PANC-1 cell line. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to examine the expression of FGF-2, FGFR-2, ERK1/2 and MMPs. In the present study, FGF-2 and FGFR-2 were expressed in PANC-1 cells and FGF-2 exerted a stimulatory effect on phosphorylated extracellular signal regulated kinase (p-ERK) expression. Celecoxib treatment suppressed FGF-2 and FGFR-2 expression and decreased MMP-2, MMP-9 and p-ERK expression in the PANC-1 cells. Furthermore, celecoxib treatment caused the resistance of PANC-1 cells to FGF-2 induced proliferation, migration and invasion ability, as well as the increase in their apoptotic rate. Our data provide evidence that targeting FGF-2 with celecoxib may be used as an effective treatment in PDAC.

  11. Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB

    Science.gov (United States)

    Soh, Hendrick; Venkatesan, Natarajan; Veena, Mysore S.; Ravichandran, Sandhiya; Zinabadi, Alborz; Basak, Saroj K.; Parvatiyar, Kislay; Srivastava, Meera; Liang, Li-Jung; Gjertson, David W.; Torres, Jorge Z.; Moatamed, Neda A.

    2016-01-01

    We and others have shown that the cystatin E/M gene is inactivated in primary human tumors, pointing to its role as a tumor suppressor gene. However, the molecular mechanism of tumor suppression is not yet understood. Using plasmid-directed cystatin E/M gene overexpression, a lentivirus-mediated tetracycline-inducible vector system, and human papillomavirus 16 (HPV 16) E6 and E7 gene-immortalized normal human epidermal keratinocytes, we demonstrated intracellular and non-cell-autonomous apoptotic growth inhibition of tumor cell lines and that growth inhibition is associated with cytoplasmic retention of NF-κB. We further demonstrated decreased phosphorylation of IκB kinase (IKKβ) and IκBα in the presence of tumor necrosis factor alpha (TNF-α), confirming the role of cystatin E/M in the regulation of the NF-κB signaling pathway. Growth suppression of nude mouse xenograft tumors carrying a tetracycline-inducible vector system was observed with the addition of doxycycline in drinking water, confirming that the cystatin E/M gene is a tumor suppressor gene. Finally, immunohistochemical analyses of cervical carcinoma in situ and primary tumors have shown a statistically significant inverse relationship between the expression of cystatin E/M and cathepsin L and a direct relationship between the loss of cystatin E/M expression and nuclear expression of NF-κB. We therefore propose that the cystatin E/M suppressor gene plays an important role in the regulation of NF-κB. PMID:27090639

  12. Resveratrol suppresses growth of cancer stem-like cells by inhibiting fatty acid synthase.

    Science.gov (United States)

    Pandey, Puspa R; Okuda, Hiroshi; Watabe, Misako; Pai, Sudha K; Liu, Wen; Kobayashi, Aya; Xing, Fei; Fukuda, Koji; Hirota, Shigeru; Sugai, Tamotsu; Wakabayashi, Go; Koeda, Keisuke; Kashiwaba, Masahiro; Suzuki, Kazuyuki; Chiba, Toshimi; Endo, Masaki; Fujioka, Tomoaki; Tanji, Susumu; Mo, Yin-Yuan; Cao, Deliang; Wilber, Andrew C; Watabe, Kounosuke

    2011-11-01

    Resveratrol is a natural polyphenolic compound and has been shown to exhibit cardio-protective as well as anti-neoplastic effects on various types of cancers. However, the exact mechanism of its anti-tumor effect is not clearly defined. Resveratrol has been shown to have strong hypolipidemic effect on normal adipocytes and as hyper-lipogenesis is a hallmark of cancer cell physiology, the effect of resveratrol on lipid synthesis in cancer stem-like cells (CD24(-)/CD44(+)/ESA(+)) that were isolated from both ER+ and ER- breast cancer cell lines was examined. The authors found that resveratrol significantly reduced the cell viability and mammosphere formation followed by inducing apoptosis in cancer stem-like cells. This inhibitory effect of resveratrol is accompanied by a significant reduction in lipid synthesis which is caused by the down-regulation of the fatty acid synthase (FAS) gene followed by up-regulation of pro-apoptotic genes, DAPK2 and BNIP3. The activation of apoptotic pathway in the cancer stem-like cells was suppressed by TOFA and by Fumonisin B1, suggesting that resveratrol-induced apoptosis is indeed through the modulation of FAS-mediated cell survival signaling. Importantly, resveratrol was able to significantly suppress the growth of cancer stem-like cells in an animal model of xenograft without showing apparental toxicity. Taken together, the results of this study indicate that resveratrol is capable of inducing apoptosis in the cancer stem-like cells through suppression of lipogenesis by modulating FAS expression, which highlights a novel mechanism of anti-tumor effect of resveratrol.

  13. NADE (p75NTR-associated cell death executor) suppresses cellular growth in vivo.

    Science.gov (United States)

    Tong, Xiangjun; Xie, Dong; Roth, Wilfried; Reed, John; Koeffler, H Phillip

    2003-06-01

    NADE, a p75NTR (low-affinity neurotrophin receptor p75) -associated cell death executor, was initially cloned from a human ovarian granulosa cell cDNA library, as an unknown protein with the name, pHGR74. It was reported to mediate nerve growth factor-induced apoptosis. We independently isolated human NADE (pHGR74) from breast cancer cell lines. Expression of NADE in various human cancer cell lines, and human and murine tissues was examined. NADE was highly expressed in human endocrine-related organs and embryotic murine tissues. Forced expression of NADE in CHO (Chinese hamster ovary) cells and MDA-MB-231 human breast cancer cells had little effect on the growth of the cells in vitro, while it dramatically suppressed cellular growth in vivo. We used the yeast two-hybrid system to search for NADE binding protein. Dynactin was identified as a candidate. The p75NTR was not found in this assay and did not co-immunoprecipitate with human NADE. Furthermore, the cells stably transfected with NADE did not respond to NGF or TNF. Thus, human and murine NADE appear to have different functions.

  14. EBP1 suppresses growth, migration, and invasion of thyroid cancer cells through upregulating RASAL expression.

    Science.gov (United States)

    Liu, Hongyan; Li, Zhenjie; Li, Liujuan; Peng, Haiying; Zhang, Zhijun

    2015-11-01

    Ebp1, a protein identified by its interactions with the ErbB3 receptor, has been characterized as a negative regulator of cancers. RAS GTPase-activating protein (RasGAP), RASAL1, was recently identified as a major tumor suppressor in thyroid cancer. In this study, we examined EBP1 expression in papillary and follicular thyroid cancer cells. We found that compared with normal thyroid cells, TPC1, WRO, and FTC133 thyroid tumor cells exhibited lower EBP1 expression at messenger RNA (mRNA) and protein levels. We then investigated the effects of forced EBP1 expression on growth, migration, and invasiveness of thyroid tumor cells. By using MTT and Boyden chamber assays, we showed that EBP1 overexpression dramatically reduced growth rate, migration, and invasiveness of K1 and FTC133 thyroid tumor cells. Furthermore, we explored the molecular mechanism underlying the effects of EBP1 on the cells by disclosing the correlation of EBP1 and RASAL1 expression. RASAL expression was elevated in thyroid tumor cells overexpressing EBP1. Knockdown RASAL by transduction of RASAL1 shRNA lentiviral particles markedly reduced RASAL levels with restoration of EBP1, and RASAL1 knockdown abrogated the effects of forced EBP1 expression on cell growth, migration, and invasiveness of thyroid tumor cells. These findings suggest that Ebp1 suppressed thyroid cancer cell lines by upregulating RASRAL expression.

  15. Dual knockdown of N-ras and epiregulin synergistically suppressed the growth of human hepatoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Meng; He, Hong-wei; Sun, Huan-xing; Ren, Kai-huan [Department of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100050 (China); Shao, Rong-guang, E-mail: shaor@bbn.cn [Department of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100050 (China)

    2009-09-18

    Hepatocellular carcinoma (HCC) is a major challenge because of its resistance to conventional cytotoxic chemotherapy and radiotherapy. Multi-targeted therapy might be a new option for HCC treatment. Our previous study showed that N-ras gene was activated in HCC and was inhibited by RNA interference. In the present study, we investigated the alternation of gene expression by microarray in N-Ras-siRNA-treated HepG2 cells. The results revealed that the EREG gene, encoding epiregulin, was dramatically up-regulated in response to silence of N-ras. We speculated that the up-regulation of epiregulin was involved in the compensatory mechanism of N-ras knockdown for cell growth. Therefore, we evaluated whether dual silence of N-ras and epiregulin display a greater suppression of cell growth. The results confirmed that dual knockdown of N-ras and epiregulin synergistically inhibited cell growth. Our results also showed that dual knockdown of N-ras and epiregulin significantly induced cell arrest at G0/G1 phase. Furthermore, Western blot assay showed that dual knockdown of N-ras and epiregulin markedly reduced the phosphorylations of ERK1/2, Akt and Rb, and inhibited the expression of cyclin D1. Our findings imply that multi-targeted silence of oncogenes might be an effective treatment for HCC.

  16. Suppression in growth hormone during overeating ameliorates the increase in insulin resistance and cardiovascular disease risk.

    Science.gov (United States)

    Cornford, Andrea S; Barkan, Ariel L; Hinko, Alexander; Horowitz, Jeffrey F

    2012-11-15

    Previously, we reported that overeating for only a few days markedly suppressed the secretion of growth hormone (GH). The purpose of the present study was to determine the role of this reduction in GH concentration on key metabolic adaptations that occur during 2 wk of overeating. Nine nonobese, healthy adults were admitted to the hospital for 2 wk, during which time they ate ∼4,000 kcal/day (70 kcal·kg fat-free mass(-1)·day(-1); 50% carbohydrate, 35% fat, and 15% protein), and their plasma GH concentration was allowed to decline naturally (control). An additional eight subjects underwent the same overeating intervention and received exogenous GH treatment (GHT) administered in four daily injections to mimic physiological GH secretion throughout the 2-wk overeating period. We measured plasma insulin and glucose concentrations in the fasting and postprandial state as well as fasting lipolytic rate, proteolytic rate, and fractional synthetic rate (FSR) using stable-isotope tracer methods. GHT prevented the fall in plasma GH concentration, maintaining plasma GH concentration at baseline levels (1.2 ± 0.2 ng/ml), which increased fasting and postprandial assessments of insulin resistance (P overeating also blunted the increase in systemic proteolysis (P overeating. In conclusion, our main findings suggest that the suppression in GH secretion that naturally occurs during the early stages of overeating may help attenuate the insulin resistance and hyperlipidemia that typically accompany overeating.

  17. Type I collagen gene suppresses tumor growth and invasion of malignant human glioma cells

    Directory of Open Access Journals (Sweden)

    Miyata Teruo

    2007-06-01

    Full Text Available Abstract Background Invasion is a hallmark of a malignant tumor, such as a glioma, and the progression is followed by the interaction of tumor cells with an extracellular matrix (ECM. This study examined the role of type I collagen in the invasion of the malignant human glioma cell line T98G by the introduction of the human collagen type I α1 (HCOL1A1 gene. Results The cells overexpressing HCOL1A1 were in a cluster, whereas the control cells were scattered. Overexpression of HCOL1A1 significantly suppressed the motility and invasion of the tumor cells. The glioma cell growth was markedly inhibited in vitro and in vivo by the overexpression of HCOL1A1; in particular, tumorigenicity completely regressed in nude mice. Furthermore, the HCOL1A1 gene induced apoptosis in glioma cells. Conclusion These results indicate that HCOL1A1 have a suppressive biological function in glioma progression and that the introduction of HCOL1A1 provides the basis of a novel therapeutic approach for the treatment of malignant human glioma.

  18. 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.

  19. Intermittent hypoxia suppression of growth hormone and insulin-like growth factor-I in the neonatal rat liver.

    Science.gov (United States)

    Cai, Charles; Ahmad, Taimur; Valencia, Gloria B; Aranda, Jacob V; Xu, Jiliu; Beharry, Kay D

    2018-03-08

    Extremely low gestational age neonates with chronic lung disease requiring oxygen therapy frequently experience fluctuations in arterial oxygen saturation or intermittent hypoxia (IH). These infants are at risk for multi-organ developmental delay, reduced growth, and short stature. The growth hormone (GH)/insulin-like growth factor-I (IGF-1) system, an important hormonal regulator of lipid and carbohydrate metabolism, promotes neonatal growth and development. We tested the hypothesis that increasing episodes of IH delay neonatal growth by influencing the GH/IGF-I axis. Newborn rats were exposed to 2, 4, 6, 8, 10, or 12 hypoxic episodes (12% O 2 ) during hyperoxia (50% O 2 ) from P0-P7, P0-P14 (IH), or allowed to recover from P7-P21 or P14-P21 (IHR) in room air (RA). RA littermates at P7, P14, and P21 served as RA controls; and groups exposed to hyperoxia only (50% O 2 ) served as zero IH controls. Histopathology of the liver; hepatic levels of GH, GHBP, IGF-I, IGFBP-3, and leptin; and immunoreactivities of GH, GHR, IGF-I and IGF-IR were determined. Pathological findings of the liver, including cellular swelling, steatosis, necrosis and focal sinusoid congestion were seen in IH, and were particularly severe in the P7 animals. Hepatic GH levels were significantly suppressed in the IH groups exposed to 6-12 hypoxic episodes per day and were not normalized during IHR. Deficits in the GH levels were associated with reduced body length and increase body weight during IHR suggesting increased adiposity and catchup fat. Catchup fat was also associated with elevations in GHBP, IGF-I, leptin. IH significantly impairs hepatic GH/IGF-1 signaling during the first few weeks of life, which is likely responsible for hepatic GH resistance, increased body fat, and hepatic steatosis. These hormonal perturbations may contribute to long-term organ and body growth impairment, and metabolic dysfunction in preterm infants experiencing frequent IH and/or apneic episodes. Copyright © 2018

  20. Genetic analysis of ectopic growth suppression during planar growth of integuments mediated by the Arabidopsis AGC protein kinase UNICORN

    Directory of Open Access Journals (Sweden)

    Enugutti Balaji

    2013-01-01

    Full Text Available Abstract Background The coordination of growth within a tissue layer is of critical importance for tissue morphogenesis. For example, cells within the epidermis undergo stereotypic cell divisions that are oriented along the plane of the layer (planar growth, thereby propagating the layered epidermal structure. Little is known about the developmental control that regulates such planar growth in plants. Recent evidence suggested that the Arabidopsis AGC VIII protein kinase UNICORN (UCN maintains planar growth by suppressing the formation of ectopic multicellular protrusions in several floral tissues including integuments. In the current model UCN controls this process during integument development by directly interacting with the ABERRANT TESTA SHAPE (ATS protein, a member of the KANADI (KAN family of transcription factors, thereby repressing its activity. Here we report on the further characterization of the UCN mechanism. Results Phenotypic analysis of flowers of ucn-1 plants impaired in floral homeotic gene activity revealed that any of the four floral whorls could produce organs carrying ucn-1 protrusions. The ectopic outgrowths of ucn integuments did not accumulate detectable signals of the auxin and cytokinin reporters DR5rev::GFP and ARR5::GUS, respectively. Furthermore, wild-type and ucn-1 seedlings showed similarly strong callus formation upon in vitro culture on callus-inducing medium. We also show that ovules of ucn-1 plants carrying the dominant ats allele sk21-D exhibited more pronounced protrusion formation. Finally ovules of ucn-1 ett-1 double mutants and ucn-1 ett-1 arf4-1 triple mutants displayed an additive phenotype. Conclusions These data deepen the molecular insight into the UCN-mediated control of planar growth during integument development. The presented evidence indicates that UCN downstream signaling does not involve the control of auxin or cytokinin homeostasis. The results also reveal that UCN interacts with ATS

  1. Managing ethically questionable parental requests: growth suppression and manipulation of puberty.

    Science.gov (United States)

    Isaacs, David; Tobin, Bernadette; Hamblin, Julie; Slaytor, Emma; Donaghue, Kim C; Munns, Craig; Kilham, Henry A

    2011-09-01

    Doctors sometimes struggle with ethically challenging requests for treatment from children's parents. For instance, we have recently had two requests by parents of children, a girl and a boy, each with a severe developmental disability, for hormonal therapy to suppress growth and puberty: the girl's parents requested, in addition, hysterectomy and mastectomy. We propose a reliable approach to assessing the ethical and legal aspects of these and other requests for 'non-therapeutic' treatment of a minor who lacks the capacity to give informed consent. We argue that a doctor should first assess whether the request is one that he or she can, in conscience, accede to, and then, if it is, seek the authorisation of a court. We outline considerations relevant to the doctor's assessment of both the ethical issues and to the need for court authorisation. © 2011 The Authors. Journal of Paediatrics and Child Health © 2011 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

  2. Plant Growth Promotion and Suppression of Bacterial Leaf Blight in Rice by Inoculated Bacteria.

    Directory of Open Access Journals (Sweden)

    Sumera Yasmin

    Full Text Available The present study was conducted to evaluate the potential of rice rhizosphere associated antagonistic bacteria for growth promotion and disease suppression of bacterial leaf blight (BLB. A total of 811 rhizospheric bacteria were isolated and screened against 3 prevalent strains of BLB pathogen Xanthomonas oryzae pv. oryzae (Xoo of which five antagonistic bacteria, i.e., Pseudomonas spp. E227, E233, Rh323, Serratia sp. Rh269 and Bacillus sp. Rh219 showed antagonistic potential (zone of inhibition 1-19 mm. Production of siderophores was found to be the common biocontrol determinant and all the strains solubilized inorganic phosphate (82-116 μg mL-1 and produced indole acetic acid (0.48-1.85 mg L-1 in vitro. All antagonistic bacteria were non-pathogenic to rice, and their co-inoculation significantly improved plant health in terms of reduced diseased leaf area (80%, improved shoot length (31%, root length (41% and plant dry weight (60% as compared to infected control plants. Furthermore, under pathogen pressure, bacterial inoculation resulted in increased activity of defense related enzymes including phenylalanine ammonia-lyase and polyphenol oxidase, along with 86% increase in peroxidase and 53% increase in catalase enzyme activities in plants inoculated with Pseudomonas sp. Rh323 as well as co-inoculated plants. Bacterial strains showed good colonization potential in the rice rhizosphere up to 21 days after seed inoculation. Application of bacterial consortia in the field resulted in an increase of 31% in grain yield and 10% in straw yield over non-inoculated plots. Although, yield increase was statistically non-significant but was accomplished with overall saving of 20% chemical fertilizers. The study showed that Pseudomonas sp. Rh323 can be used to develop dual-purpose inoculum which can serve not only to suppress BLB but also to promote plant growth in rice.

  3. Halofuginone suppresses growth of human uterine leiomyoma cells in a mouse xenograft model.

    Science.gov (United States)

    Koohestani, Faezeh; Qiang, Wenan; MacNeill, Amy L; Druschitz, Stacy A; Serna, Vanida A; Adur, Malavika; Kurita, Takeshi; Nowak, Romana A

    2016-07-01

    Does halofuginone (HF) inhibit the growth of human uterine leiomyoma cells in a mouse xenograft model? HF suppresses the growth of human uterine leiomyoma cells in a mouse xenograft model through inhibiting cell proliferation and inducing apoptosis. Uterine leiomyomas are the most common benign tumors of the female reproductive tract. HF can suppress the growth of human uterine leiomyoma cells in vitro. The mouse xenograft model reflects the characteristics of human leiomyomas. Primary leiomyoma smooth muscle cells from eight patients were xenografted under the renal capsule of adult, ovariectomized NOD-scid IL2Rγ(null) mice (NSG). Mice were treated with two different doses of HF or vehicle for 4 weeks with six to eight mice per group. Mouse body weight measurements and immunohistochemical analysis of body organs were carried out to assess the safety of HF treatment. Xenografted tumors were measured and analyzed for cellular and molecular changes induced by HF. Ovarian steroid hormone receptors were evaluated for possible modulation by HF. Treatment of mice carrying human UL xenografts with HF at 0.25 or 0.50 mg/kg body weight for 4 weeks resulted in a 35-40% (P leiomyoma cells in an in vivo model, HF was administered to mice whose tolerance and metabolism of the drug may differ from that in humans. Also, the longer term effects of HF treatment are yet unclear. The results of this study showing the effectiveness of HF in reducing UL tumor growth by interfering with the main cellular processes regulating cell proliferation and apoptosis are in agreement with previous studies on the effects of HF on other fibrotic diseases. HF can be considered as a candidate for reducing the size of leiomyomas, particularly prior to surgery. This project was funded by NIH PO1HD057877 and R01 HD064402. Authors report no competing interests. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights

  4. 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.

  5. 'Obligate' anaerobic Salmonella strain YB1 suppresses liver tumor growth and metastasis in nude mice.

    Science.gov (United States)

    Li, Chang-Xian; Yu, Bin; Shi, Lei; Geng, Wei; Lin, Qiu-Bin; Ling, Chang-Chun; Yang, Mei; Ng, Kevin T P; Huang, Jian-Dong; Man, Kwan

    2017-01-01

    The antitumor properties of bacteria have been demonstrated over the past decades. However, the efficacy is limited and unclear. Furthermore, systemic infection remains a serious concern in bacteria treatment. In this study, the effect of YB1, a rationally designed 'obligate' anaerobic Salmonella typhimurium strain, on liver tumor growth and metastasis in a nude mouse orthotopic liver tumor model was investigated. The orthotopic liver tumor model was established in nude mice using the hepatocellular carcinoma cell line MHCC-97L. Two weeks after orthotopic liver tumor implantation, YB1, SL7207 and saline were respectively administered through the tail vein of the mice. Longitudinal monitoring of tumor growth and metastasis was performed using Xenogen IVIS, and direct measurements of tumor volume were taken 3 weeks after treatment. In vitro , MHCC-97L and PLC cells were incubated with YB1 or SL7207 under anaerobic conditions. YB1 was observed to invade tumor cells and induce tumor cell apoptosis and death. The results revealed that all mice in the YB1 group were alive 3 weeks after YB1 injection while all mice in the SL7207 group died within 11 days of the SL7207 injection. The body weight decreased by ~9% on day 1 after YB1 injection and but subsequently recovered. Liver tumor growth and metastases were significantly inhibited following YB1 treatment. By contrast to the control group, a large number of Gr1-positive cells were detected on days 1 to 21 following YB1 treatment. Furthermore, YB1 also effectively invaded tumor cells and induced tumor cell apoptosis and death. In conclusion, YB1 suppressed liver tumor growth and metastasis in a nude mice liver tumor model. The potential mechanism may be through enhancing innate immune response and inducing tumor cell apoptosis and cell death.

  6. Masked Uncontrolled Hypertension in CKD.

    Science.gov (United States)

    Agarwal, Rajiv; Pappas, Maria K; Sinha, Arjun D

    2016-03-01

    Masked uncontrolled hypertension (MUCH) is diagnosed in patients treated for hypertension who are normotensive in the clinic but hypertensive outside. In this study of 333 veterans with CKD, we prospectively evaluated the prevalence of MUCH as determined by ambulatory BP monitoring using three definitions of hypertension (daytime hypertension ≥135/85 mmHg; either nighttime hypertension ≥120/70 mmHg or daytime hypertension; and 24-hour hypertension ≥130/80 mmHg) or by home BP monitoring (hypertension ≥135/85 mmHg). The prevalence of MUCH was 26.7% by daytime ambulatory BP, 32.8% by 24-hour ambulatory BP, 56.1% by daytime or night-time ambulatory BP, and 50.8% by home BP. To assess the reproducibility of the diagnosis, we repeated these measurements after 4 weeks. Agreement in MUCH diagnosis by ambulatory BP was 75-78% (κ coefficient for agreement, 0.44-0.51), depending on the definition used. In contrast, home BP showed an agreement of only 63% and a κ coefficient of 0.25. Prevalence of MUCH increased with increasing clinic systolic BP: 2% in the 90-110 mmHg group, 17% in the 110-119 mmHg group, 34% in the 120-129 mmHg group, and 66% in the 130-139 mmHg group. Clinic BP was a good determinant of MUCH (receiver operating characteristic area under the curve 0.82; 95% confidence interval 0.76-0.87). In diagnosing MUCH, home BP was not different from clinic BP. In conclusion, among people with CKD, MUCH is common and reproducible, and should be suspected when clinic BP is in the prehypertensive range. Confirmation of MUCH diagnosis should rely on ambulatory BP monitoring. Copyright © 2016 by the American Society of Nephrology.

  7. CD147 silencing inhibits tumor growth by suppressing glucose transport in melanoma.

    Science.gov (United States)

    Su, Juan; Gao, Tianyuan; Jiang, Minghao; Wu, Lisha; Zeng, Weiqi; Zhao, Shuang; Peng, Cong; Chen, Xiang

    2016-10-04

    Melanoma is a very malignant disease and there are still no effective treatments. CD147 participates in the carcinogenesis of multiple human cancers and GLUT-1, as a glucose transporter, is associated with tumor growth. However, the function of CD147 and GLUT-1 in melanoma have not been completely understood. Thus, in this study we investigated the expression of CD147 and GLUT-1 in melanoma tissue, which were overexpressed compared with that in nevus tissue. In addition, CD147 and GLUT-1 were co-localized in the cytoplasm of human melanoma A375 cells. Immunoprecipitation proved that CD147 interacted with GLUT-1 at D105-199. Silencing CD147 by specific siRNA could downregulate GLUT-1 level via inhibiting PI3K/Akt signaling and decrease glucose uptake in A375 cells. In vivo experiments also supported that CD147 knockdown suppressed the tumor growth in melanoma subcutaneous mice model, observed by micro PET/CT. Our results could help validate CD147 as a new therapeutic target for treating melanoma.

  8. Kaempferol suppresses bladder cancer tumor growth by inhibiting cell proliferation and inducing apoptosis.

    Science.gov (United States)

    Dang, Qiang; Song, Wenbin; Xu, Defeng; Ma, Yanmin; Li, Feng; Zeng, Jin; Zhu, Guodong; Wang, Xinyang; Chang, Luke S; He, Dalin; Li, Lei

    2015-09-01

    The effects of the flavonoid compound, kaempferol, which is an inhibitor of cancer cell proliferation and an inducer of cell apoptosis have been shown in various cancers, including lung, pancreatic, and ovarian, but its effect has never been studied in bladder cancer. Here, we investigated the effects of kaempferol on bladder cancer using multiple in vitro cell lines and in vivo mice studies. The MTT assay results on various bladder cancer cell lines showed that kaempferol enhanced bladder cancer cell cytotoxicity. In contrast, when analyzed by the flow cytometric analysis, DNA ladder experiment, and TUNEL assay, kaempferol significantly was shown to induce apoptosis and cell cycle arrest. These in vitro results were confirmed in in vivo mice studies using subcutaneous xenografted mouse models. Consistent with the in vitro results, we found that treating mice with kaempferol significant suppression in tumor growth compared to the control group mice. Tumor tissue staining results showed decreased expressions of the growth related markers, yet increased expressions in apoptosis markers in the kaempferol treated group mice tissues compared to the control group mice. In addition, our in vitro and in vivo data showed kaempferol can also inhibit bladder cancer invasion and metastasis. Further mechanism dissection studies showed that significant down-regulation of the c-Met/p38 signaling pathway is responsible for the kaempferol mediated cell proliferation inhibition. All these findings suggest kaempferol might be an effective and novel chemotherapeutic drug to apply for the future therapeutic agent to combat bladder cancer. © 2014 Wiley Periodicals, Inc.

  9. CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis.

    Directory of Open Access Journals (Sweden)

    Ishan Roy

    Full Text Available Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites.

  10. SH003 suppresses breast cancer growth by accumulating p62 in autolysosomes.

    Science.gov (United States)

    Choi, Youn Kyung; Cho, Sung-Gook; Choi, Yu-Jeong; Yun, Yee Jin; Lee, Kang Min; Lee, Kangwook; Yoo, Hye-Hyun; Shin, Yong Cheol; Ko, Seong-Gyu

    2017-10-24

    Drug markets revisits herbal medicines, as historical usages address their therapeutic efficacies with less adverse effects. Moreover, herbal medicines save both cost and time in development. SH003, a modified version of traditional herbal medicine extracted from Astragalus membranaceus (Am), Angelica gigas (Ag), and Trichosanthes Kirilowii Maximowicz (Tk) with 1:1:1 ratio (w/w) has been revealed to inhibit tumor growth and metastasis on highly metastatic breast cancer cells, both in vivo and in vitro with no toxicity. Meanwhile, autophagy is imperative for maintenance cellular homeostasis, thereby playing critical roles in cancer progression. Inhibition of autophagy by pharmacological agents induces apoptotic cell death in cancer cells, resulting in cancer treatment. In this study, we demonstrate that SH003-induced autophagy via inhibiting STAT3 and mTOR results in an induction of lysosomal p62/SQSTM1 accumulation-mediated reactive oxygen species (ROS) generation and attenuates tumor growth. SH003 induced autophagosome and autolysosome formation by inhibiting activation of STAT3- and mTOR-mediated signaling pathways. However, SH003 blocked autophagy-mediated p62/SQSTM1 degradation through reducing of lysosomal proteases, Cathepsins, resulting in accumulation of p62/SQSTM1 in the lysosome. The accumulation of p62/SQSTM1 caused the increase of ROS, which resulted in the induction of apoptotic cell death. Therefore, we conclude that SH003 suppresses breast cancer growth by inducing autophagy. In addition, SH003-induced p62/SQSTM1 could function as an important mediator for ROS generation-dependent cell death suggesting that SH003 may be useful for treating breast cancer.

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Identification of derlin-1 as a novel growth factor-responsive endothelial antigen by suppression subtractive hybridization

    International Nuclear Information System (INIS)

    Ran Yuliang; Jiang Yangfu; Zhong Xing; Zhou Zhuan; Liu Haiyan; Hu Hai; Lou Jinning; Yang Zhihua

    2006-01-01

    Endothelial cells play an important regulatory role in embryonic development, reproductive functions, tumor growth and progression. In the present study, the suppression subtractive hybridization (SSH) method was employed to identify differentially expressed genes between non-stimulated endothelial cells and activated endothelial cells. Following mRNA isolation of non-stimulated and hepatocellular carcinoma homogenate-stimulated cells, cDNAs of both populations were prepared and subtracted by suppressive PCR. Sequencing of the enriched cDNAs identified a couple of genes differentially expressed, including derlin-1. Derlin-1 was significantly up-regulated by tumor homogenates, VEGF, and endothelial growth supplements in a dose-dependent manner. Knock-down of derlin-1 triggered endothelial cell apoptosis, inhibited endothelial cell proliferation, and blocked the formation of a network of tubular-like structures. Our data reveal that derlin-1 is a novel growth factor-responsive endothelial antigen that promotes endothelial cell survival and growth

  13. Clinical correlation to differences in ranibizumab and aflibercept vascular endothelial growth factor suppression times.

    Science.gov (United States)

    Fauser, Sascha; Muether, Philipp S

    2016-11-01

    To determine clinical correlations to intraocular vascular endothelial growth factor A (VEGF-A) suppression times (VSTs) on the treatment of neovascular age-related macular degeneration (nAMD) with ranibizumab (Lucentis) or aflibercept (Eylea). Seven of 89 treatment-naïve nAMD eyes showed persistent choroidal neovascular membrane (CNV) activity throughout a spectral domain optical coherence tomography (SD-OCT)-driven pro re nata (PRN) regimen of intravitreal ranibizumab injections over 28±4 months. The treatment was switched to PRN aflibercept injections and patients were followed for another 15±2 months. A total of 160 aqueous humour specimens were collected before the intravitreal injections, and their VEGF-A concentrations were assayed by Luminex multiplex bead analysis (Luminex, Austin, Texas, USA). Intraocular VEGF-A concentrations were correlated to CNV activity shown by SD-OCT. The mean duration of suppression of VEGF-A concentrations in aqueous humour below the lower limit of quantification of our assay was 34±5 (26-69) days for ranibizumab and 67±14 (49-89) days for aflibercept (p<0.001). The percentual reduction of central retinal volume (CRV) 6 weeks after injection was higher for aflibercept compared with ranibizumab (p=0.009). The time point of clinical re-activity occurred about 50% earlier than the respective VST for each ranibizumab and aflibercept. The VST under aflibercept treatment exceeded that under ranibizumab treatment by a factor of 2. This difference correlated with differential clinical CRV reduction 6 weeks after the respective injection. For both medications, clinical activity was found at a time point as early as 50% of the individual VST. NCT01213667, post-results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  14. MELATONIN-INDUCED SUPPRESSION OF PC12 CELL GROWTH IS MEDIATED BY ITS GI COUPLED TRANSMEMBRANE RECEPTORS. (R826248)

    Science.gov (United States)

    The effects of pertussis toxin, an uncoupler of Gi protein from adenylate cyclase, and luzindole, a competitive inhibitor of melatonin receptor binding, were examined for their ability to inhibit melatonin-induced suppression of PC12 cell growth. Both agents inhibited the mela...

  15. WNT10B functional dualism: beta-catenin/Tcf-dependent growth promotion or independent suppression with deregulated expression in cancer.

    Science.gov (United States)

    Yoshikawa, Hirohide; Matsubara, Kenichi; Zhou, Xiaoling; Okamura, Shu; Kubo, Takahiko; Murase, Yaeko; Shikauchi, Yuko; Esteller, Manel; Herman, James G; Wei Wang, Xin; Harris, Curtis C

    2007-11-01

    We found aberrant DNA methylation of the WNT10B promoter region in 46% of primary hepatocellular carcinoma (HCC) and 15% of colon cancer samples. Three of 10 HCC and one of two colon cancer cell lines demonstrated low or no expression, and 5-aza-2'deoxycytidine reactivated WNT10B expression with the induction of demethylation, indicating that WNT10B is silenced by DNA methylation in some cancers, whereas WNT10B expression is up-regulated in seven of the 10 HCC cell lines and a colon cancer cell line. These results indicate that WNT10B can be deregulated by either overexpression or silencing in cancer. We found that WNT10B up-regulated beta-catenin/Tcf activity. However, WNT10B-overexpressing cells demonstrated a reduced growth rate and anchorage-independent growth that is independent of the beta-catenin/Tcf activation, because mutant beta-catenin-transduced cells did not suppress growth, and dominant-negative hTcf-4 failed to alleviate the growth suppression by WNT10B. Although WNT10B expression alone inhibits cell growth, it acts synergistically with the fibroblast growth factor (FGF) to stimulate cell growth. WNT10B is bifunctional, one function of which is involved in beta-catenin/Tcf activation, and the other function is related to the down-regulation of cell growth through a different mechanism. We suggest that FGF switches WNT10B from a negative to a positive cell growth regulator.

  16. Growth suppression by transforming growth factor beta 1 of human small-cell lung cancer cell lines is associated with expression of the type II receptor

    DEFF Research Database (Denmark)

    Nørgaard, P; Damstrup, L; Rygaard, K

    1994-01-01

    was observed in two cell lines expressing only type III receptor and in TGF-beta-r negative cell lines. In two cell lines expressing all three receptor types, growth suppression was accompanied by morphological changes. To evaluate the possible involvement of the retinoblastoma protein (pRb) in mediating...

  17. Nimotuzumab enhances temozolomide-induced growth suppression of glioma cells expressing mutant EGFR in vivo

    International Nuclear Information System (INIS)

    Nitta, Yusuke; Shimizu, Saki; Shishido-Hara, Yukiko; Suzuki, Kaori; Shiokawa, Yoshiaki; Nagane, Motoo

    2016-01-01

    A mutant form of epidermal growth factor receptor (EGFR), EGFRvIII, is common in glioblastoma (GBM) and confers enhanced tumorigenic activity and drug resistance. Nimotuzumab, an anti-EGFR antibody, has shown preclinical and clinical activity to GBM, but its specific activity against EGFRvIII has not been fully investigated. Human glioma U87MG or LNZ308 cells overexpressing either wild-type (wt) EGFR or EGFRvIII were treated with nimotuzumab, temozolomide, or both. Expression and phosphorylation status of molecules were determined by Western blot analysis. Methylation status of promoter region of O 6 -methylguanine-DNA methyltransferase (MGMT) was detected by methylation-specific PCR. Antitumor activity was tested using nude mice bearing either subcutaneous or intracerebral xenografts along with analyses of EGFR phosphorylation status, proliferation, apoptosis, and vessel density. Nimotuzumab treatment resulted in reduction of EGFRvIII tyrosine phosphorylation with a decrease in Akt phosphorylation that was greater than that of wtEGFR. Correspondingly, antitumor effects, growth suppression and survival elongation, were more significant in mice bearing either subcutaneous or intracerebral tumor expressing EGFRvIII than in those expressing wtEGFR. These effects were markedly increased when temozolomide was combined with nimotuzumab. The post-treatment recurrent brain tumors exhibited a decrease in expression of the mismatch repair (MMR) proteins, MSH6 and MLH1, but their methylated MGMT status did not changed. Nimotuzumab has in vivo antitumor activity against GBM, especially those expressing EGFRvIII, when combined with temozolomide. This could provide a basis for preselection of patients with GBM by EGFR status who might benefit from the nimotuzumab and temozolomide combination therapy

  18. Suppression of the emittance growth induced by coherent synchrotron radiation in triple-bend achromats

    International Nuclear Information System (INIS)

    Huang Xiyang; Jiao Yi; Xu Gang; Cui Xiaohao

    2015-01-01

    The coherent synchrotron radiation (CSR) effect in a bending path plays an important role in transverse emittance dilution in high-brightness light sources and linear colliders, where the electron beams are of short bunch length and high peak current. Suppression of the emittance growth induced by CSR is critical to preserve the beam quality and help improve the machine performance. It has been shown that the CSR effect in a double-bend achromat (DBA) can be analyzed with the two-dimensional point-kick analysis method. In this paper, this method is applied to analyze the CSR effect in a triple-bend achromat (TBA) with symmetric layout, which is commonly used in the optics designs of energy recovery linacs (ERLs). A condition of cancelling the CSR linear effect in such a TBA is obtained, and is verified through numerical simulations. It is demonstrated that emittance preservation can be achieved with this condition, and to a large extent, has a high tolerance to the fluctuation of the initial transverse phase space distribution of the beam. (authors)

  19. BCL2-BH4 antagonist BDA-366 suppresses human myeloma growth.

    Science.gov (United States)

    Deng, Jiusheng; Park, Dongkyoo; Wang, Mengchang; Nooka, Ajay; Deng, Qiaoya; Matulis, Shannon; Kaufman, Jonathan; Lonial, Sagar; Boise, Lawrence H; Galipeau, Jacques; Deng, Xingming

    2016-05-10

    Multiple myeloma (MM) is a heterogeneous plasma cell malignancy and remains incurable. B-cell lymphoma-2 (BCL2) protein correlates with the survival and the drug resistance of myeloma cells. BH3 mimetics have been developed to disrupt the binding between BCL2 and its pro-apoptotic BCL2 family partners for the treatment of MM, but with limited therapeutic efficacy. We recently identified a small molecule BDA-366 as a BCL2 BH4 domain antagonist, converting it from an anti-apoptotic into a pro-apoptotic molecule. In this study, we demonstrated that BDA-366 induces robust apoptosis in MM cell lines and primary MM cells by inducing BCL2 conformational change. Delivery of BDA-366 substantially suppressed the growth of human MM xenografts in NOD-scid/IL2Rγnull mice, without significant cytotoxic effects on normal hematopoietic cells or body weight. Thus, BDA-366 functions as a novel BH4-based BCL2 inhibitor and offers an entirely new tool for MM therapy.

  20. The oncoprotein HBXIP suppresses gluconeogenesis through modulating PCK1 to enhance the growth of hepatoma cells.

    Science.gov (United States)

    Shi, Hui; Fang, Runping; Li, Yinghui; Li, Leilei; Zhang, Weiying; Wang, Huawei; Chen, Fuquan; Zhang, Shuqin; Zhang, Xiaodong; Ye, Lihong

    2016-11-28

    Hepatitis B X-interacting protein (HBXIP) as an oncoprotein plays crucial roles in the development of cancer, involving glucose metabolism reprogramming. In this study, we are interested in whether the oncoprotein HBXIP is involved in the modulation of gluconeogenesis in liver cancer. Here, we showed that the expression level of phosphoenolpyruvate carboxykinase (PCK1), a key enzyme of gluconeogenesis, was lower in clinical hepatocellular carcinoma (HCC) tissues than that in normal tissues. Mechanistically, HBXIP inhibited the expression of PCK1 through down-regulating transcription factor FOXO1 in hepatoma cells, and up-regulated miR-135a targeting the 3'UTR of FOXO1 mRNA in the cells. In addition, HBXIP increased the phosphorylation levels of FOXO1 protein by activating PI3K/Akt pathway, leading to the export of FOXO1 from nucleus to cytoplasm. Strikingly, over-expression of PCK1 could abolish the HBXIP-promoted growth of hepatoma cells in vitro and in vivo. Thus, we conclude that the oncoprotein HBXIP is able to depress the gluconeogenesis through suppressing PCK1 to promote hepatocarcinogenesis, involving miR-135a/FOXO1 axis and PI3K/Akt/p-FOXO1 pathway. Our finding provides new insights into the mechanism by which oncoprotein HBXIP modulates glucose metabolism reprogramming in HCC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth.

    Science.gov (United States)

    Lyu, Junfang; Yang, Eun Ju; Head, Sarah A; Ai, Nana; Zhang, Baoyuan; Wu, Changjie; Li, Ruo-Jing; Liu, Yifan; Yang, Chen; Dang, Yongjun; Kwon, Ho Jeong; Ge, Wei; Liu, Jun O; Shim, Joong Sup

    2017-11-28

    Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for in-depth mechanistic studies to link cholesterol trafficking and angiogenesis. Cepharanthine inhibited the endolysosomal trafficking of free-cholesterol and low-density lipoprotein in HUVEC by binding to Niemann-Pick disease, type C1 (NPC1) protein and increasing the lysosomal pH. The blockade of cholesterol trafficking led to a cholesterol-dependent dissociation of mTOR from the lysosomes and inhibition of its downstream signaling. Cepharanthine inhibited angiogenesis in HUVEC and in zebrafish in a cholesterol-dependent manner. Furthermore, cepharanthine suppressed tumor growth in vivo by inhibiting angiogenesis and it enhanced the antitumor activity of the standard chemotherapy cisplatin in lung and breast cancer xenografts in mice. Altogether, these results strongly support the idea that cholesterol trafficking is a viable drug target for anti-angiogenesis and that the inhibitors identified among existing drugs, such as cepharanthine, could be potential anti-angiogenic and antitumor agents. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Suppression of tumor growth by a new glycosaminoglycan isolated from the African giant snail Achatina fulica.

    Science.gov (United States)

    Lee, Yeon Sil; Yang, Hyun Ok; Shin, Kuk Hyun; Choi, Hyung Seok; Jung, Sang Hoon; Kim, Yong Man; Oh, Deok Kun; Linhardt, Robert J; Kim, Yeong Shik

    2003-03-28

    Acharan sulfate is a new type of glycosaminoglycan from the giant African snail, Achatina fulica. Acharan sulfate, which has a primary repeating disaccharide structure of alpha-D-N-acetylglucosaminyl-2-O-sulfo-alpha-L-iduronic acid, was studied as a potential antitumor agent in both in vivo and in vitro assays. The antiangiogenic activity of acharan sulfate was evaluated in the chorioallantoic membrane assay and by measuring its effect on the proliferation of calf pulmonary artery endothelial cells. In vivo, a matrigel plug assay showed that acharan sulfate suppressed basic fibroblast growth factor (bFGF)-stimulated angiogenesis and lowered the hemoglobin (Hb) content inside the plug. Acharan sulfate was administered s.c. at two doses for 15 days to C57BL/6 mice implanted with murine Lewis lung carcinoma in the back. It was also administered i.p. to ICR mice bearing sarcoma 180 at a dose of 30 mg/kg. Subcutaneous injection of acharan sulfate at doses of 10 and 30 mg/kg decreased tumor weight and tumor volume by 40% without toxicity or resistance. Intraperitoneal injection of acharan sulfate also decreased tumor weight and volume by 40% in sarcoma 180-bearing mice. These results suggest that the antitumor activity of acharan sulfate may be related to the inhibition of angiogenesis.

  3. Excess TSH causes abnormal skeletal development in young mice with hypothyroidism via suppressive effects on the growth plate.

    Science.gov (United States)

    Endo, Toyoshi; Kobayashi, Tetsuro

    2013-09-01

    Hypothyroidism in the young leads to irreversible growth failure. hyt/hyt Mice have a nonfunctional TSH receptor (TSHR) and are severely hypothyroid, but growth retardation was not observed in adult mice. We found that epiphysial cartilage as well as cultured chondrocytes expressed functional TSHR at levels comparable to that seen in the thyroid, and that addition of TSH to cultured chondrocytes suppressed expression of chondrocyte differentiation marker genes such as Sox-9 and type IIa collagen. Next, we compared the long bone phenotypes of two distinct mouse models of hypothyroidism: thyroidectomized (THYx) mice and hyt/hyt mice. Although both THYx and hyt/hyt mice were severely hypothyroid and had similar serum Ca(2+) and growth hormone levels, the tibia was shorter and the proliferating and hypertrophic zones in the growth plate was significantly narrower in THYx mice than in hyt/hyt mice. Supplementation of hyt/hyt mice thyroid hormone resulted in a wider growth plate compared with that of wild-type mice. Expressions of chondrocyte differentiation marker genes Sox-9 and type IIa collagen in growth plate from THYx mice were 52 and 60% lower than those of hyt/hyt mice, respectively. High serum TSH causes abnormal skeletal development in young mice with hypothyroidism via suppressive effects on the growth plate.

  4. 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

  5. Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling

    International Nuclear Information System (INIS)

    Bharadwaj, Alamelu G.; Goodrich, Nathaniel P.; McAtee, Caitlin O.; Haferbier, Katie; Oakley, Gregory G.; Wahl, James K.; Simpson, Melanie A.

    2011-01-01

    Hyaluronan (HA) production has been functionally implicated in prostate tumorigenesis and metastasis. We previously used prostate tumor cells overexpressing the HA synthesizing enzyme HAS3 or the clinically relevant hyaluronidase Hyal1 to show that excess HA production suppresses tumor growth, while HA turnover accelerates spontaneous metastasis from the prostate. Here, we examined pathways responsible for effects of HAS3 and Hyal1 on tumor cell phenotype. Detailed characterization of cell cycle progression revealed that expression of Hyal1 accelerated cell cycle re-entry following synchronization, whereas HAS3 alone delayed entry. Hyal1 expressing cells exhibited a significant reduction in their ability to sustain ERK phosphorylation upon stimulation by growth factors, and in their expression of the cyclin-dependent kinase inhibitor p21. In contrast, HAS3 expressing cells showed prolonged ERK phosphorylation and increased expression of both p21 and p27, in asynchronous and synchronized cultures. Changes in cell cycle regulatory proteins were accompanied by HA-induced suppression of N-cadherin, while E-cadherin expression and β-catenin expression and distribution remained unchanged. Our results are consistent with a model in which excess HA synthesis suppresses cell proliferation by promoting homotypic E-cadherin mediated cell-cell adhesion, consequently signaling to elevate cell cycle inhibitor expression and suppress G1- to S-phase transition.

  6. The Methanol Extract of Angelica sinensis Induces Cell Apoptosis and Suppresses Tumor Growth in Human Malignant Brain Tumors

    Directory of Open Access Journals (Sweden)

    Yu-Ling Lin

    2013-01-01

    Full Text Available Glioblastoma multiforme (GBM is a highly vascularized and invasive neoplasm. The methanol extract of Angelica sinensis (AS-M is commonly used in traditional Chinese medicine to treat several diseases, such as gastric mucosal damage, hepatic injury, menopausal symptoms, and chronic glomerulonephritis. AS-M also displays potency in suppressing the growth of malignant brain tumor cells. The growth suppression of malignant brain tumor cells by AS-M results from cell cycle arrest and apoptosis. AS-M upregulates expression of cyclin kinase inhibitors, including p16, to decrease the phosphorylation of Rb proteins, resulting in arrest at the G0-G1 phase. The expression of the p53 protein is increased by AS-M and correlates with activation of apoptosis-associated proteins. Therefore, the apoptosis of cancer cells induced by AS-M may be triggered through the p53 pathway. In in vivo studies, AS-M not only suppresses the growth of human malignant brain tumors but also significantly prolongs patient survival. In addition, AS-M has potent anticancer effects involving cell cycle arrest, apoptosis, and antiangiogenesis. The in vitro and in vivo anticancer effects of AS-M indicate that this extract warrants further investigation and potential development as a new antibrain tumor agent, providing new hope for the chemotherapy of malignant brain cancer.

  7. Suppression of polymorphonuclear (PMN) and monocyte-mediated inhibition of Candida albicans growth by delta-9-tetrahydrocannabinol

    International Nuclear Information System (INIS)

    Djeu, J.Y.; Parapanios, A.; Halkias, D.; Friedman, H.

    1986-01-01

    This study was an in vitro attempt to identify the effector cells responsible for growth inhibition of the opportunistic fungus, candida albicans, and to determine if THC or another marijuana derivatives, 11-hydroxyTHC, would adversely affect their function. Using a 24h radiolabel assay, the authors found that growth inhibition of C. albicans was primarily mediated by PMN and monocytes that could be isolated normal human peripheral blood. Both effector cell types caused almost complete inhibition of Candida growth at effector/target ratio of 300/1 and inhibition was often still seen at 30/1-. Incubation of PMN, PBL, or monocytes for 1 hr at 37C with THC or 11-hydroxyTHC caused a marked suppression of function in all 3 cell populations. Maximal suppression was obtained with 7.5-10μg/ml of the drugs in medium containing 10% fetal bovine serum (FBS) or with 2-4μg/ml in 1% FBS. These drug concentrations did not affect lymphoid cell viability or candida growth in the absence of lymphoid effector cells. Marijuana derivatives, therefore, are doubly dangerous in that opportunistic fungi such as C. albicans can grow in their presence while the effector cells that control fungal growth are readily inactivated

  8. Docetaxel-loaded solid lipid nanoparticles suppress breast cancer cells growth with reduced myelosuppression toxicity

    Directory of Open Access Journals (Sweden)

    Yuan Q

    2014-10-01

    Full Text Available Qing Yuan,1 Jing Han,1,2 Wenshu Cong,1 Ying Ge,3 Dandan Ma,1,3,4 Zhaoxia Dai,3,4 Yaping Li,5 Xiaolin Bi1,3,4 1CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 2School of Life Sciences, Anhui University, Hefei, 3Cancer Center, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 4Graduate School, Dalian Medical University, Dalian, 5Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China Abstract: Docetaxel is an adjuvant chemotherapy drug widely used to treat multiple solid tumors; however, its toxicity and side effects limit its clinical efficacy. Herein, docetaxel-loaded solid lipid nanoparticles (DSNs were developed to reduce systemic toxicity of docetaxel while still keeping its anticancer activity. To evaluate its anticancer activity and toxicity, and to understand the molecular mechanisms of DSNs, different cellular, molecular, and whole genome transcription analysis approaches were utilized. The DSNs showed lower cytotoxicity compared with the commercial formulation of docetaxel (Taxotere® and induced more apoptosis at 24 hours after treatment in vitro. DSNs can cause the treated cancer cells to arrest in the G2/M phase in a dose-dependent manner similar to Taxotere. They can also suppress tumor growth very effectively in a mice model with human xenograft breast cancer. Systemic analysis of gene expression profiles by microarray and subsequent verification experiments suggested that both DSNs and Taxotere regulate gene expression and gene function, including DNA replication, DNA damage response, cell proliferation, apoptosis, and cell cycle regulation. Some of these genes expressed differentially at the protein level although their messenger RNA expression level was similar under Taxotere and DSN treatment. Moreover, DSNs improved the main side effect of Taxotere by greatly

  9. Measles virus C protein suppresses gamma-activated factor formation and virus-induced cell growth arrest

    International Nuclear Information System (INIS)

    Yokota, Shin-ichi; Okabayashi, Tamaki; Fujii, Nobuhiro

    2011-01-01

    Measles virus (MeV) produces two accessory proteins, V and C, from the P gene. These accessory proteins have been reported to contribute to efficient virus proliferation through the modulation of host cell events. Our previous paper described that Vero cell-adapted strains of MeV led host cells to growth arrest through the upregulation of interferon regulatory factor 1 (IRF-1), and wild strains did not. In the present study, we found that C protein expression levels varied among MeV strains in infected SiHa cells. C protein levels were inversely correlated with IRF-1 expression levels and with cell growth arrest. Forced expression of C protein released cells from growth arrest. C-deficient recombinant virus efficiently upregulated IRF-1 and caused growth arrest more efficiently than the wild-type virus. C protein preferentially bound to phosphorylated STAT1 and suppressed STAT1 dimer formation. We conclude that MeV C protein suppresses IFN-γ signaling pathway via inhibition of phosphorylated STAT1 dimerization.

  10. Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model.

    Science.gov (United States)

    Koskimaki, Jacob E; Karagiannis, Emmanouil D; Tang, Benjamin C; Hammers, Hans; Watkins, D Neil; Pili, Roberto; Popel, Aleksander S

    2010-02-01

    Angiogenesis is the formation of neovasculature from a pre-existing vascular network. Progression of solid tumors including lung cancer is angiogenesis-dependent. We previously introduced a bioinformatics-based methodology to identify endogenous anti-angiogenic peptide sequences, and validated these predictions in vitro in human umbilical vein endothelial cell (HUVEC) proliferation and migration assays. One family of peptides with high activity is derived from the alpha-fibrils of type IV collagen. Based on the results from the in vitro screening, we have evaluated the ability of a 20 amino acid peptide derived from the alpha5 fibril of type IV collagen, pentastatin-1, to suppress vessel growth in an angioreactor-based directed in vivo angiogenesis assay (DIVAA). In addition, pentastatin-1 suppressed tumor growth with intraperitoneal peptide administration in a small cell lung cancer (SCLC) xenograft model in nude mice using the NCI-H82 human cancer cell line. Pentastatin-1 decreased the invasion of vessels into angioreactors in vivo in a dose dependent manner. The peptide also decreased the rate of tumor growth and microvascular density in vivo in a small cell lung cancer xenograft model. The peptide treatment significantly decreased the invasion of microvessels in angioreactors and the rate of tumor growth in the xenograft model, indicating potential treatment for angiogenesis-dependent disease, and for translational development as a therapeutic agent for lung cancer.

  11. Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model

    International Nuclear Information System (INIS)

    Koskimaki, Jacob E; Karagiannis, Emmanouil D; Tang, Benjamin C; Hammers, Hans; Watkins, D Neil; Pili, Roberto; Popel, Aleksander S

    2010-01-01

    Angiogenesis is the formation of neovasculature from a pre-existing vascular network. Progression of solid tumors including lung cancer is angiogenesis-dependent. We previously introduced a bioinformatics-based methodology to identify endogenous anti-angiogenic peptide sequences, and validated these predictions in vitro in human umbilical vein endothelial cell (HUVEC) proliferation and migration assays. One family of peptides with high activity is derived from the α-fibrils of type IV collagen. Based on the results from the in vitro screening, we have evaluated the ability of a 20 amino acid peptide derived from the α5 fibril of type IV collagen, pentastatin-1, to suppress vessel growth in an angioreactor-based directed in vivo angiogenesis assay (DIVAA). In addition, pentastatin-1 suppressed tumor growth with intraperitoneal peptide administration in a small cell lung cancer (SCLC) xenograft model in nude mice using the NCI-H82 human cancer cell line. Pentastatin-1 decreased the invasion of vessels into angioreactors in vivo in a dose dependent manner. The peptide also decreased the rate of tumor growth and microvascular density in vivo in a small cell lung cancer xenograft model. The peptide treatment significantly decreased the invasion of microvessels in angioreactors and the rate of tumor growth in the xenograft model, indicating potential treatment for angiogenesis-dependent disease, and for translational development as a therapeutic agent for lung cancer

  12. miR-409-3p suppresses breast cancer cell growth and invasion by targeting Akt1

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Guoqiang [Department of Breast Surgery, Qilu Hospital, Shandong University, Jinan 250012 (China); Department of Thyroid and Breast Surgery, Hospital Affiliated to Binzhou Medical University, 661 Second Huanghe Street, Binzhou 256603 (China); Liu, Zengyan [Department of Hematology, Hospital Affiliated to Binzhou Medical University, 661 Second Huanghe Street, Binzhou 256603 (China); Xu, Hao [Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029 (China); Yang, Qifeng, E-mail: qifengy_sdu1@163.com [Department of Breast Surgery, Qilu Hospital, Shandong University, Jinan 250012 (China)

    2016-01-08

    Altered levels and functions of microRNAs (miRNAs) are correlated with carcinogenesis. While miR-409-3p has been shown to play important roles in several cancer types, its function in the context of breast cancer (BC) remains unknown. In this study, miR-409-3p was significantly downregulated in BC tissues and cell lines, compared with the corresponding control counterparts. Overexpression of miR-409-3p inhibited BC cell proliferation, migration and invasion in vitro and suppressed tumor growth in vivo. Notably, miR-409-3p induced downregulation of Akt1 protein through binding to its 3′ untranslated region (UTR). Conversely, restoring Akt1 expression rescued the suppressive effects of miR-409-3p. Our data collectively indicate that miR-409-3p functions as a tumor suppressor in BC through downregulating Akt1, supporting the targeting of the novel miR-409-3p/Akt1 axis as a potentially effective therapeutic approach for BC. - Highlights: • miR-409-3p inhibits proliferation, migration and invasion of BC cells. • miR-409-3p suppresses tumor growth in nude mice. • Akt1 is a direct downstream target of miR-409-3p. • Ectopic expression of Akt1 reverses the effects of miR-409-3p on cell proliferation, migration and invasion.

  13. Green tea polyphenol epigallocatechin-3-gallate suppresses melanoma growth by inhibiting inflammasome and IL-1β secretion

    International Nuclear Information System (INIS)

    Ellis, Lixia Z.; Liu, Weimin; Luo, Yuchun; Okamoto, Miyako; Qu, Dovina; Dunn, Jeffrey H.; Fujita, Mayumi

    2011-01-01

    Highlights: ► EGCG inhibits melanoma cell growth at physiological doses (0.1–1 μM). ► EGCG inhibits melanoma cell growth via inflammasomes and IL-1β suppression. ► Inflammasomes and IL-1β could be potential targets for future melanoma therapeutics. -- Abstract: Epigallocatechin-3-gallate (EGCG), the major polyphenolic component of green tea, has been demonstrated to possess anti-inflammatory, antioxidant, anti-mutagenic and anti-carcinogenic properties. The anti-melanoma effect of EGCG has been previously suggested, but no clear mechanism of action has been established. In this study, we demonstrated that EGCG inhibits melanoma cell growth at physiological doses (0.1–1 μM). In the search for mechanisms of EGCG-mediated melanoma cell suppression, we found that NF-κB was inhibited, and that reduced NF-κB activity was associated with decreased IL-1β secretion from melanoma cells. Since inflammasomes are involved in IL-1β secretion, we investigated whether IL-1β suppression was mediated by inflammasomes, and found that EGCG treatment led to downregulation of the inflammasome component, NLRP1, and reduced caspase-1 activation. Furthermore, silencing the expression of NLRP1 abolished EGCG-induced inhibition of tumor cell proliferation both in vitro and in vivo, suggesting a key role of inflammasomes in EGCG efficacy. This paper provides a novel mechanism for EGCG-induced melanoma inhibition: inflammasome downregulation → decreased IL-1β secretion → decreased NF-κB activities → decreased cell growth. In addition, it suggests inflammasomes and IL-1β could be potential targets for future melanoma therapeutics.

  14. Growth of Murine Splenic Tissue Is Suppressed by Lymphotoxin β-Receptor Signaling (LTβR) Originating from Splenic and Non-Splenic Tissues

    DEFF Research Database (Denmark)

    Milićević, Novica M; Nohroudi, Klaus; Schmidt, Friederike

    2016-01-01

    LTβR signaling. Two-dimensional differential gel electrophoresis and subsequent mass spectrometry of stromal splenic tissue was applied to screen for potential factors mediating the LTβR dependent suppressive activity. Thus, LTβR dependent growth suppression is involved in regulating the size...

  15. U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo

    Directory of Open Access Journals (Sweden)

    Rafal Goraczniak

    2013-01-01

    Full Text Available U1 Adaptor is a recently discovered oligonucleotide-based gene-silencing technology with a unique mechanism of action that targets nuclear pre-mRNA processing. U1 Adaptors have two distinct functional domains, both of which must be present on the same oligonucleotide to exert their gene-silencing function. Here, we present the first in vivo use of U1 Adaptors by targeting two different human genes implicated in melanomagenesis, B-cell lymphoma 2 (BCL2 and metabotropic glutamate receptor 1 (GRM1, in a human melanoma cell xenograft mouse model system. Using a newly developed dendrimer delivery system, anti-BCL2 U1 Adaptors were very potent and suppressed tumor growth at doses as low as 34 µg/kg with twice weekly intravenous (iv administration. Anti-GRM1 U1 Adaptors suppressed tumor xenograft growth with similar potency. Mechanism of action was demonstrated by showing target gene suppression in tumors and by observing that negative control U1 Adaptors with just one functional domain show no tumor suppression activity. The anti-BCL2 and anti-GRM1 treatments were equally effective against cell lines harboring either wild-type or a mutant V600E B-RAF allele, the most common mutation in melanoma. Treatment of normal immune-competent mice (C57BL6 indicated no organ toxicity or immune stimulation. These proof-of-concept studies represent an in-depth (over 800 mice in ~108 treatment groups validation that U1 Adaptors are a highly potent gene-silencing therapeutic and open the way for their further development to treat other human diseases.

  16. A comprehensive siRNA screen for kinases that suppress macroautophagy in optimal growth conditions

    DEFF Research Database (Denmark)

    Szyniarowski, Piotr; Corcelle-Termeau, Elisabeth; Farkas, Thomas

    2011-01-01

    , whereas CSNK1A1, BUB1, PKLR and NEK4 suppressed autophagosome formation downstream or independent of mTORC1. Importantly, all identified kinases except for BUB1 regulated macroautophagy also in immortalized MCF-10A breast epithelial cells. The kinases identified here shed light to the complex regulation...

  17. Caffeic acid phenethyl ester suppresses melanoma tumor growth by inhibiting PI3K/AKT/XIAP pathway.

    Science.gov (United States)

    Pramanik, Kartick C; Kudugunti, Shashi K; Fofaria, Neel M; Moridani, Majid Y; Srivastava, Sanjay K

    2013-09-01

    Melanoma is highly metastatic and resistant to chemotherapeutic drugs. Our previous studies have demonstrated that caffeic acid phenethyl ester (CAPE) suppresses the growth of melanoma cells and induces reactive oxygen species generation. However, the exact mechanism of the growth suppressive effects of CAPE was not clear. Here, we determined the potential mechanism of CAPE against melanoma in vivo and in vitro. Administration of 10 mg/kg/day CAPE substantially suppressed the growth of B16F0 tumor xenografts in C57BL/6 mice. Tumors from CAPE-treated mice showed reduced phosphorylation of phosphoinositide 3-kinase, AKT, mammalian target of rapamycin and protein level of X-linked inhibitor of apoptosis protein (XIAP) and enhanced the cleavage of caspase-3 and poly (ADP ribose) polymerase. In order to confirm the in vivo observations, melanoma cells were treated with CAPE. CAPE treatment suppressed the activating phosphorylation of phosphoinositide 3-kinase at Tyr 458, phosphoinositide-dependent kinase-1 at Ser 241, mammalian target of rapamycin at Ser 2448 and AKT at Ser 473 in B16F0 and SK-MEL-28 cells in a concentration and time-dependent study. Furthermore, the expression of XIAP, survivin and BCL-2 was downregulated by CAPE treatment in both cell lines. Significant apoptosis was observed by CAPE treatment as indicated by cleavage of caspase-3 and poly (ADP ribose) polymerase. AKT kinase activity was inhibited by CAPE in a concentration-dependent manner. CAPE treatment increased the nuclear translocation of XIAP, indicating increased apoptosis in melanoma cells. To confirm the involvement of reactive oxygen species in the inhibition of AKT/XIAP pathway, cells were treated with antioxidant N-acetyl-cysteine (NAC) prior to CAPE treatment. Our results indicate that NAC blocked CAPE-mediated AKT/XIAP inhibition and protected the cells from apoptosis. Because AKT regulates XIAP, their interaction was examined by immunoprecipitation studies. Our results show that CAPE

  18. 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.

  19. The poorly explored impact of uncontrolled asthma

    DEFF Research Database (Denmark)

    O'Byrne, Paul M; Pedersen, Søren; Schatz, Michael

    2013-01-01

    The goal of asthma management is to achieve disease control; however, despite the availability of effective and safe medications, for many patients asthma remains uncontrolled. One reason for this is the fear of long-term side effects from the regular use of inhaled corticosteroids (ICSs). Adverse...... effects of poorly controlled asthma (for example, obesity, pneumonia, and risks to the fetus) can be perceived as side effects of ICSs. Poorly controlled asthma adversely affects children's cardiovascular fitness, while children with well-controlled asthma perform at the same level as their peers....... Children with uncontrolled asthma also have a higher frequency of obesity than children with controlled asthma. Stress can affect asthma control, and children with poorly controlled asthma are more likely to have learning disabilities compared with those with good control. In adults, focused attention...

  20. Acute compartment syndrome caused by uncontrolled hypothyroidism.

    Science.gov (United States)

    Modi, Anar; Amin, Hari; Salzman, Matthew; Morgan, Farah

    2017-06-01

    Acute compartment syndrome is increased tissue pressure exceeding perfusion pressure in a closed compartment resulting in nerve and muscle ischemia. Common precipitating causes are crush injuries, burns, substance abuse, osseous or vascular limb trauma. This is a case of 42year old female with history of hypothyroidism who presented to emergency room with acute onset of severe pain and swelling in right lower extremity. Physical examination was concerning for acute compartment syndrome of right leg which was confirmed by demonstration of elevated compartmental pressures. No precipitating causes were readily identified. Further laboratory testing revealed uncontrolled hypothyroidism. Management included emergent fasciotomy and initiating thyroid hormone replacement. This case represents a rare association between acute compartment syndrome and uncontrolled hypothyroidism. We also discuss the pathogenesis of compartment syndrome in hypothyroid patients and emphasize the importance of evaluating for less common causes, particularly in setting of non-traumatic compartment syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Generic conditions for suppressing the coherent synchrotron radiation induced emittance growth in a two-dipole achromat

    Science.gov (United States)

    Jiao, Yi; Cui, Xiaohao; Huang, Xiyang; Xu, Gang

    2014-06-01

    The effect of the coherent synchrotron radiation (CSR) becomes evident, and leads to increased beam energy spread and transverse emittance dilution, as both the emittance and bunch length of the electron beams are continuously pushed down in present and forthcoming high-brightness light sources and linear colliders. Suppressing this effect is important to preserve the expected machine performance. Methods of the R-matrix analysis and the Courant-Snyder formalism analysis have been proposed to evaluate and to suppress the emittance growth due to CSR in achromatic cells. In this paper a few important modifications are made on these two methods, which enable us to prove that these two methods are equivalent to each other. With the modified analysis, we obtain explicit and generic conditions of cancelling the CSR-driven emittance excitation in a single achromat consisting of two dipoles of arbitrary bending angles. In spite of the fact that the analysis constrains itself in a linear regime, based on the assumption that CSR-induced particle energy deviation is proportional to both θ and ρ1/3, with θ being the bending angle and ρ the bending radius, it is demonstrated through ELEGANT simulations that the conditions derived from this analysis are still effective in suppressing the emittance growth when a more detailed one-dimensional CSR model is considered. In addition, it illustrates that the emittance growth can be reduced to a lower level with the proposed conditions than with the other two approaches, such as matching the beam envelope to the CSR kick and setting the cell-to-cell betatron phase advance to an appropriate value.

  2. Endo-Perio Lesion and Uncontrolled Diabetes

    OpenAIRE

    Dhoum, Sara; Laslami, Kaoutar; Rouggani, Fatimazahraa; El Ouazzani, Amal; Jabri, Mouna

    2018-01-01

    This work is to discuss the management of an endo-perio lesion, which represents a challenge to clinicians when it comes to diagnosis and prognosis of the involved teeth and especially with an altered general condition. A 50-year-old female patient with uncontrolled diabetes type 2 is suffering from a purulent discharge coming from the upper right canine. Endodontic and periodontal treatments were realized with 36 months radiological and clinical follow-up with the collaboration of her intern...

  3. Endo-Perio Lesion and Uncontrolled Diabetes.

    Science.gov (United States)

    Dhoum, Sara; Laslami, Kaoutar; Rouggani, Fatimazahraa; El Ouazzani, Amal; Jabri, Mouna

    2018-01-01

    This work is to discuss the management of an endo-perio lesion, which represents a challenge to clinicians when it comes to diagnosis and prognosis of the involved teeth and especially with an altered general condition. A 50-year-old female patient with uncontrolled diabetes type 2 is suffering from a purulent discharge coming from the upper right canine. Endodontic and periodontal treatments were realized with 36 months radiological and clinical follow-up with the collaboration of her internist doctor.

  4. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth.

    Directory of Open Access Journals (Sweden)

    Ron Firestein

    2008-04-01

    Full Text Available Numerous longevity genes have been discovered in model organisms and altering their function results in prolonged lifespan. In mammals, some have speculated that any health benefits derived from manipulating these same pathways might be offset by increased cancer risk on account of their propensity to boost cell survival. The Sir2/SIRT1 family of NAD(+-dependent deacetylases is proposed to underlie the health benefits of calorie restriction (CR, a diet that broadly suppresses cancer in mammals. Here we show that CR induces a two-fold increase SIRT1 expression in the intestine of rodents and that ectopic induction of SIRT1 in a beta-catenin-driven mouse model of colon cancer significantly reduces tumor formation, proliferation, and animal morbidity in the absence of CR. We show that SIRT1 deacetylates beta-catenin and suppresses its ability to activate transcription and drive cell proliferation. Moreover, SIRT1 promotes cytoplasmic localization of the otherwise nuclear-localized oncogenic form of beta-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of beta-catenin in 81 human colon tumor specimens analyzed. Taken together, these observations show that SIRT1 suppresses intestinal tumor formation in vivo and raise the prospect that therapies targeting SIRT1 may be of clinical use in beta-catenin-driven malignancies.

  5. Breviscapine suppresses the growth of non-small cell lung cancer

    Indian Academy of Sciences (India)

    Breviscapine (BVP) has previously been shown to inhibit the proliferation of hepatocellular carcinoma cells.However, little is known about the effects of BVP on non-small cell lung cancer (NSCLC) growth. Here, we aimedto study the effects of BVP on human NSCLC growth. We employed A549, NCL-H460 and A549 cells ...

  6. Procedure for growing Bi4Ge3O12 bismuth germanate single crystals with suppressed growth defects

    International Nuclear Information System (INIS)

    Zikmund, J.; Blazek, K.; Jarolimek, O.; Horak, J.

    1991-01-01

    The method developed allows high-quality scintillator material to be grown reproducibly by the Czochralski method. The crystals attain diameters up to 80 mm and lengths up to 200 mm. The growth is performed on instruments equipped with devices for continuous measurement of weight increments of the growing crystals with a precision better than 10 mg. The growth parameters are controlled with a computer and based on actual data. The crystals are grown using an axial temperature gradient within the range of 25 to 35 degC/cm and a constant drawing rate within the range of 0.5 to 1.2 mm/h. An interface shape suitable for the suppression of defect development is achieved through a combination of the weight increment and rotation of the crystal. (M.D.)

  7. Down-Regulation by Resveratrol of Basic Fibroblast Growth Factor-Stimulated Osteoprotegerin Synthesis through Suppression of Akt in Osteoblasts

    Directory of Open Access Journals (Sweden)

    Gen Kuroyanagi

    2014-10-01

    Full Text Available It is firmly established that resveratrol, a natural food compound abundantly found in grape skins and red wine, has beneficial properties for human health. In the present study, we investigated the effect of basic fibroblast growth factor (FGF-2 on osteoprotegerin (OPG synthesis in osteoblast-like MC3T3-E1 cells and whether resveratrol affects the OPG synthesis. FGF-2 stimulated both the OPG release and the expression of OPG mRNA. Resveratrol significantly suppressed the FGF-2-stimulated OPG release and the mRNA levels of OPG. SRT1720, an activator of SIRT1, reduced the FGF-2-induced OPG release and the OPG mRNA expression. PD98059, an inhibitor of upstream kinase activating p44/p42 mitogen-activated protein (MAP kinase, had little effect on the FGF-2-stimulated OPG release. On the other hand, SB203580, an inhibitor of p38 MAP kinase, SP600125, an inhibitor of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK, and Akt inhibitor suppressed the OPG release induced by FGF-2. Resveratrol failed to affect the FGF-2-induced phosphorylation of p44/p42 MAP kinase, p38 MAP kinase or SAPK/JNK. The phosphorylation of Akt induced by FGF-2 was significantly suppressed by resveratrol or SRT1720. These findings strongly suggest that resveratrol down-regulates FGF-2-stimulated OPG synthesis through the suppression of the Akt pathway in osteoblasts and that the inhibitory effect of resveratrol is mediated at least in part by SIRT1 activation.

  8. Effusanin E suppresses nasopharyngeal carcinoma cell growth by inhibiting NF-κB and COX-2 signaling.

    Directory of Open Access Journals (Sweden)

    Mingzhu Zhuang

    Full Text Available Rabdosia serra is well known for its antibacterial, anti-inflammatory and antitumor activities, but no information has been available for the active compounds derived from this plant in inhibiting human nasopharyngeal carcinoma (NPC cell growth. In this study, we isolated and purified a natural diterpenoid from Rabdosia serra and identified its chemical structure as effusanin E and elucidated its underlying mechanism of action in inhibiting NPC cell growth. Effusanin E significantly inhibited cell proliferation and induced apoptosis in NPC cells. Effusanin E also induced the cleavage of PARP, caspase-3 and -9 proteins and inhibited the nuclear translocation of p65 NF-κB proteins. Moreover, effusanin E abrogated the binding of NF-κB to the COX-2 promoter, thereby inhibiting the expression and promoter activity of COX-2. Pretreatment with a COX-2 or NF-κB-selective inhibitor (celecoxib or ammonium pyrrolidinedithiocarbamate had an additive effect on the effusanin E-mediated inhibition of proliferation, while pretreatment with an activator of NF-κB/COX-2 (lipopolysaccharides abrogated the effusanin E-mediated inhibition of proliferation. Effusanin E also significantly suppressed tumor growth in a xenograft mouse model without obvious toxicity, furthermore, the expression of p50 NF-κB and COX-2 were down-regulated in the tumors of nude mice. These data suggest that effusanin E suppresses p50/p65 proteins to down-regulate COX-2 expression, thereby inhibiting NPC cell growth. Our findings provide new insights into exploring effusanin E as a potential therapeutic compound for the treatment of human nasopharyngeal carcinoma.

  9. Androgen Receptor-Mediated Growth Suppression of HPr-1AR and PC3-Lenti-AR Prostate Epithelial Cells.

    Directory of Open Access Journals (Sweden)

    Young-Chae Kim

    Full Text Available The androgen receptor (AR mediates the developmental, physiologic, and pathologic effects of androgens including 5α-dihydrotestosterone (DHT. However, the mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells are not well understood, though they are central to prostate development, homeostasis, and neoplasia. Here, we identify androgen-responsive genes that restrain cell cycle progression and proliferation of human prostate epithelial cell lines (HPr-1AR and PC3-Lenti-AR, and we investigate the mechanisms through which AR regulates their expression. DHT inhibited proliferation of HPr-1AR and PC3-Lenti-AR, and cell cycle analysis revealed a prolonged G1 interval. In the cell cycle, the G1/S-phase transition is initiated by the activity of cyclin D and cyclin-dependent kinase (CDK complexes, which relieve growth suppression. In HPr-1AR, cyclin D1/2 and CDK4/6 mRNAs were androgen-repressed, whereas CDK inhibitor, CDKN1A, mRNA was androgen-induced. The regulation of these transcripts was AR-dependent, and involved multiple mechanisms. Similar AR-mediated down-regulation of CDK4/6 mRNAs and up-regulation of CDKN1A mRNA occurred in PC3-Lenti-AR. Further, CDK4/6 overexpression suppressed DHT-inhibited cell cycle progression and proliferation of HPr-1AR and PC3-Lenti-AR, whereas CDKN1A overexpression induced cell cycle arrest. We therefore propose that AR-mediated growth suppression of HPr-1AR involves cyclin D1 mRNA decay, transcriptional repression of cyclin D2 and CDK4/6, and transcriptional activation of CDKN1A, which serve to decrease CDK4/6 activity. AR-mediated inhibition of PC3-Lenti-AR proliferation occurs through a similar mechanism, albeit without down-regulation of cyclin D. Our findings provide insight into AR-mediated regulation of prostate epithelial cell proliferation.

  10. Pokemon siRNA Delivery Mediated by RGD-Modified HBV Core Protein Suppressed the Growth of Hepatocellular Carcinoma.

    Science.gov (United States)

    Kong, Jing; Liu, Xiaoping; Jia, Jianbo; Wu, Jinsheng; Wu, Ning; Chen, Jun; Fang, Fang

    2015-10-01

    Hepatocellular carcinoma (HCC) is a deadly human malignant tumor that is among the most common cancers in the world, especially in Asia. Hepatitis B virus (HBV) infection has been well established as a high risk factor for hepatic malignance. Studies have shown that Pokemon is a master oncogene for HCC growth, suggesting it as an ideal therapeutic target. However, efficient delivery system is still lacking for Pokemon targeting treatment. In this study, we used core proteins of HBV, which is modified with RGD peptides, to construct a biomimetic vector for the delivery of Pokemon siRNAs (namely, RGD-HBc-Pokemon siRNA). Quantitative PCR and Western blot assays revealed that RGD-HBc-Pokemon siRNA possessed the highest efficiency of Pokemon suppression in HCC cells. In vitro experiments further indicated that RGD-HBc-Pokemon-siRNA exerted a higher tumor suppressor activity on HCC cell lines, evidenced by reduced proliferation and attenuated invasiveness, than Pokemon-siRNA or RGD-HBc alone. Finally, animal studies demonstrated that RGD-HBc-Pokemon siRNA suppressed the growth of HCC xenografts in mice by a greater extent than Pokemon-siRNA or RGD-HBc alone. Based on the above results, Pokemon siRNA delivery mediated by RGD-modified HBV core protein was shown to be an effective strategy of HCC gene therapy.

  11. Ganoderma lucidum suppresses growth of breast cancer cells through the inhibition of Akt/NF-kappaB signaling.

    Science.gov (United States)

    Jiang, Jiahua; Slivova, Veronika; Harvey, Kevin; Valachovicova, Tatiana; Sliva, Daniel

    2004-01-01

    Ganoderma lucidum (Reishi, Lingzhi) is a popular Asian mushroom that has been used for more than 2 millennia for the general promotion of health and was therefore called the "Mushroom of Immortality." Ganoderma lucidum was also used in traditional Chinese medicine to prevent or treat a variety of diseases, including cancer. We previously demonstrated that Ganoderma lucidum suppresses the invasive behavior of breast cancer cells by inhibiting the transcription factor NF-kappaB. However, the molecular mechanisms responsible for the inhibitory effects of Ganoderma lucidum on the growth of highly invasive and metastatic breast cancer cells has not been fully elucidated. Here, we show that Ganoderma lucidum inhibits proliferation of breast cancer MDA-MB-231 cells by downregulating Akt/NF-kappaB signaling. Ganoderma lucidum suppresses phosphorylation of Akt on Ser473 and downregulates the expression of Akt, which results in the inhibition of NF-kappaB activity in MDA-MB-231 cells. The biological effect of Ganoderma lucidum was demonstrated by cell cycle arrest at G0/G1, which was the result of the downregulation of expression of NF-kappaB-regulated cyclin D1, followed by the inhibition of cdk4. Our results suggest that Ganoderma lucidum inhibits the growth of MDA-MB-231 breast cancer cells by modulating Akt/NF-kappaB signaling and could have potential therapeutic use for the treatment of breast cancer.

  12. Delayed puberty caused by hyperthyroidism in ram lambs is not a result of suppression in body growth.

    Science.gov (United States)

    Chandrasekhar, Y; D'Occhio, M J; Setchell, B P

    1986-03-01

    Over a period of 8 weeks ram lambs (16 weeks old) were made hyperthyroidal (serum thyroxine approximately equal to 150 ng/ml, compared with control approximately equal to 48 ng/ml) by daily subcutaneous injections of thyroxine or maintained at a constant body weight by restriction of the feed intake. Hyperthyroidal and restricted-intake lambs remained at a constant body weight during the period of treatment whilst control rams gained body weight. Testicular growth was normal in restricted-intake lambs but was suppressed in hyperthyroidal animals. Hyperthyroidism, but not feed restriction, was also associated with decrease in LH pulse frequency (1.3 +/- 0.3/12 h compared with controls 4.8 +/- 0.9/12 h. Hyperthyroidal lambs showed normal LH responses to exogenous LHRH. After cessation of treatment testicular growth continued to be suppressed for up to 16 weeks in previously hyperthyroidic rams; thereafter testes began to increase in size but at 30 weeks after treatment were still smaller than those of control rams. It is concluded that elevated thyroxine concentrations directly influence sexual maturation in ram lambs through actions at hypothalamic and/or higher brain centres which control LH secretion. Transient hyperthyroidism during sexual maturation may cause permanent impairment of sexual development.

  13. Rapid suppression of growth hormone concentration by overeating: potential mediation by hyperinsulinemia.

    Science.gov (United States)

    Cornford, Andrea S; Barkan, Ariel L; Horowitz, Jeffrey F

    2011-03-01

    The very low GH concentration in obesity is commonly attributed to high body fat mass; however, the influence of overeating on GH secretion is not clear. The aim of the study was to examine the effects of 2 wk of overeating on changes in GH secretion. Subjects were admitted to the hospital and stayed within the Michigan Clinical Research Unit throughout the entire 2-wk overeating period. We studied seven healthy, nonobese men (body mass index, 24 ± 1 kg/m(2); age, 25 ± 1 yr). Subjects ate standardized meals containing 70 kcal/kg fat free mass/d (∼4000 kcal/d) for 2 wk. Twenty-four-hour plasma concentrations of GH (every 20 min) and insulin (every 2 h) were measured before overeating (baseline), on d 3, and after 2 wk of overeating. Compared with baseline, average 24-h plasma GH concentration declined nearly 80% by d 3 of overeating (1.30 ± 0.18 vs. 0.36 ± 0.09 ng/ml; P = 0.01). This marked suppression of GH secretion occurred in the absence of an increase in body weight (77.0 ± 2.2 vs. 76.4 ± 2.4 kg). At the same time, average 24-h insulin concentration doubled (16.6 ± 2.1 vs. 31.7 ± 5.8 μU/ml; P = 0.009). After 2 wk, body weight significantly increased (79.0 ± 2.1 kg; P overeating markedly suppressed GH secretion before any measurable weight gain and was accompanied by chronic hyperinsulinemia. Increased body weight and body fat by 2 wk of overeating did not further suppress GH secretion.

  14. Conjugated docosahexaenoic acid suppresses KPL-1 human breast cancer cell growth in vitro and in vivo: potential mechanisms of action

    International Nuclear Information System (INIS)

    Tsujita-Kyutoku, Miki; Ogawa, Yutaka; Tsubura, Airo; Yuri, Takashi; Danbara, Naoyuki; Senzaki, Hideto; Kiyozuka, Yasuhiko; Uehara, Norihisa; Takada, Hideho; Hada, Takahiko; Miyazawa, Teruo

    2004-01-01

    The present study was conducted to examine the effect of conjugated docosahexaenoic acid (CDHA) on cell growth, cell cycle progression, mode of cell death, and expression of cell cycle regulatory and/or apoptosis-related proteins in KPL-1 human breast cancer cell line. This effect of CDHA was compared with that of docosahexaenoic acid (DHA). KPL-1 cell growth was assessed by colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay; cell cycle progression and mode of cell death were examined by flow cytometry; and levels of expression of p53, p21 Cip1/Waf1 , cyclin D 1 , Bax, and Bcl-2 proteins were examined by Western blotting analysis. In vivo tumor growth was examined by injecting KPL-1 cells subcutaneously into the area of the right thoracic mammary fat pad of female athymic mice fed a CDHA diet. CDHA inhibited KPL-1 cells more effectively than did DHA (50% inhibitory concentration for 72 hours: 97 μmol/l and 270 μmol/l, respectively). With both CDHA and DHA growth inhibition was due to apoptosis, as indicated by the appearance of a sub-G 1 fraction. The apoptosis cascade involved downregulation of Bcl-2 protein; Bax expression was unchanged. Cell cycle progression was due to G 0 /G 1 arrest, which involved increased expression of p53 and p21 Cip1/Waf1 , and decreased expression of cyclin D 1 . CDHA modulated cell cycle regulatory proteins and apoptosis-related proteins in a manner similar to that of parent DHA. In the athymic mouse system 1.0% dietary CDHA, but not 0.2%, significantly suppressed growth of KPL-1 tumor cells; CDHA tended to decrease regional lymph node metastasis in a dose dependent manner. CDHA inhibited growth of KPL-1 human breast cancer cells in vitro more effectively than did DHA. The mechanisms of action involved modulation of apoptosis cascade and cell cycle progression. Dietary CDHA at 1.0% suppressed KPL-1 cell growth in the athymic mouse system

  15. Growth theory after Keynes, part I: the unfortunate suppression of the Harrod-Domar model

    Directory of Open Access Journals (Sweden)

    Hendrik Van den Berg

    2013-11-01

    Full Text Available After Harrod and Domar independently developed a dynamic Keynesian circular flow model to illustrate the instability of a growing economy, mainstream economists quickly reduced their model to a supply side-only growth model, which they subsequently rejected as too simplistic and replaced with Solow’s neoclassical growth model. The rejection process of first diminishing the model and then replaced it with a neoclassical alternative was similar to how the full Keynesian macroeconomic paradigm was diminished into IS-LM analysis and then replaced by a simplistic neoclassical framework that largely ignored the demand side of the economy. Furthermore, subsequent work by mainstream economists has resulted in a logically inconsistent framework for analyzing economic growth; the popular endogenous growth models, which use Schumpeter’s concept of profit-driven creative destruction to explain the technological change that Solow left as exogenous, are not logically compatible with the Solow model.

  16. Suppression of progranulin expression inhibits bladder cancer growth and sensitizes cancer cells to cisplatin

    OpenAIRE

    Buraschi, Simone; Xu, Shi-Qiong; Stefanello, Manuela; Moskalev, Igor; Morcavallo, Alaide; Genua, Marco; Tanimoto, Ryuta; Birbe, Ruth; Peiper, Stephen C.; Gomella, Leonard G.; Belfiore, Antonino; Black, Peter C.; Iozzo, Renato V.; Morrione, Andrea

    2016-01-01

    We have recently demonstrated a critical role for progranulin in bladder cancer. Progranulin contributes, as an autocrine growth factor, to the transformed phenotype by modulating Akt-and MAPK-driven motility, invasion and anchorage-independent growth. Progranulin also induces F-actin remodeling by interacting with the F-actin binding protein drebrin. In addition, progranulin is overexpressed in invasive bladder cancer compared to normal tissue controls, suggesting that progranulin might play...

  17. Biocontrol traits of plant growth suppressive arbuscular mycorrhizal fungi against root rot in tomato caused by Pythium aphanidermatum

    DEFF Research Database (Denmark)

    Larsen, John; Graham, James H.; Cubero, Jaime

    2012-01-01

    Arbuscular mycorrhizal (AM) fungi known to cause plant growth depressions in tomato were examined for their biocontrol effects against root rot caused by Pythium aphanidermatum. The main hypothesis was that plant growth suppressive AM fungi would elicit a defence response in the host plant reduci...

  18. Overexpressed CacyBP/SIP leads to the suppression of growth in renal cell carcinoma

    International Nuclear Information System (INIS)

    Sun, Shiren; Ning, Xiaoxuan; Liu, Jie; Liu, Lili; Chen, Yu; Han, Shuang; Zhang, Yanqi; Liang, Jie; Wu, Kaichun; Fan, Daiming

    2007-01-01

    Calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP), a target protein of S100, has been identified as a component of a novel ubiquitinylation complex leading to β-catenin degradation, which was found to be related to the malignant phenotypes of gastric cancer. However, the roles of CacyBP/SIP in renal cell carcinoma still remain unclear. In the present study, we had analyzed the expression of the CacyBP/SIP protein in human renal cancer cells and clinical tissue samples. The possible roles of CacyBP/SIP in regulating the malignant phenotype of renal cancer cells were also investigated. The results demonstrated that the expression of CacyBP/SIP was markedly down-regulated in renal cell carcinoma tissues and cell lines. Ectopic overexpression of CacyBP/SIP in A498 cells inhibited the proliferation of this cell and delayed cell cycle progression significantly, which might be related to the down-regulation of Cyclin D1 through reducing β-catenin protein. CacyBP/SIP also suppressed colony formation in soft agar and its tumorigenicity in nude mice. Taken together, our work showed that CacyBP/SIP, as a novel down-regulated gene in renal cell carcinoma, suppressed proliferation and tumorigenesis of renal cancer cells

  19. Synergistic effect of obesity and lipid ingestion in suppressing the growth hormone response to exercise in children.

    Science.gov (United States)

    Oliver, Stacy R; Hingorani, Sunita R; Rosa, Jaime S; Zaldivar, Frank P; Galassetti, Pietro R

    2012-07-01

    Diet plays an important role in modulating exercise responses, including activation of the growth hormone (GH)/insulin-like growth factor-I (IGF-1) axis. Obesity and fat ingestion were separately shown to reduce exercise GH responses, but their combined effect, especially important in children, has not been studied. We therefore measured the GH response to exercise [30-min intermittent cycling, ten 2-min bouts at ~80% maximal aerobic capacity (Vo(2max)), separated by 1-min rest], started 45 min after ingestion of a high-fat meal (HFM) in 16 healthy [controls; body mass index percentile (BMI%ile) 51 ± 7], and 19 obese (Ob, BMI%ile 97 ± 0.4) children. Samples were drawn at baseline (premeal), and at start, peak, and 30 min postexercise. In the Ob group, a marked ~75% suppression of the GH response (ng/ml) to exercise was observed (2.4 ± 0.6 vs. 10.6 ± 2.1, P fasting conditions. Our data indicate that the reduction in the GH response to exercise, already present in obese children vs. healthy controls, is considerably amplified by ingestion of fat nutrients shortly before exercise, implying a potentially downstream negative impact on growth factor homeostasis and long-term modulation of physiological growth.

  20. Endo-Perio Lesion and Uncontrolled Diabetes

    Directory of Open Access Journals (Sweden)

    Sara Dhoum

    2018-01-01

    Full Text Available This work is to discuss the management of an endo-perio lesion, which represents a challenge to clinicians when it comes to diagnosis and prognosis of the involved teeth and especially with an altered general condition. A 50-year-old female patient with uncontrolled diabetes type 2 is suffering from a purulent discharge coming from the upper right canine. Endodontic and periodontal treatments were realized with 36 months radiological and clinical follow-up with the collaboration of her internist doctor.

  1. Exosomes serve as nanoparticles to suppress tumor growth and angiogenesis in gastric cancer by delivering hepatocyte growth factor siRNA.

    Science.gov (United States)

    Zhang, Haiyang; Wang, Yi; Bai, Ming; Wang, Junyi; Zhu, Kegan; Liu, Rui; Ge, Shaohua; Li, JiaLu; Ning, Tao; Deng, Ting; Fan, Qian; Li, Hongli; Sun, Wu; Ying, Guoguang; Ba, Yi

    2018-03-01

    Exosomes derived from cells have been found to mediate signal transduction between cells and to act as efficient carriers to deliver drugs and small RNA. Hepatocyte growth factor (HGF) is known to promote the growth of both cancer cells and vascular cells, and the HGF-cMET pathway is a potential clinical target. Here, we characterized the inhibitory effect of HGF siRNA on tumor growth and angiogenesis in gastric cancer. In addition, we showed that HGF siRNA packed in exosomes can be transported into cancer cells, where it dramatically downregulates HGF expression. A cell co-culture model was used to show that exosomes loaded with HGF siRNA suppress proliferation and migration of both cancer cells and vascular cells. Moreover, exosomes were able to transfer HGF siRNA in vivo, decreasing the growth rates of tumors and blood vessels. The results of our study demonstrate that exosomes have potential for use in targeted cancer therapy by delivering siRNA. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  2. MiR-30a-5p suppresses tumor growth in colon carcinoma by targeting DTL

    DEFF Research Database (Denmark)

    Baraniskin, Alexander; Birkenkamp-Demtröder, Karin; Maghnouj, Abdelouahid

    2012-01-01

    MicroRNAs (miRNAs) are small non-coding RNAs that are involved in different biological processes by suppressing target gene expression. Altered expression of miR-30a-5p has been reported in colon carcinoma. To elucidate its potential biological role in colon cancer, miR-30a-5p was overexpressed via...... with in silico miRNA target prediction, we identified the denticleless protein homolog (DTL) as a potential miRNA-30a-5p target. Subsequent reporter gene assays confirmed the predicted miR-30a-5p binding site in the 3'untranslated region of DTL. Importantly, overexpression of DTL in HCT116 cells partially...... is frequently overexpressed in colorectal cancer. Thus, our data suggest that restoring miR-30a-5p function may prove useful as therapeutic strategy for tumors with reduced miR-30a-5p expression....

  3. Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution

    DEFF Research Database (Denmark)

    Pedersen, Line; Idorn, Manja; Olofsson, Gitte H.

    2016-01-01

    Regular exercise reduces the risk of cancer and disease recurrence. Yet the mechanisms behind this protection remain to be elucidated. In this study, tumor-bearing mice randomized to voluntary wheel running showed over 60% reduction in tumor incidence and growth across five different tumor models....... Microarray analysis revealed training-induced upregulation of pathways associated with immune function. NK cell infiltration was significantly increased in tumors from running mice, whereas depletion of NK cells enhanced tumor growth and blunted the beneficial effects of exercise. Mechanistic analyses showed...

  4. Transforming growth factor-β suppresses metastasis in a subset of human colon carcinoma cells

    International Nuclear Information System (INIS)

    Simms, Neka A K; Rajput, Ashwani; Sharratt, Elizabeth A; Ongchin, Melanie; Teggart, Carol A; Wang, Jing; Brattain, Michael G

    2012-01-01

    TGFβ signaling has typically been associated with suppression of tumor initiation while the role it plays in metastasis is generally associated with progression of malignancy. However, we present evidence here for an anti-metastatic role of TGFβ signaling. To test the importance of TGFβ signaling to cell survival and metastasis we compared human colon carcinoma cell lines that are either non-tumorigenic with TGFβ response (FET), or tumorigenic with TGFβ response (FETα) or tumorigenic with abrogated TGFβ response via introduction of dominant negative TGFβRII (FETα/DN) and their ability to metastasize. Metastatic competency was assessed by orthotopic transplantation. Metastatic colony formation was assessed histologically and by imaging. Abrogation of TGFβ signaling through introduction of a dominant negative TGFβ receptor II (TGFβRII) in non-metastatic FETα human colon cancer cells permits metastasis to distal organs, but importantly does not reduce invasive behavior at the primary site. Loss of TGFβ signaling in FETα-DN cells generated enhanced cell survival capabilities in response to cellular stress in vitro. We show that enhanced cellular survival is associated with increased AKT phosphorylation and cytoplasmic expression of inhibitor of apoptosis (IAP) family members (survivin and XIAP) that elicit a cytoprotective effect through inhibition of caspases in response to stress. To confirm that TGFβ signaling is a metastasis suppressor, we rescued TGFβ signaling in CBS metastatic colon cancer cells that had lost TGFβ receptor expression due to epigenetic repression. Restoration of TGFβ signaling resulted in the inhibition of metastatic colony formation in distal organs by these cells. These results indicate that TGFβ signaling has an important role in the suppression of metastatic potential in tumors that have already progressed to the stage of an invasive carcinoma. The observations presented here indicate a metastasis suppressor role for TGF

  5. Autocatalytic caspase-3 driven by human telomerase reverse transcriptase promoter suppresses human ovarian carcinoma growth in vitro and in mice.

    Science.gov (United States)

    Song, Yue; Xia, Zhijun; Shen, Keng; Zhai, Xingyue

    2013-05-01

    To construct recombinant adenoviruses AdHT-rev-casp3 and Ad-rev-casp3, which express autocatalysis caspase-3 driven by human telomerase reverse transcriptase promoter and cytomegalovirus promoter, respectively; and to investigate their antitumor effects on ovarian cancer in vitro and in vivo. Cell viabilities were determined using the cell counting kit 8 and flow cytometry. Reverse transcriptase polymerase chain reaction and immunoblotting assays were used to detect cellular apoptotic activities after treatments. Tumor growth and survival of mice bearing AO cells were studied. AdHT-rev-casp3 significantly suppressed the survival of AO cells in a dose-dependent modality with a viability rate of 60.45% ± 7.8% at an multiplicity of infection (MOI) of 70 and 42.18 ± 5.3% at an MOI of 100, which was somewhat lower than that of the AO cells treated with Ad-rev-casp3 (32.28% ± 5.3% and 21.84% ± 3.4%, respectively). In contrast, AdHT-rev-casp3 induced little human umbilical vein epithelial cell (HUVEC) death with a viability rate of 98.52% ± 6.9% at an MOI of 70, whereas Ad-rev-casp3 induced significant cell death in HUVEC with a viability rate of 27.14% ± 5.4%. Additionally, AdHT-rev-casp3 (MOI = 70) caused significant apoptosis in AO cells with an apoptotic rate of 25.97%, whereas it caused undetectable apoptosis in HUVECs with the rate of only 1.75%. Ad-rev-casp3 (MOI = 70) caused strong apoptosis in both AO and HUVECs, with the rate of 35.82% and 38.12%, respectively. AdHT-rev-casp3 caused markedly higher levels of active caspase-3, causing no detectable active caspase-3 expression in HUVECs. The tumor growth suppression rate of AdHT-rev-casp3 was 54.94%, significantly higher than that of phosphate-buffered saline at the end point of the study. AdHT-rev-casp3 significantly improved the survival of mice receiving intraperitoneal inoculation of AO cells with little liver damage, with the mean survival of 177 ± 12 days. AdHT-rev-casp3 causes effective apoptosis

  6. Sulfur amino acid deficiency upregulates intestinal methionine cycle activity and suppresses epithelial growth in neonatal pigs.

    Science.gov (United States)

    We recently showed that the developing gut is a significant site of methionine transmethylation to homocysteine and transsulfuration to cysteine. We hypothesized that sulfur amino acid (SAA) deficiency would preferentially reduce mucosal growth and antioxidant function in neonatal pigs. Neonatal pi...

  7. Does Prolonged Therapy with a Long-Acting Stimulant Suppress Growth in Children with ADHD?

    Science.gov (United States)

    Spencer, Thomas J.; Faraone, Stephen V.; Biederman, Joseph; Lerner, Marc; Cooper, Kimberly M.; Zimmerman, Brenda

    2006-01-01

    Objective: To investigate whether prolonged therapy with a long-acting stimulant affects growth in children with attention-deficit/hyperactivity disorder (ADHD). Method: One hundred seventy-eight children ages 6 to 13 years received OROS methylphenidate (OROS MPH, CONCERTA) for at least 21 months. Height and weight were measured monthly during the…

  8. THE RED-TIDE DINOFLAGELLATE, ALEXANDRIUM MONILATUM, SUPPRESSES GROWTH OF MIXED NATURAL PHYTOPLANKTON

    Science.gov (United States)

    Alexandrium monilatum is a large, chain-forming, autotrophic dinoflagellate associated with red-tides and fish kills along the US Gulf of Mexico coast. When cultured inocula of A. monilatum were added to nutrient-amended seawater samples, growth rates and biomass yields of the na...

  9. Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation

    International Nuclear Information System (INIS)

    Retamales, A.; Zuloaga, R.; Valenzuela, C.A.; Gallardo-Escarate, C.; Molina, A.; Valdés, J.A.

    2015-01-01

    Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors. - Highlights: • IGF-1 inhibits Myostatin canonical signaling pathway through IGF-1R/PI3K/Akt pathway. • IGF-1 promotes myoblast differentiation through a direct blocking of Myostatin signaling pathway. • IGF-1 induces the interaction of Akt with Smad3 in skeletal myoblast

  10. 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.

  11. Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Retamales, A.; Zuloaga, R.; Valenzuela, C.A. [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Gallardo-Escarate, C. [Laboratory of Biotechnology and Aquatic Genomics, Universidad de Concepción, Concepción (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile); Molina, A. [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile); Valdés, J.A., E-mail: jvaldes@unab.cl [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile)

    2015-08-21

    Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors. - Highlights: • IGF-1 inhibits Myostatin canonical signaling pathway through IGF-1R/PI3K/Akt pathway. • IGF-1 promotes myoblast differentiation through a direct blocking of Myostatin signaling pathway. • IGF-1 induces the interaction of Akt with Smad3 in skeletal myoblast.

  12. Combination of Bifunctional Alkylating Agent and Arsenic Trioxide Synergistically Suppresses the Growth of Drug-Resistant Tumor Cells

    Directory of Open Access Journals (Sweden)

    Pei-Chih Lee

    2010-05-01

    Full Text Available Drug resistance is a crucial factor in the failure of cancer chemotherapy. In this study, we explored the effect of combining alkylating agents and arsenic trioxide (ATO on the suppression of tumor cells with inherited or acquired resistance to therapeutic agents. Our results showed that combining ATO and a synthetic derivative of 3a-aza-cyclopenta[a]indenes (BO-1012, a bifunctional alkylating agent causing DNA interstrand cross-links, was more effective in killing human cancer cell lines (H460, H1299, and PC3 than combining ATO and melphalan or thiotepa. We further demonstrated that the combination treatment of H460 cells with BO-1012 and ATO resulted in severe G2/M arrest and apoptosis. In a xenograft mouse model, the combination treatment with BO-1012 and ATO synergistically reduced tumor volumes in nude mice inoculated with H460 cells. Similarly, the combination of BO-1012 and ATO effectively reduced the growth of cisplatin-resistant NTUB1/P human bladder carcinoma cells. Furthermore, the repair of BO-1012-induced DNA interstrand cross-links was significantly inhibited by ATO, and consequently, γH2AX was remarkably increased and formed nuclear foci in H460 cells treated with this drug combination. In addition, Rad51 was activated by translocating and forming foci in nuclei on treatment with BO-1012, whereas its activation was significantly suppressed by ATO. We further revealed that ATO might mediate through the suppression of AKT activity to inactivate Rad51. Taken together, the present study reveals that a combination of bifunctional alkylating agents and ATO may be a rational strategy for treating cancers with inherited or acquired drug resistance.

  13. 17-AAG suppresses growth and invasion of lung adenocarcinoma cells via regulation of the LATS1/YAP pathway.

    Science.gov (United States)

    Ye, Xiang-Yun; Luo, Qing-Quan; Xu, Yun-Hua; Tang, Nai-Wang; Niu, Xiao-Min; Li, Zi-Ming; Shen, Sheng-Ping; Lu, Shun; Chen, Zhi-Wei

    2015-03-01

    The large tumour suppressor 1 (LATS1) signalling network has been proved to be an essential regulator within the cell, participating in multiple cellular phenotypes. However, it is unclear concerning the clinical significance of LATS1 and the regulatory mechanisms of 17-Allylamino-17- demethoxygeldanamycin (17-AAG) in lung adenocarcinoma (LAC). The aim of the present study was to investigate the correlation of LATS1 and yes-associated protein (YAP) expression with clinicopathological characteristics in LAC patients, and the effects of 17-AAG on biological behaviours of LAC cells. Subcutaneous LAC tumour models were further established to observe the tumour growth in nude mice. The results showed that the positive expression of LATS1 was significantly lowered (26.7% versus 68.0%, P AAG inhibited proliferation and invasion, and induced cell apoptosis and cycle arrest in LAC cells together with increased expression of E-cadherin and p-LATS1, and decreased expression of YAP and connective tissue growth factor. Tumour volumes and weight were much smaller in 17-AAG-treated groups than those in untreated group (P AAG suppresses growth and invasion of LAC cells via regulation of the LATS1/YAP pathway in vitro and in vivo, suggesting that we may provide a promising therapeutic strategy for the treatment of human LAC. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  14. 17-AAG suppresses growth and invasion of lung adenocarcinoma cells via regulation of the LATS1/YAP pathway

    Science.gov (United States)

    Ye, Xiang-Yun; Luo, Qing-Quan; Xu, Yun-Hua; Tang, Nai-Wang; Niu, Xiao-Min; Li, Zi-Ming; Shen, Sheng-Ping; Lu, Shun; Chen, Zhi-Wei

    2015-01-01

    The large tumour suppressor 1 (LATS1) signalling network has been proved to be an essential regulator within the cell, participating in multiple cellular phenotypes. However, it is unclear concerning the clinical significance of LATS1 and the regulatory mechanisms of 17-Allylamino-17- demethoxygeldanamycin (17-AAG) in lung adenocarcinoma (LAC). The aim of the present study was to investigate the correlation of LATS1 and yes-associated protein (YAP) expression with clinicopathological characteristics in LAC patients, and the effects of 17-AAG on biological behaviours of LAC cells. Subcutaneous LAC tumour models were further established to observe the tumour growth in nude mice. The results showed that the positive expression of LATS1 was significantly lowered (26.7% versus 68.0%, P AAG inhibited proliferation and invasion, and induced cell apoptosis and cycle arrest in LAC cells together with increased expression of E-cadherin and p-LATS1, and decreased expression of YAP and connective tissue growth factor. Tumour volumes and weight were much smaller in 17-AAG-treated groups than those in untreated group (P AAG suppresses growth and invasion of LAC cells via regulation of the LATS1/YAP pathway in vitro and in vivo, suggesting that we may provide a promising therapeutic strategy for the treatment of human LAC. PMID:25712415

  15. Suppression of SOX18 by siRNA inhibits cell growth and invasion of breast cancer cells.

    Science.gov (United States)

    Zhang, Jianxiang; Ma, Yanmei; Wang, Shoujun; Chen, Fu; Gu, Yuanting

    2016-06-01

    Breast cancer is the most common malignancy in women around the world, and its incidence and mortality rates are still rising. An increasing number of studies have reported that SOX18 plays an important role in various cancers. However, the role of SOX18 in breast cancer remains poorly understood. In this study, we aimed to investigate the biological role and potential molecular mechanism of SOX18 in breast cancer. We found that the mRNA and protein expression levels of SOX18 were prevalently and significantly overexpressed in human breast cancer cell lines. Next, we performed loss-of-function experiments by transfection of two breast cancer cell lines, BT-474 and MCF-7, with SOX18 small interfering RNAs (siRNA). Results showed that SOX18 siRNA transfection significantly suppressed mRNA and protein expression of SOX18 in breast cancer cells. Furthermore, knockdown of SOX18 significantly inhibited cell proliferation and invasion, but promoted apoptosis in breast cancer cells. Importantly, several oncogenic proteins, including the Ras homolog gene family member A (RhoA), platelet-derived growth factor B (PDGFB), Insulin-like growth factor 1 receptor (IGF-1R), and matrix metalloproteinase-7 (MMP-7), were markedly decreased by SOX18 siRNA. Taken together, the results of our study suggest that knockdown of SOX18 inhibits breast cancer cell growth and invasion, possibly by downregulating downstream oncogenic proteins, providing novel insights into the development of breast cancer therapy through targeting of SOX18.

  16. Melatonin suppresses thyroid cancer growth and overcomes radioresistance via inhibition of p65 phosphorylation and induction of ROS

    Directory of Open Access Journals (Sweden)

    Zhen-Wei Zou

    2018-06-01

    Full Text Available Thyroid cancer is the most common endocrine carcinoma with increasing incidence worldwide and anaplastic subtypes are frequently associated with cancer related death. Radioresistance of thyroid cancer often leads to therapy failure and cancer-related death. In this study, we found that melatonin showed potent suppressive roles on NF-κB signaling via inhibition of p65 phosphorylation and generated redox stress in thyroid cancer including the anaplastic subtypes. Our data showed that melatonin significantly decreased cell viability, suppressed cell migration and induced apoptosis in thyroid cancer cell lines in vitro and impaired tumor growth in the subcutaneous mouse model in vivo. By contrast, irradiation of thyroid cancer cells resulted in elevated level of phosphorylated p65, which could be reversed by cotreatment with melatonin. Consequently, melatonin synergized with irradiation to induce cytotoxicity to thyroid cancer, especially in the undifferentiated subgroups. Taken together, our results suggest that melatonin may exert anti-tumor activities against thyroid carcinoma by inhibition of p65 phosphorylation and induction of reactive oxygen species. Radio-sensitization by melatonin may have clinical benefits in thyroid cancer. Keywords: Melatonin, Thyroid cancer, Radioresistance, p65, Reactive oxygen species

  17. Inhibition of PI3K by ZSTK474 suppressed tumor growth not via apoptosis but G0/G1 arrest

    International Nuclear Information System (INIS)

    Dan, Shingo; Yoshimi, Hisashi; Okamura, Mutsumi; Mukai, Yumiko; Yamori, Takao

    2009-01-01

    Phosphoinositide 3-kinase (PI3K) is a potential target in cancer therapy. Inhibition of PI3K is believed to induce apoptosis. We recently developed a novel PI3K inhibitor ZSTK474 with antitumor efficacy. In this study, we have examined the underlying mode of action by which ZSTK474 exerts its antitumor efficacy. In vivo, ZSTK474 effectively inhibited the growth of human cancer xenografts. In parallel, ZSTK474 treatment suppressed the expression of phospho-Akt, suggesting effective PI3K inhibition, and also suppressed the expression of nuclear cyclin D1 and Ki67, both of which are hallmarks of proliferation. However, ZSTK474 treatment did not increase TUNEL-positive apoptotic cells. In vitro, ZSTK474 induced marked G 0 /G 1 arrest, but did not increase the subdiploid cells or activate caspase, both of which are hallmarks of apoptosis. These results clearly indicated that inhibition of PI3K by ZSTK474 did not induce apoptosis but rather induced strong G 0 /G 1 arrest, which might cause its efficacy in tumor cells.

  18. A novel mouse monoclonal antibody targeting ErbB2 suppresses breast cancer growth

    Energy Technology Data Exchange (ETDEWEB)

    Kawa, Seiji [Division of Oncology, Institute of Medical Science, University of Tokyo, Shirokanedai 4-6-1, Minato-ku, Tokyo 108-8639 (Japan); Matsushita, Hirohisa; Ohbayashi, Hirokazu [Department of Research and Development, Nichirei Biosciences Inc., Tokyo 104-8402 (Japan); Semba, Kentaro [Department of Life Science and Medical Bio-Science, School of Science and Engineering, Waseda University, Tokyo 169-8555 (Japan); Yamamoto, Tadashi, E-mail: tyamamot@ims.u-tokyo.ac.jp [Division of Oncology, Institute of Medical Science, University of Tokyo, Shirokanedai 4-6-1, Minato-ku, Tokyo 108-8639 (Japan)

    2009-07-03

    Overexpression of ErbB2 in breast cancer is associated with increased recurrence and worse prognosis. Accumulating evidences suggest that molecular targeted therapy is a promising anticancer strategy. In this study, we produced a novel anti-ErbB2 monoclonal antibody, 6G10, that recognized an epitope distinct from the trastuzumab binding site. 6G10 induced aggregation of BT474 breast cancer cells and inhibited proliferation of various breast cancer cell lines including BT474. A growth inhibition assay showed that 6G10 had EC{sub 50} values comparable to trastuzumab, indicating that the drugs have a similar level of potency. Furthermore, intraperitoneal administration of 6G10 completely inhibited the growth of xenografted tumors derived from BT474 and SK-BR-3 cells. These data suggested that 6G10 has great therapeutic potential and could be administered to patients alternatively, or synergistically, with trastuzumab.

  19. Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth.

    Science.gov (United States)

    McIntyre, Alan; Hulikova, Alzbeta; Ledaki, Ioanna; Snell, Cameron; Singleton, Dean; Steers, Graham; Seden, Peter; Jones, Dylan; Bridges, Esther; Wigfield, Simon; Li, Ji-Liang; Russell, Angela; Swietach, Pawel; Harris, Adrian L

    2016-07-01

    Tumor hypoxia is associated clinically with therapeutic resistance and poor patient outcomes. One feature of tumor hypoxia is activated expression of carbonic anhydrase IX (CA9), a regulator of pH and tumor growth. In this study, we investigated the hypothesis that impeding the reuptake of bicarbonate produced extracellularly by CA9 could exacerbate the intracellular acidity produced by hypoxic conditions, perhaps compromising cell growth and viability as a result. In 8 of 10 cancer cell lines, we found that hypoxia induced the expression of at least one bicarbonate transporter. The most robust and frequent inductions were of the sodium-driven bicarbonate transporters SLC4A4 and SLC4A9, which rely upon both HIF1α and HIF2α activity for their expression. In cancer cell spheroids, SLC4A4 or SLC4A9 disruption by either genetic or pharmaceutical approaches acidified intracellular pH and reduced cell growth. Furthermore, treatment of spheroids with S0859, a small-molecule inhibitor of sodium-driven bicarbonate transporters, increased apoptosis in the cell lines tested. Finally, RNAi-mediated attenuation of SLC4A9 increased apoptosis in MDA-MB-231 breast cancer spheroids and dramatically reduced growth of MDA-MB-231 breast tumors or U87 gliomas in murine xenografts. Our findings suggest that disrupting pH homeostasis by blocking bicarbonate import might broadly relieve the common resistance of hypoxic tumors to anticancer therapy. Cancer Res; 76(13); 3744-55. ©2016 AACR. ©2016 American Association for Cancer Research.

  20. Suppression of the in vitro growth and development of Microdochium nivale by phosphite

    OpenAIRE

    Dempsey, J.; Wilson, I.; spencer-phillips, P.; Arnold, D.

    2018-01-01

    The ascomycete fungus Microdochium nivale is a major pathogen of many species of the gramineae. Control measures rely heavily on chemical fungicides, making alternative means of disease reduction desirable. Phosphite (PO33-,) has proven efficacy in reducing susceptibility of different species of gramineae to oomycetes, and has adverse effects on the in vitro growth of numerous other pathogens. The effect of phosphorous acid (H3PO3), phosphoric acid (H3PO4), dihydrogen potassium phosphite (KH2...

  1. Nimotuzumab enhances temozolomide?induced growth suppression of glioma cells expressing mutant EGFR in vivo

    OpenAIRE

    Nitta, Yusuke; Shimizu, Saki; Shishido?Hara, Yukiko; Suzuki, Kaori; Shiokawa, Yoshiaki; Nagane, Motoo

    2016-01-01

    Abstract A mutant form of epidermal growth factor receptor (EGFR), EGFRvIII, is common in glioblastoma (GBM) and confers enhanced tumorigenic activity and drug resistance. Nimotuzumab, an anti?EGFR antibody, has shown preclinical and clinical activity to GBM, but its specific activity against EGFRvIII has not been fully investigated. Human glioma U87MG or LNZ308 cells overexpressing either wild?type (wt) EGFR or EGFRvIII were treated with nimotuzumab, temozolomide, or both. Expression and pho...

  2. FOXD3 suppresses tumor growth and angiogenesis in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Yan, Jun-Hai; Zhao, Chun-Liu; Ding, Lan-Bao; Zhou, Xi

    2015-01-01

    The transcription factor forkhead box D3 (FOXD3), widely studied as a transcriptional repressor in embryogenesis, participates in the carcinogenesis of many cancers. However, the expression pattern and role of FOXD3 in non-small cell lung cancer (NSCLC) have not been well characterized. We report that FOXD3 is significantly downregulated in NSCLC cell lines and clinical tissues. FOXD3 overexpression significantly inhibits cell growth and results in G1 cell cycle arrest in NSCLC A549 and H1299 cells. In a xenograft tumor model, FOXD3 overexpression inhibits tumor growth and angiogenesis. Remarkably, expression of vascular endothelial growth factor (VEGF) was reduced in FOXD3 overexpression models both in vitro and in vivo. These findings suggest that FOXD3 plays a potential tumor suppressor role in NSCLC progression and represents a promising clinical prognostic marker and therapeutic target for this disease. - Highlights: • FOXD3 is downregulated in NSCLC cell lines and tissues. • FOXD3 overexpression inhibited cell proliferation in NSCLC cells. • FOXD3 overexpression led to decreased angiogenesis in NSCLC cells in vitro and in vivo.

  3. Suppression of progranulin expression inhibits bladder cancer growth and sensitizes cancer cells to cisplatin.

    Science.gov (United States)

    Buraschi, Simone; Xu, Shi-Qiong; Stefanello, Manuela; Moskalev, Igor; Morcavallo, Alaide; Genua, Marco; Tanimoto, Ryuta; Birbe, Ruth; Peiper, Stephen C; Gomella, Leonard G; Belfiore, Antonino; Black, Peter C; Iozzo, Renato V; Morrione, Andrea

    2016-06-28

    We have recently demonstrated a critical role for progranulin in bladder cancer. Progranulin contributes, as an autocrine growth factor, to the transformed phenotype by modulating Akt-and MAPK-driven motility, invasion and anchorage-independent growth. Progranulin also induces F-actin remodeling by interacting with the F-actin binding protein drebrin. In addition, progranulin is overexpressed in invasive bladder cancer compared to normal tissue controls, suggesting that progranulin might play a key role in driving the transition to the invasive phenotype of urothelial cancer. However, it is not established whether targeting progranulin could have therapeutic effects on bladder cancer. In this study, we stably depleted urothelial cancer cells of endogenous progranulin by shRNA approaches and determined that progranulin depletion severely inhibited the ability of tumorigenic urothelial cancer cells to migrate, invade and grow in anchorage-independency. We further demonstrate that progranulin expression is critical for tumor growth in vivo, in both xenograft and orthotopic tumor models. Notably, progranulin levels correlated with response to cisplatin treatment and were upregulated in bladder tumors. Our data indicate that progranulin may constitute a novel target for therapeutic intervention in bladder tumors. In addition, progranulin may serve as a novel biomarker for bladder cancer.

  4. Inhibition of Stromal PlGF Suppresses the Growth of Prostate Cancer Xenografts

    Directory of Open Access Journals (Sweden)

    Dietmar Abraham

    2013-09-01

    Full Text Available The growth and vascularization of prostate cancer is dependent on interactions between cancer cells and supporting stromal cells. The primary stromal cell type found in prostate tumors is the carcinoma-associated fibroblast, which produces placental growth factor (PlGF. PlGF is a member of the vascular endothelial growth factor (VEGF family of angiogenic molecules and PlGF mRNA levels increase after androgen deprivation therapy in prostate cancer. In this study, we show that PlGF has a direct dose-dependent proliferative effect on human PC-3 prostate cancer cells in vitro and fibroblast-derived PlGF increases PC-3 proliferation in co-culture. In xenograft tumor models, intratumoral administration of murine PlGF siRNA reduced stromal-derived PlGF expression, reduced tumor burden and decreased the number of Ki-67 positive proliferating cells associated with reduced vascular density. These data show that targeting stromal PlGF expression may represent a therapeutic target for the treatment of prostate cancer.

  5. FOXD3 suppresses tumor growth and angiogenesis in non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Jun-Hai; Zhao, Chun-Liu [Department of Respiratory Medicine, Luwan Branch of Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20020 (China); Ding, Lan-Bao [Department of Nuclear Medicine, Shanghai 10th People' s Hospital, Tongji University School of Medicine, Shanghai 200072 (China); Zhou, Xi, E-mail: modelmap@139.com [Department of Respiratory Medicine, Luwan Branch of Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20020 (China)

    2015-10-09

    The transcription factor forkhead box D3 (FOXD3), widely studied as a transcriptional repressor in embryogenesis, participates in the carcinogenesis of many cancers. However, the expression pattern and role of FOXD3 in non-small cell lung cancer (NSCLC) have not been well characterized. We report that FOXD3 is significantly downregulated in NSCLC cell lines and clinical tissues. FOXD3 overexpression significantly inhibits cell growth and results in G1 cell cycle arrest in NSCLC A549 and H1299 cells. In a xenograft tumor model, FOXD3 overexpression inhibits tumor growth and angiogenesis. Remarkably, expression of vascular endothelial growth factor (VEGF) was reduced in FOXD3 overexpression models both in vitro and in vivo. These findings suggest that FOXD3 plays a potential tumor suppressor role in NSCLC progression and represents a promising clinical prognostic marker and therapeutic target for this disease. - Highlights: • FOXD3 is downregulated in NSCLC cell lines and tissues. • FOXD3 overexpression inhibited cell proliferation in NSCLC cells. • FOXD3 overexpression led to decreased angiogenesis in NSCLC cells in vitro and in vivo.

  6. Resveratrol Suppresses Growth and Migration of Myelodysplastic Cells by Inhibiting the Expression of Elevated Cyclin D1 (CCND1).

    Science.gov (United States)

    Zhou, Wei; Xu, Shilin; Ying, Yi; Zhou, Ruiqing; Chen, Xiaowei

    2017-11-01

    Myelodysplastic syndromes (MDS) are a group of heterogeneous diseases characterized by poorly formed blood cells. We wanted to elucidate the underlying molecular mechanism to better determine pathogenesis, prognosis, diagnosis, and treatment for patients with MDS. We compared gene expression levels between normal and MDS tissue samples by immunohistochemical analysis. We studied the proliferation, survival, and migration of MDS cells using the EDU assay, colony formation, and transwell assays. We assessed the apoptotic rate and cell cycle status using flow cytometry and Hoechst staining. Finally, we evaluated RNA and protein expressions using polymerase chain reaction and Western blots, respectively. We found that resveratrol suppressed SKM-1 (an advanced MDS cell line) proliferation in a dose-dependent manner. Consistent with this finding, the EDU and colony formation assays also showed that resveratrol inhibited SKM-1 growth. Moreover, flow cytometry and Hoechst 33258 staining demonstrated that resveratrol induced apoptosis and a change in cell cycle status in SKM-1 cells, while the transwell assay showed that resveratrol reduced the migratory ability of SKM-1 cells. Resveratrol also decreased the expression of CCND1 (a gene that encodes the cyclin D1 protein) and increased expressions of KMT2A [lysine (K)-specific methyltransferase 2A] and caspase-3, suggesting that resveratrol exerts its effect by regulating CCND1 in SKM-1 cells. In addition, a combination of resveratrol and the PI3K/AKT inhibitor LY294002 exhibited a stronger inhibitory effect on the SKM-1 cells, compared with resveratrol alone. Our study proved that resveratrol suppresses SKM-1 growth and migration by inhibiting CCND1 expression. This finding provides novel insights into the pathogenesis of MDS and might help develop new diagnosis and treatment for patients with MDS.

  7. Adeno-associated virus-mediated doxycycline-regulatable TRAIL expression suppresses growth of human breast carcinoma in nude mice

    International Nuclear Information System (INIS)

    Zheng, Liu; Weilun, Zhang; Minghong, Jiang; Yaxi, Zhang; Shilian, Liu; Yanxin, Liu; Dexian, Zheng

    2012-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) functions as a cytokine to selectively kill various cancer cells without toxicity to most normal cells. Numerous studies have demonstrated the potential use of recombinant soluble TRAIL as a cancer therapeutic agent. We have showed previous administration of a recombinant adeno-associated virus (rAAV) vector expressing soluble TRAIL results in an efficient suppression of human tumor growth in nude mice. In the present study, we introduced Tet-On gene expression system into the rAAV vector to control the soluble TRAIL expression and evaluate the efficiency of the system in cancer gene therapy. Controllability of the Tet-On system was determined by luciferase activity assay, and Western blotting and enzyme-linked immunoabsorbent assay. Cell viability was determined by MTT assay. The breast cancer xenograft animal model was established and recombinant virus was administrated through tail vein injection to evaluate the tumoricidal activity. The expression of soluble TRAIL could be strictly controlled by the Tet-On system in both normal and cancer cells. Transduction of human cancer cell lines with rAAV-TRE-TRAIL&rAAV-Tet-On under the presence of inducer doxycycline resulted in a considerable cell death by apoptosis. Intravenous injection of the recombinant virus efficiently suppressed the growth of human breast carcinoma in nude mice when activated by doxycycline. These data suggest that rAAV-mediated soluble TRAIL expression under the control of the Tet-On system is a promising strategy for breast cancer therapy

  8. Adeno-associated virus-mediated doxycycline-regulatable TRAIL expression suppresses growth of human breast carcinoma in nude mice

    Directory of Open Access Journals (Sweden)

    Zheng Liu

    2012-04-01

    Full Text Available Abstract Background Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL functions as a cytokine to selectively kill various cancer cells without toxicity to most normal cells. Numerous studies have demonstrated the potential use of recombinant soluble TRAIL as a cancer therapeutic agent. We have showed previous administration of a recombinant adeno-associated virus (rAAV vector expressing soluble TRAIL results in an efficient suppression of human tumor growth in nude mice. In the present study, we introduced Tet-On gene expression system into the rAAV vector to control the soluble TRAIL expression and evaluate the efficiency of the system in cancer gene therapy. Methods Controllability of the Tet-On system was determined by luciferase activity assay, and Western blotting and enzyme-linked immunoabsorbent assay. Cell viability was determined by MTT assay. The breast cancer xenograft animal model was established and recombinant virus was administrated through tail vein injection to evaluate the tumoricidal activity. Results The expression of soluble TRAIL could be strictly controlled by the Tet-On system in both normal and cancer cells. Transduction of human cancer cell lines with rAAV-TRE-TRAIL&rAAV-Tet-On under the presence of inducer doxycycline resulted in a considerable cell death by apoptosis. Intravenous injection of the recombinant virus efficiently suppressed the growth of human breast carcinoma in nude mice when activated by doxycycline. Conclusion These data suggest that rAAV-mediated soluble TRAIL expression under the control of the Tet-On system is a promising strategy for breast cancer therapy.

  9. Suppression of tumor growth and angiogenesis by a specific antagonist of the cell-surface expressed nucleolin.

    Directory of Open Access Journals (Sweden)

    Damien Destouches

    Full Text Available BACKGROUND: Emerging evidences suggest that nucleolin expressed on the cell surface is implicated in growth of tumor cells and angiogenesis. Nucleolin is one of the major proteins of the nucleolus, but it is also expressed on the cell surface where is serves as a binding protein for variety of ligands implicated in cell proliferation, differentiation, adhesion, mitogenesis and angiogenesis. METHODOLOGY/PRINCIPAL FINDINGS: By using a specific antagonist that binds the C-terminal tail of nucleolin, the HB-19 pseudopeptide, here we show that the growth of tumor cells and angiogenesis are suppressed in various in vitro and in vivo experimental models. HB-19 inhibited colony formation in soft agar of tumor cell lines, impaired migration of endothelial cells and formation of capillary-like structures in collagen gel, and reduced blood vessel branching in the chick embryo chorioallantoic membrane. In athymic nude mice, HB-19 treatment markedly suppressed the progression of established human breast tumor cell xenografts in nude mice, and in some cases eliminated measurable tumors while displaying no toxicity to normal tissue. This potent antitumoral effect is attributed to the direct inhibitory action of HB-19 on both tumor and endothelial cells by blocking and down regulating surface nucleolin, but without any apparent effect on nucleolar nucleolin. CONCLUSION/SIGNIFICANCE: Our results illustrate the dual inhibitory action of HB-19 on the tumor development and the neovascularization process, thus validating the cell-surface expressed nucleolin as a strategic target for an effective cancer drug. Consequently, the HB-19 pseudopeptide provides a unique candidate to consider for innovative cancer therapy.

  10. Herbal Extract SH003 Suppresses Tumor Growth and Metastasis of MDA-MB-231 Breast Cancer Cells by Inhibiting STAT3-IL-6 Signaling

    Directory of Open Access Journals (Sweden)

    Youn Kyung Choi

    2014-01-01

    Full Text Available Cancer inflammation promotes cancer progression, resulting in a high risk of cancer. Here, we demonstrate that our new herbal extract, SH003, suppresses both tumor growth and metastasis of MDA-MB-231 breast cancer cells via inhibiting STAT3-IL-6 signaling path. Our new herbal formula, SH003, mixed extract from Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, suppressed MDA-MB-231 tumor growth and lung metastasis in vivo and reduced the viability and metastatic abilities of MDA-MB-231 cells in vitro. Furthermore, SH003 inhibited STAT3 activation, which resulted in a reduction of IL-6 production. Therefore, we conclude that SH003 suppresses highly metastatic breast cancer growth and metastasis by inhibiting STAT3-IL-6 signaling path.

  11. A local anesthetic, ropivacaine, suppresses activated microglia via a nerve growth factor-dependent mechanism and astrocytes via a nerve growth factor-independent mechanism in neuropathic pain

    Directory of Open Access Journals (Sweden)

    Sakamoto Atsuhiro

    2011-01-01

    Full Text Available Abstract Background Local anesthetics alleviate neuropathic pain in some cases in clinical practice, and exhibit longer durations of action than those predicted on the basis of the pharmacokinetics of their blocking effects on voltage-dependent sodium channels. Therefore, local anesthetics may contribute to additional mechanisms for reversal of the sensitization of nociceptive pathways that occurs in the neuropathic pain state. In recent years, spinal glial cells, microglia and astrocytes, have been shown to play critical roles in neuropathic pain, but their participation in the analgesic effects of local anesthetics remains largely unknown. Results Repetitive epidural administration of ropivacaine reduced the hyperalgesia induced by chronic constrictive injury of the sciatic nerve. Concomitantly with this analgesia, ropivacaine suppressed the increases in the immunoreactivities of CD11b and glial fibrillary acidic protein in the dorsal spinal cord, as markers of activated microglia and astrocytes, respectively. In addition, epidural administration of a TrkA-IgG fusion protein that blocks the action of nerve growth factor (NGF, which was upregulated by ropivacaine in the dorsal root ganglion, prevented the inhibitory effect of ropivacaine on microglia, but not astrocytes. The blockade of NGF action also abolished the analgesic effect of ropivacaine on neuropathic pain. Conclusions Ropivacaine provides prolonged analgesia possibly by suppressing microglial activation in an NGF-dependent manner and astrocyte activation in an NGF-independent manner in the dorsal spinal cord. Local anesthetics, including ropivacaine, may represent a new approach for glial cell inhibition and, therefore, therapeutic strategies for neuropathic pain.

  12. SKLB188 inhibits the growth of head and neck squamous cell carcinoma by suppressing EGFR signalling.

    Science.gov (United States)

    Barzegar, Mansoureh; Ma, Shuang; Zhang, Chao; Chen, Xin; Gu, Ying; Shang, Chaowei; Jiang, Xiaojuan; Yang, Jiao; Nathan, Cherie-Ann; Yang, Shengyong; Huang, Shile

    2017-10-10

    Overexpression of epidermal growth factor receptor (EGFR) occurs in approximately 90% of head and neck squamous cell carcinoma (HNSCC), and is correlated with poor prognosis. Thus, targeting EGFR is a promising strategy for treatment of HNSCC. Several small molecule EGFR inhibitors have been tested in clinical trials for treatment of HNSCC, but none of them are more effective than the current chemotherapeutic drugs. Thus, it is urgently needed to develop novel EGFR inhibitors for HNSCC treatment. By screening an in-house focused library containing approximately 650 000 known kinase inhibitors and kinase inhibitor-like compounds containing common kinase inhibitor core scaffolds, we identified SKLB188 as a lead compound for inhibition of EGFR. The anticancer effects of SKLB188 on HNSCC cells were investigated by in vitro cell growth, cell cycle and apoptosis assays, as well as in vivo FaDu xenograft mouse model. Molecular docking, in vitro kinase profiling and western blotting were performed to characterise EGFR as the molecular target. SKLB188 inhibited HNSCC cell proliferation by inducing G 1 cell cycle arrest, which was associated with downregulating the expression of Cdc25A, cyclins D1/A and cyclin-dependent kinases (CDK2/4), and upregulating the expression of cyclin-dependent kinase (CDK) inhibitors (p21 Cip1 and p27 Kip1 ), leading to decreased phosphorylation of Rb. SKLB188 also induced caspase-dependent apoptosis of HNSCC cells by downregulating the expression of Mcl-1 and survivin. Molecular docking revealed that SKLB188 could bind to the kinase domain of EGFR through hydrogen bonds and hydrophobic interactions. In vitro kinase assay showed that SKLB188 inhibited the activity of a recombinant human EGFR very potently (IC 50 =5 nM). Western blot analysis demonstrated that SKLB188 inhibited the phosphorylation of EGFR and its downstream targets, extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and Akt in the cells. In addition, SKLB188 dose

  13. Cooperative Testing of Uncontrollable Timed Systems

    DEFF Research Database (Denmark)

    David, Alexandre; Larsen, Kim Guldstrand; Li, Shuhao

    2008-01-01

    the SUT against the test purpose as long as the SUT reacts to our moves in a cooperative style. We present an operational framework of cooperative winning strategy generation, test case derivation and execution. The test method is proved to be sound and complete. Preliminary experimental results indicate......Abstract. This paper deals with targeted testing of timed systems with uncontrollable behavior. The testing activity is viewed as a game between the tester and the system under test (SUT) towards a given test purpose. The SUT is modeled as Timed Game Automaton and the test purpose is specified...... in Timed CTL formula. We can employ a timed game solver UPPAAL-TIGA to check if the test purpose is ture w.r.t. the model, and if yes, to generate a winning strategy and use it for black-box conformance testing. Specifically, we show that in case the checking yields a negative result, we can still test...

  14. Lemur Tyrosine Kinase-3 Suppresses Growth of Prostate Cancer Via the AKT and MAPK Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Pengcheng Sun

    2017-08-01

    Full Text Available Background/Aims: Lemur tyrosine kinase (LMTK-3 is a member of the receptor tyrosine kinase (RTK family. Abnormal expression of LMTK-3 exists in various types of cancers, especially in endocrine-resistant breast cancers; however, the precise level of expression and the biological function in prostate cancer are poorly understood. Methods: In the present study, we determined the expression of LMTK-3 in prostate cancer using immunohistochemistry and Western blotting. We infected PC3 and LNCaP cells with lentivirus-LMTK-3 and observed the biologic characteristics of the PC3 and LNCaP cells in vitro with TUNEL, and migration and invasion assays, respectively. We also established a transplant tumor model of human prostate cancer with infected cells in 15 BALB/c-nu/nu nude mice. Results: LMTK-3 was expressed in prostate epithelial cells. There was a significant decline in the level of LMTK-3 expression in prostate cancers compared to normal tissues. LMTK-3 inhibited PC3 and LNCaP cell growth, migration, and invasion, and induced cell apoptosis in vitro. We also observed that LMTK-3 induced PC3 cell apoptosis in vivo. Further study showed that LMTK-3 inhibited phosphorylation of AKT and ERK, and promoted phosphorylation and activation of p38 kinase and Jun kinase (JNK. Conclusion: Recombinant lentivirus with enhanced expression of LMTK-3 inhibited prostate cancer cell growth and induced apoptosis in vitro and in vivo. AKT and MAPK signaling pathways may contribute to the process.

  15. Suppression of Peroxiredoxin 4 in Glioblastoma Cells Increases Apoptosis and Reduces Tumor Growth

    Science.gov (United States)

    Kim, Tae Hyong; Song, Jieun; Alcantara Llaguno, Sheila R.; Murnan, Eric; Liyanarachchi, Sandya; Palanichamy, Kamalakannan; Yi, Ji-Yeun; Viapiano, Mariano Sebastian; Nakano, Ichiro; Yoon, Sung Ok; Wu, Hong; Parada, Luis F.; Kwon, Chang-Hyuk

    2012-01-01

    Glioblastoma multiforme (GBM), the most common and aggressive primary brain malignancy, is incurable despite the best combination of current cancer therapies. For the development of more effective therapies, discovery of novel candidate tumor drivers is urgently needed. Here, we report that peroxiredoxin 4 (PRDX4) is a putative tumor driver. PRDX4 levels were highly increased in a majority of human GBMs as well as in a mouse model of GBM. Reducing PRDX4 expression significantly decreased GBM cell growth and radiation resistance in vitro with increased levels of ROS, DNA damage, and apoptosis. In a syngenic orthotopic transplantation model, Prdx4 knockdown limited GBM infiltration and significantly prolonged mouse survival. These data suggest that PRDX4 can be a novel target for GBM therapies in the future. PMID:22916164

  16. Suppression of peroxiredoxin 4 in glioblastoma cells increases apoptosis and reduces tumor growth.

    Directory of Open Access Journals (Sweden)

    Tae Hyong Kim

    Full Text Available Glioblastoma multiforme (GBM, the most common and aggressive primary brain malignancy, is incurable despite the best combination of current cancer therapies. For the development of more effective therapies, discovery of novel candidate tumor drivers is urgently needed. Here, we report that peroxiredoxin 4 (PRDX4 is a putative tumor driver. PRDX4 levels were highly increased in a majority of human GBMs as well as in a mouse model of GBM. Reducing PRDX4 expression significantly decreased GBM cell growth and radiation resistance in vitro with increased levels of ROS, DNA damage, and apoptosis. In a syngenic orthotopic transplantation model, Prdx4 knockdown limited GBM infiltration and significantly prolonged mouse survival. These data suggest that PRDX4 can be a novel target for GBM therapies in the future.

  17. FOXO/TXNIP pathway is involved in the suppression of hepatocellular carcinoma growth by glutamate antagonist MK-801

    International Nuclear Information System (INIS)

    Yamaguchi, Fuminori; Hirata, Yuko; Akram, Hossain; Kamitori, Kazuyo; Dong, Youyi; Sui, Li; Tokuda, Masaaki

    2013-01-01

    Accumulating evidence has suggested the importance of glutamate signaling in cancer growth, yet the signaling pathway has not been fully elucidated. N-methyl-D-aspartic acid (NMDA) receptor activates intracellular signaling pathways such as the extracellular-signal-regulated kinase (ERK) and forkhead box, class O (FOXO). Suppression of lung carcinoma growth by NMDA receptor antagonists via the ERK pathway has been reported. However, series of evidences suggested the importance of FOXO pathways for the regulation of normal and cancer cell growth. In the liver, FOXO1 play important roles for the cell proliferation such as hepatic stellate cells as well as liver metabolism. Our aim was to investigate the involvement of the FOXO pathway and the target genes in the growth inhibitory effects of NMDA receptor antagonist MK-801 in human hepatocellular carcinoma. Expression of NMDAR1 in cancer cell lines from different tissues was examined by Western blot. NMDA receptor subunits in HepG2, HuH-7, and HLF were examined by reverse transcriptase polymerase chain reaction (RT-PCR), and growth inhibition by MK-801 and NBQX was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of MK-801 on the cell cycle were examined by flow cytometry and Western blot analysis. Expression of thioredoxin-interacting protein (TXNIP) and p27 was determined by real-time PCR and Western blotting. Activation of the FOXO pathway and TXNIP induction were examined by Western blotting, fluorescence microscopy, Chromatin immunoprecipitation (ChIP) assay, and reporter gene assay. The effects of TXNIP on growth inhibition were examined using the gene silencing technique. NMDA receptor subunits were expressed in all cell lines examined, and MK-801, but not NBQX, inhibited cell growth of hepatocellular carcinomas. Cell cycle analysis showed that MK-801 induced G1 cell cycle arrest by down-regulating cyclin D1 and up-regulating p27. MK-801 dephosphorylated

  18. FOXO/TXNIP pathway is involved in the suppression of hepatocellular carcinoma growth by glutamate antagonist MK-801

    Science.gov (United States)

    2013-01-01

    Background Accumulating evidence has suggested the importance of glutamate signaling in cancer growth, yet the signaling pathway has not been fully elucidated. N-methyl-D-aspartic acid (NMDA) receptor activates intracellular signaling pathways such as the extracellular-signal-regulated kinase (ERK) and forkhead box, class O (FOXO). Suppression of lung carcinoma growth by NMDA receptor antagonists via the ERK pathway has been reported. However, series of evidences suggested the importance of FOXO pathways for the regulation of normal and cancer cell growth. In the liver, FOXO1 play important roles for the cell proliferation such as hepatic stellate cells as well as liver metabolism. Our aim was to investigate the involvement of the FOXO pathway and the target genes in the growth inhibitory effects of NMDA receptor antagonist MK-801 in human hepatocellular carcinoma. Methods Expression of NMDAR1 in cancer cell lines from different tissues was examined by Western blot. NMDA receptor subunits in HepG2, HuH-7, and HLF were examined by reverse transcriptase polymerase chain reaction (RT-PCR), and growth inhibition by MK-801 and NBQX was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of MK-801 on the cell cycle were examined by flow cytometry and Western blot analysis. Expression of thioredoxin-interacting protein (TXNIP) and p27 was determined by real-time PCR and Western blotting. Activation of the FOXO pathway and TXNIP induction were examined by Western blotting, fluorescence microscopy, Chromatin immunoprecipitation (ChIP) assay, and reporter gene assay. The effects of TXNIP on growth inhibition were examined using the gene silencing technique. Results NMDA receptor subunits were expressed in all cell lines examined, and MK-801, but not NBQX, inhibited cell growth of hepatocellular carcinomas. Cell cycle analysis showed that MK-801 induced G1 cell cycle arrest by down-regulating cyclin D1 and up-regulating p

  19. Identification and characterization of MEL-3, a novel AR antagonist that suppresses prostate cancer cell growth.

    Science.gov (United States)

    Helsen, Christine; Marchand, Arnaud; Chaltin, Patrick; Munck, Sebastian; Voet, Arnout; Verstuyf, Annemieke; Claessens, Frank

    2012-06-01

    Antiandrogens are an important component of prostate cancer therapy as the androgen receptor (AR) is the key regulator of prostate cancer growth and survival. Current AR antagonists, such as bicalutamide and hydroxyflutamide, have a low affinity for the AR and as a result block AR signaling insufficiently. Moreover, many patients develop a resistance for bicalutamide or hydroxyflutamide during therapy or show a clinical improvement after withdrawal of the antiandrogen. New and more effective AR antagonists are needed to ensure follow-up of these patients. We therefore developed a screening system to identify novel AR antagonists from a collection of compounds. MEL-3 [8-(propan-2-yl)-5,6-dihydro-4H-pyrazino[3,2,1-jk]carbazole] was selected as potent inhibitor of the AR and was further characterized in vitro. On different prostate cancer cell lines MEL-3 displayed an improved therapeutic profile compared with bicalutamide. Not only cell growth was inhibited but also the expression of androgen-regulated genes: PSA and FKBP5. Prostate cancer is often associated with mutated ARs that respond to a broadened spectrum of ligands including the current antiandrogens used in the clinic, hydroxyflutamide and bicalutamide. The activity of two mutant receptors (AR T877A and AR W741C) was shown to be reduced in presence of MEL-3, providing evidence that MEL-3 can potentially be a follow-up treatment for bicalutamide- and hydroxyflutamide-resistant patients. The mechanism of action of MEL-3 on the molecular level was further explored by comparing the structure-activity relationship of different chemical derivatives of MEL-3 with the in silico docking of MEL-3 derivatives in the binding pocket of the AR. ©2012 AACR

  20. TOFA suppresses ovarian cancer cell growth in vitro and in vivo.

    Science.gov (United States)

    Li, Shu; Qiu, Lihua; Wu, Buchu; Shen, Haoran; Zhu, Jing; Zhou, Liang; Gu, Liying; Di, Wen

    2013-08-01

    A characteristic feature of cancer cells is the activation of de novo fatty acid synthesis. Acetyl‑CoA carboxylase (ACC) is a key enzyme in fatty acid synthesis, accelerating the reaction that carboxylates cytosolic acetyl‑CoA to form malonyl‑CoA. ACC is highly expressed in several types of human cancer and is important in breast and prostate cancer cell growth. The aim of the present study was to investigate the effects of 5‑tetradecyloxy‑2‑furoic acid (TOFA), an allosteric inhibitor of ACC, on the proliferation and cell cycle progression of the ovarian cancer cell lines COC1 and COC1/DDP. TOFA was found to be cytotoxic to COC1 and COC1/DDP cells with a 50% inhibitory concentration (IC50) of ~26.1 and 11.6 µg/ml, respectively. TOFA inhibited the proliferation of the cancer cells examined in a time‑ and dose‑dependent manner, arrested the cells in the G0/G1 cell cycle phase and induced apoptosis. The expression of the cell cycle regulating proteins cyclin D1 and cyclin-dependent kinase (CDK) 4, as well as the expression of the apoptosis‑related proteins caspase‑3 and Bcl‑2, were detected by western blot analysis. Cyclin D1, CDK4 and Bcl‑2 protein expression was inhibited by TOFA, while caspase‑3 was cleaved and activated. To the best of our knowledge, the present study demonstrated for the first time that TOFA inhibits COC1/DDP cell growth in ovarian tumor mouse xenografts. By inhibiting ACC, TOFA may be a promising small molecule agent for ovarian cancer therapy.

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

    Directory of Open Access Journals (Sweden)

    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.

  2. 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

  3. The selective external carotid arterial embolization treatment of uncontrollable epistaxis

    International Nuclear Information System (INIS)

    Yao Qunli; Liu Yizhi; Ni Caifang

    2004-01-01

    Objective: To evaluate the selective external carotid arterial embolization of uncontrollable epistaxis. Methods: 27 procedures of super-selective external carotid arterial embolization were performed with absorbable gelfoam by using Seldinger's method in 26 cases with uncontrollable epistaxis. Results: 27 procedures of super-selective intra-arterial embolization of uncontrollable epistaxis were all successful without any serious complication. Conclusions: Selective external carotid arterial embolization is safe, effective and successful in the treatment of severe epistaxis. (authors)

  4. Processes on Uncontrolled Aerodromes and Safety Indicators - Part II

    Directory of Open Access Journals (Sweden)

    Vladimír Plos

    2014-01-01

    Full Text Available This article follows on the Part I, where the basic processes on uncontrolled aerodromes were introduced. The uncontrolled aerodromes face with the growing traffic and from that result the higher workload on AFIS officer. This means a higher potential for dangerous situations.The article describes some models of sub-processes and creates several safety indicators related to the operation at uncontrolled aerodromes. Thanks to monitoring and evaluation of safety indicators can be adopted targeted safety measures and thus increase safety on small uncontrolled aerodromes.

  5. Tubulin binding cofactor C (TBCC) suppresses tumor growth and enhances chemosensitivity in human breast cancer cells

    International Nuclear Information System (INIS)

    Hage-Sleiman, Rouba; Herveau, Stéphanie; Matera, Eva-Laure; Laurier, Jean-Fabien; Dumontet, Charles

    2010-01-01

    Microtubules are considered major therapeutic targets in patients with breast cancer. In spite of their essential role in biological functions including cell motility, cell division and intracellular transport, microtubules have not yet been considered as critical actors influencing tumor cell aggressivity. To evaluate the impact of microtubule mass and dynamics on the phenotype and sensitivity of breast cancer cells, we have targeted tubulin binding cofactor C (TBCC), a crucial protein for the proper folding of α and β tubulins into polymerization-competent tubulin heterodimers. We developed variants of human breast cancer cells with increased content of TBCC. Analysis of proliferation, cell cycle distribution and mitotic durations were assayed to investigate the influence of TBCC on the cell phenotype. In vivo growth of tumors was monitored in mice xenografted with breast cancer cells. The microtubule dynamics and the different fractions of tubulins were studied by time-lapse microscopy and lysate fractionation, respectively. In vitro sensitivity to antimicrotubule agents was studied by flow cytometry. In vivo chemosensitivity was assayed by treatment of mice implanted with tumor cells. TBCC overexpression influenced tubulin fraction distribution, with higher content of nonpolymerizable tubulins and lower content of polymerizable dimers and microtubules. Microtubule dynamicity was reduced in cells overexpressing TBCC. Cell cycle distribution was altered in cells containing larger amounts of TBCC with higher percentage of cells in G2-M phase and lower percentage in S-phase, along with slower passage into mitosis. While increased content of TBCC had little effect on cell proliferation in vitro, we observed a significant delay in tumor growth with respect to controls when TBCC overexpressing cells were implanted as xenografts in vivo. TBCC overexpressing variants displayed enhanced sensitivity to antimicrotubule agents both in vitro and in xenografts. These

  6. Growth Promotion and Disease Suppression Ability of a Streptomyces sp. CB-75 from Banana Rhizosphere Soil

    Science.gov (United States)

    Chen, Yufeng; Zhou, Dengbo; Qi, Dengfeng; Gao, Zhufen; Xie, Jianghui; Luo, Yanping

    2018-01-01

    An actinomycete strain, CB-75, was isolated from the soil of a diseased banana plantation in Hainan, China. Based on phenotypic and molecular characteristics, and 99.93% sequence similarity with Streptomyces spectabilis NBRC 13424 (AB184393), the strain was identified as Streptomyces sp. This strain exhibited broad-spectrum antifungal activity against 11 plant pathogenic fungi. Type I polyketide synthase (PKS-I) and non-ribosomal peptide synthetase (NRPS) were detected, which were indicative of the antifungal compounds that Streptomyces sp. CB-75 could produce. An ethyl acetate extract from the strain exhibited the lowest minimum inhibitory concentration (MIC) against Colletotrichum musae (ATCC 96167) (0.78 μg/ml) and yielded the highest antifungal activity against Colletotrichum gloeosporioides (ATCC 16330) (50.0 μg/ml). Also, spore germination was significantly inhibited by the crude extract. After treatment with the crude extract of Streptomyces sp. CB-75 at the concentration 2 × MIC, the pathogenic fungi showed deformation, shrinkage, collapse, and tortuosity when observed by scanning electron microscopy (SEM). By gas chromatography-mass spectrometry (GC-MS) of the crude extract, 18 chemical constituents were identified; (Z)-13-docosenamide was the major constituent. Pot experiments showed that the incidence of banana seedlings was reduced after using Streptomyces sp. CB-75 treatment. The disease index was 10.23, and the prevention and control effect was 83.12%. Furthermore, Streptomyces sp. CB-75 had a growth-promoting effect on banana plants. The chlorophyll content showed 88.24% improvement, the leaf area, root length, root diameter, plant height, and stem showed 88.24, 90.49, 136.17, 61.78, and 50.98% improvement, respectively, and the shoot fresh weight, root fresh weight, shoot dry weight, and root dry weight showed 82.38, 72.01, 195.33, and 113.33% improvement, respectively, compared with treatment of fermentation broth without Streptomyces sp. CB-75

  7. Andrographolide Suppress Tumor Growth by Inhibiting TLR4/NF-κB Signaling Activation in Insulinoma

    Science.gov (United States)

    Zhang, Qian-Qian; Ding, Yi; Lei, Yan; Qi, Cui-Ling; He, Xiao-Dong; Lan, Tian; Li, Jiang-Chao; Gong, Ping; Yang, Xuesong; Geng, Jian-Guo; Wang, Li-Jing

    2014-01-01

    Insulinomas are rare tumors, and approximately 10% of insulinomas are malignant. Accumulating evidence has implicated that we still lack effective therapy to treat the patients who are diagnosed with rare malignant insulinoma. Previous studies have reported that Andrographolide (Andro) could inhibit cell cycle progression, reduce cell invasion and induce cell apoptosis in many common cancer cells. However, the effects of andro are cell type-dependent. So we emplored the β-TC-6 cells and the RIP1-Tag2 transgenic mouse model of endogenously growing insulinoma model to elucidate the possible anti-cancer effect of Andro on insulinoma, an uncommon type of malignant cancers in this study. Our experiments revealed that Andro significantly inhibited tumor growth at both the early-stage and the advanced-stage of insulinoma through targeting the TLR4/NF-κB signaling pathway. This work initially provides the evidence that the TLR4/NF-κB signaling pathway might be vital as a potential therapeutic target, and also indispensable in Andro-mediated anti-cancer effect in insulinoma. PMID:24719558

  8. Suppression of vascular endothelial growth factor expression by cannabinoids in a canine osteosarcoma cell line

    Directory of Open Access Journals (Sweden)

    Figueiredo AS

    2013-07-01

    Full Text Available Andreza S Figueiredo,1 Hiram J García-Crescioni,1 Sandra C Bulla,1 Matthew K Ross,2 Chelsea McIntosh,1 Kari Lunsford,3 Camilo Bulla11Department of Pathobiology and Population Medicine, 2Department of Basic Sciences, 3Department of Clinical Sciences and Animal Health Center, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USAAbstract: Vascular endothelial growth factor (VEGF is a key regulator in both physiologic and pathologic angiogenesis, and cannabinoids decrease VEGF release in human and murine cancer cells. The aim of this study was to assess the in vitro effects of a synthetic cannabinoid, WIN-55,212-2, on the expression of the proangiogenic factor VEGF-A in the canine osteosarcoma cell line 8. After analysis of gene expression by quantitative real-time polymerase chain reaction, the compound decreased VEGF-A expression by 35% ± 10% (P < 0.0001 as compared with the control. This synthetic cannabinoid shows promise as a potential inhibitor of angiogenesis, and further studies are warranted to investigate its in vivo effects and to explore the potential of this and related compounds as adjuvant cancer therapy in the dog.Keywords: dog, cancer, angiogenesis, cannabinoids

  9. Camptothecin disrupts androgen receptor signaling and suppresses prostate cancer cell growth

    International Nuclear Information System (INIS)

    Liu, Shicheng; Yuan, Yiming; Okumura, Yutaka; Shinkai, Norihiro; Yamauchi, Hitoshi

    2010-01-01

    The androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers. The present study demonstrates that the topoisomerase I inhibitor camptothecin selectively inhibits androgen-responsive growth of prostate cancer cells. Camptothecin strikingly inhibited mutated and wild-type AR protein expression in LNCaP and PC-3/AR cells. This inhibition coincided with decreased androgen-mediated AR phosphorylation at Ser 81 and reduced androgen-mediated AR transcriptional activity in a dose-dependent manner. Additionally, camptothecin disrupted the association between AR and heat shock protein 90 and impeded binding of the synthetic androgen [ 3 H]R1881 to AR in LNCaP cells. Camptothecin also blocked androgen-induced AR nuclear translocation, leading to downregulation of the AR target gene PSA. In addition to decreasing the intracellular and secreted prostate-specific antigen (PSA) levels, camptothecin markedly inhibited androgen-stimulated PSA promoter activity. Collectively, our data reveal that camptothecin not only serves as a traditional genotoxic agent but, by virtue of its ability to target and disrupt AR, may also be a novel candidate for the treatment of prostate cancer.

  10. A morel improved growth and suppressed Fusarium infection in sweet corn.

    Science.gov (United States)

    Yu, Dan; Bu, Fangfang; Hou, Jiaojiao; Kang, Yongxiang; Yu, Zhongdong

    2016-12-01

    A post-fire morel collected from Populus simonii stands in Mt. Qingling was identified as Morchella crassipes Mes-20 by using nuclear ribosomal DNA internal transcribed spacer phylogeny. It was inoculated into sweet corn to observe colonized roots in purified culture and in greenhouse experiments. The elongation and maturation zones of sweet corn were remarkably colonized at the cortex intercellular and intracellular cells, vessel cells, and around the Casparian strip, forming ectendomycorrhiza-like structures. Colonization was also observed in the zone of cell division proximal to the root cap. Greenhouse assays with sweet corn showed that this morel stimulated the development of the root system and significantly increased the dry root biomass. M. crassipes also significantly reduced the incidence of Fusarium verticillioides in the kernels of mature ears when inoculated into young ears before Fusarium inoculation and prevented Fusarium infection in corn ears compared with that of the control in the greenhouse. When grown under axenic conditions, M. crassipes produced the phytohormones abscisic acid, indole-3-acetic acid, and salicylic acid. The benefits to plants elicited by M. crassipes may result from these phytohormones which may improve the drought resistance, biomass growth and resistance to Fusarium.

  11. Manic fringe inhibits tumor growth by suppressing Notch3 degradation in lung cancer.

    Science.gov (United States)

    Yi, Fuming; Amarasinghe, Baru; Dang, Thao P

    2013-01-01

    Notch signaling plays an essential role in development as well as cancer. We have previously shown that Notch3 is important for lung cancer growth and survival. Notch receptors are activated through the interaction with their ligands, resulting in proteolytic cleavage of the receptors. This interaction is modulated by Fringe, a family of fucose-specific β1,3 N-acetylglucosaminyltransferases that modify the extracellular subunit of Notch receptors. Studies in developmental models showed that Fringe enhances Notch's response to Delta ligands at the expense of Jagged ligands. We observed that Manic Fringe expression is down-regulated in lung cancer. Since Jagged1, a known ligand for Notch3, is often over-expressed in lung cancer, we hypothesized that Fringe negatively regulates Notch3 activation. In this study, we show that re-expression of Manic Fringe down-regulates Notch3 target genes HES1 and HeyL and reduces tumor phenotype in vitro and in vivo. The mechanism for this phenomenon appears to be related to modulation of Notch3 protein stability. Proteasome inhibition reverses Manic Fringe-induced protein turnover. Taken together, our data provide the first evidence that Manic Fringe functions as a tumor suppressor in the lung and that the mechanism of its anti-tumor activity is mediated by inhibition of Notch3 activation.

  12. Growth suppression of MCF-7 cancer cell-derived xenografts in nude mice by caveolin-1

    International Nuclear Information System (INIS)

    Wu Ping; Wang Xiaohui; Li Fei; Qi Baoju; Zhu Hua; Liu Shuang; Cui Yeqing; Chen Jianwen

    2008-01-01

    Caveolin-1 is an essential structural constituent of caveolae membrane domains that has been implicated in mitogenic signaling and oncogenesis. However, the exact functional role of caveolin-1 still remains controversial. In this report, utilizing MCF-7 human breast adenocarcinoma cells stably transfected with caveolin-1 (MCF-7/cav-1 cells), we demonstrate that caveolin-1 expression dramatically inhibits invasion and migration of these cells. Importantly, in vivo experiments employing xenograft tumor models demonstrated that expression of caveolin-1 results in significant growth inhibition of breast tumors. Moreover, a dramatic delay in tumor progression was observed in MCF-7/cav-1 cells as compared with MCF-7 cells. Histological analysis of tumor sections demonstrated a marked decrease in the percentage of proliferating tumor cells (Ki-67 assay) along with an increase in apoptotic tumor cells (TUNEL assay) in MCF-7/cav-1-treated animals. Our current findings provide for the first time in vivo evidence that caveolin-1 can indeed function as a tumor suppressor in human breast adenocarcinoma derived from MCF-7 cells rather than as a tumor promoter

  13. Ruxolitinib combined with vorinostat suppresses tumor growth and alters metabolic phenotype in hematological diseases.

    Science.gov (United States)

    Civallero, Monica; Cosenza, Maria; Pozzi, Samantha; Sacchi, Stefano

    2017-11-28

    JAK-2 dysregulation plays an important role as an oncogenic driver, and is thus a promising therapeutic target in hematological malignancies. Ruxolitinib is a pyrrolo[2.3-d]pyrimidine derivative with inhibitory activity against JAK1 and JAK2, moderate activity against TYK2, and minor activity against JAK3. Vorinostat is an HDAC inhibitor that reduces JAK-2 expression, thus affecting JAK-2 mRNA expression and increasing JAK-2 proteasomal deterioration. Here we hypothesized that the combination of ruxolitinib and vorinostat could have synergistic effects against hematological disease. We tested combinations of low doses of ruxolitinib and vorinostat in 12 cell lines, and observed highly synergistic cytotoxic action in six cell lines, which was maintained for up to 120 h in the presence of stromal cells. The sensitivity of the six cell lines may be explained by the broad effects of the drug combination, which can affect various targets. Treatment with the combination of ruxolitinib and vorinostat appeared to induce a possible reversal of the Warburg effect, with associated ROS production, apoptotic events, and growth inhibition. Decreased glucose metabolism may have markedly sensitized the six more susceptible cell lines to combined treatment. Therapeutic inhibition of the JAK/STAT pathway seems to offer substantial anti-tumor benefit, and combined therapy with ruxolitinib and vorinostat may represent a promising novel therapeutic modality for hematological neoplasms.

  14. microRNA 21-mediated suppression of Sprouty1 by Pokemon affects liver cancer cell growth and proliferation.

    Science.gov (United States)

    Jin, Xiu-Li; Sun, Qin-Sheng; Liu, Feng; Yang, Hong-Wei; Liu, Min; Liu, Hong-Xia; Xu, Wei; Jiang, Yu-Yang

    2013-07-01

    Transcriptional repressor Pokemon is a critical factor in embryogenesis, development, cell proliferation, differentiation, and oncogenesis, thus behaving as an oncogene. Oncomine database suggests a potential correlation between the expressions of Pokemon and Sprouty1. This study investigated the regulatory role of Pokemon in Sprouty1 expression and the effect on liver cancer cell growth and proliferation, revealing a novel miR-21-mediated regulatory circuit. In normal (HL-7702) and cancer (QGY-7703) liver cell lines, Sprouty1 expression is inversely correlated with Pokemon levels. Targeted expression or siRNA-mediated silencing showed that Pokemon is a repressor of Sprouty1 expression at both mRNA and protein levels, but Pokemon cannot affect the promoter activity of Sprouty1. Sprouty1 is a target of miR-21 and interestingly, we found that miR-21 is up-regulated by Pokemon in liver cancer cells. Luciferase reporter assays showed that Pokemon up-regulated miR-21 transcription in a dose-dependent manner, and ChIP assay exhibited a direct binding of Pokemon to the miR-21 promoter at -747 to -399 bp. Site-directed mutagenesis of the GC boxes at -684 to -679 bp and -652 to -647 bp of miR-21 promoter abolished the regulatory activity by Pokemon. Furthermore, we found that the modulation of Pokemon and miR-21 expression affected the growth and proliferation of liver cancer cells QGY-7703. In summary, our findings demonstrate that Pokemon suppresses Sprouty1 expression through a miR-21-mediated mechanism, affecting the growth and proliferation of liver cancer cells. This study recognized miR-21 and Sprouty1 as novel targets of the Pokemon regulatory network. Copyright © 2013 Wiley Periodicals, Inc.

  15. Met inactivation by S-allylcysteine suppresses the migration and invasion of nasopharyngeal cancer cells induced by hepatocyte growth factor

    Energy Technology Data Exchange (ETDEWEB)

    Cho, O Yeon; Hwang, Hye Sook; Lee, Bok Soon; Oh, Young Taek; Kim, Chul Ho; Chun, Mi Son [Ajou University School of Medicine, Suwon (Korea, Republic of)

    2015-12-15

    Past studies have reported that S-allylcysteine (SAC) inhibits the migration and invasion of cancer cells through the restoration of E-cadherin, the reduction of matrix metalloproteinase (MMP) and Slug protein expression, and inhibition of the production of reactive oxygen species (ROS). Furthermore, evidence is emerging that shows that ROS induced by radiation could increase Met activation. Following on these reports of SAC and Met, we investigated whether SAC could suppress Met activation. Wound healing, invasion, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium (MTT), soft agar colony forming, western blotting, and gelatin zymography assays were performed in the human nasopharyngeal cancer cell lines HNE1 and HONE1 treated with SAC (0, 10, 20, or 40 mM) and hepatocyte growth factor (HGF). This study showed that SAC could suppress the migration and invasion of HNE1 and HONE1 cell lines by inhibiting p-Met. An increase of migration and invasion induced by HGF and its decrease in a dose dependent manner by SAC in wound healing and invasion assays was observed. The reduction of p-Met by SAC was positively correlated with p-focal adhesion kinase (p-FAK) and p-extracellular related kinase (p-ERK in both cell lines). SAC reduced Slug, MMP2, and MMP9 involved in migration and invasion with the inhibition of Met-FAK signaling. These results suggest that SAC inhibited not only Met activation but also the downstream FAK, Slug, and MMP expression. Finally, SAC may be a potent anticancer compound for nasopharyngeal cancer treated with radiotherapy.

  16. A crucial role of activin A-mediated growth hormone suppression in mouse and human heart failure.

    Directory of Open Access Journals (Sweden)

    Noritoshi Fukushima

    Full Text Available Infusion of bone marrow-derived mononuclear cells (BMMNC has been reported to ameliorate cardiac dysfunction after acute myocardial infarction. In this study, we investigated whether infusion of BMMNC is also effective for non-ischemic heart failure model mice and the underlying mechanisms. Intravenous infusion of BMMNC showed transient cardioprotective effects on animal models with dilated cardiomyopathy (DCM without their engraftment in heart, suggesting that BMMNC infusion improves cardiac function via humoral factors rather than their differentiation into cardiomyocytes. Using conditioned media from sorted BMMNC, we found that the cardioprotective effects were mediated by growth hormone (GH secreted from myeloid (Gr-1(+ cells and the effects was partially mediated by signal transducer and activator of transcription 3 in cardiomyocytes. On the other hand, the GH expression in Gr-1(+ cells was significantly downregulated in DCM mice compared with that in healthy control, suggesting that the environmental cue in heart failure might suppress the Gr-1(+ cells function. Activin A was upregulated in the serum of DCM models and induced downregulation of GH levels in Gr-1(+ cells and serum. Furthermore, humoral factors upregulated in heart failure including angiotensin II upregulated activin A in peripheral blood mononuclear cells (PBMNC via activation of NFκB. Similarly, serum activin A levels were also significantly higher in DCM patients with heart failure than in healthy subjects and the GH levels in conditioned medium from PBMNC of DCM patients were lower than that in healthy subjects. Inhibition of activin A increased serum GH levels and improved cardiac function of DCM model mice. These results suggest that activin A causes heart failure by suppressing GH activity and that inhibition of activin A might become a novel strategy for the treatment of heart failure.

  17. Growth-suppressing and algicidal properties of an extract from Arundo donax, an invasive riparian plant, against Prymnesium parvum, an invasive harmful alga

    Science.gov (United States)

    Patino, Reynaldo; Rashel, Rakib H.; Rubio, Amede; Longing, Scott

    2018-01-01

    This study examined the ability of acidic and neutral/alkaline fractions of a methanolic extract from giant reed (Arundo donax) and of two of its constituents, gramine and skatole, to inhibit growth of the ichthyotoxic golden alga (Prymnesium parvum) in batch culture. For this study, growth suppression was defined as inhibition of maximum cell density, algicidal activity as early occurrence of negative growth, and algistatic activity as lack of net growth. The acidic fraction did not affect algal growth. The neutral/alkaline fraction showed growth-suppressing and algicidal activities but no signs of algistatic activity – namely, cells in cultures surviving a partial-algicidal exposure concentration (causing transient negative growth) were later able to initiate positive growth but at higher concentrations, algicidal activity was full and irreversible. Gramine suppressed growth more effectively than skatole and at the highest concentration tested, gramine also showed partial-algicidal and algistatic activity. While the partial-algicidal activities of the neutral/alkaline fraction and of gramine were short-lived (≤6 days) and thus may share similar mechanisms, algistatic activity was unique to gramine and persisted for >3 weeks. Given gramine’s reported concentration in the neutral/alkaline fraction, its corresponding level of algicidal activity is much lower than the fraction’s suggesting the latter contains additional potent algicides. Inhibition of maximum cell density by all test compounds was associated with reductions in exponential growth rate, and in the case of the neutral/alkaline fraction and gramine also reductions in early (pre-exponential) growth. These results indicate that giant reed is a potential source of natural products to control golden alga blooms. Giant reed is an invasive species in North America, thus also providing incentive for research into strategies to couple management efforts for both species.

  18. A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice.

    Science.gov (United States)

    Fokidis, H Bobby; Yieng Chin, Mei; Ho, Victor W; Adomat, Hans H; Soma, Kiran K; Fazli, Ladan; Nip, Ka Mun; Cox, Michael; Krystal, Gerald; Zoubeidi, Amina; Tomlinson Guns, Emma S

    2015-06-01

    likely to be mechanistic drivers behind the observed tumor growth suppression. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Sirt2 suppresses glioma cell growth through targeting NF-κB–miR-21 axis

    International Nuclear Information System (INIS)

    Li, Ya’nan; Dai, Dongwei; Lu, Qiong; Fei, Mingyu; Li, Mengmeng; Wu, Xi

    2013-01-01

    Highlights: •Sirt2 expression is down-regulated in human glioma tissues and cell lines. •Sirt2 regresses glioma cell growth and colony formation via inducing apoptosis. •miR-21 is essential for the functions of Sirt2 in glioma cells. •Sirt2 deacetylates p65 to decrease miR-21 expression. -- Abstract: Sirtuins are NAD + -dependent deacetylases that regulate numerous cellular processes including aging, DNA repair, cell cycle, metabolism, and survival under stress conditions. The roles of sirtuin family members are widely studied in carcinogenesis. However, their roles in glioma remain unclear. Here we report that Sir2 was under expressed in human glioma tissues and cell lines. We found that Sirt2 overexpression decreased cell proliferation and colony formation capacity. In addition, Sirt2 overexpression induced cellular apoptosis via up-regulating cleaved caspase 3 and Bax, and down-regulating anti-apoptotic protein Bcl-2. Sirt2 knockdown obtained opposing results. We showed that Sirt2 overexpression inhibited miR-21 expression, and Sirt2 was not sufficient to reduce cell proliferation and colony formation as well as to induce apoptosis when miR-21 was knocked down in glioma cells. Mechanically, we demonstrated that Sirt2 deacetylated p65 at K310 and blocked p65 binding to the promoter region of miR-21, thus regressing the transcription of miR-21. In summary, Sirt2 is critical in human glioma via NF-κB–miR-21 pathway and Sirt2 activator may serve as candidate drug for glioma therapy

  20. Flood Plain Aggradation Rates Based on Tree-Ring Growth-Suppression Dates

    Science.gov (United States)

    Friedman, J. M.

    2003-12-01

    When woody riparian plants are partially buried subsequent tree rings of the buried stems resemble those of roots. Annual rings in a buried stem are narrower and have larger vessels then those in unburied sections of the same stem. We have used this phenomenon to date flood plain sediments exposed in trenches, along two ephemeral streams in New Mexico (Rio Puerco and Chaco Wash) where the sediments are predominantly silt and very fine sand and the plants are predominantly tamarisk and willow. Cross dating down the stem allows dating of the first growth-season following burial by thick beds, and constrains the age of all stratigraphic units deposited since germination of the tree. We observed that the anatomical reaction to burial increases with bed thickness and cumulative deposition. Beds that are thicker than 30 cm can be dated to the year of the deposition event. Beds 10 to 30 cm thick can usually be dated to within several years. The period of deposition of multiple very thin beds can be constrained to the decade. Results can be improved by analyzing multiple stems from one tree and multiple trees linked together by the stratigraphy. Along our study streams, sites far from the channel tend to have moderate and relatively steady point-aggradation rates. Levees next to the channel tend to have the thickest deposits per flood and variable long-term rates, which can differ from the whole flood plain aggradation rates by several fold. Cross-sectionally averaged flood plain aggradation has been as large as a meter per decade along our study streams.

  1. Uncontrollable chronic stress reduces growth disparities in farmed Atlantic salmon

    DEFF Research Database (Denmark)

    Vindas, Marco A; Madaro, Angelico; Fraser, Thomas W.K.

    2017-01-01

    Individual variation in behavior and physiological traits in a wide variety of animals has been the focus of numerous studies in recent years. In this context, early life experiences shape responses that individuals have to subsequent environments, i.e. developmental plasticity. In this experimen...

  2. Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells

    International Nuclear Information System (INIS)

    Karnevi, Emelie; Said, Katarzyna; Andersson, Roland; Rosendahl, Ann H

    2013-01-01

    Epidemiological studies have shown direct associations between type 2 diabetes and obesity, both conditions associated with hyperglycaemia and hyperinsulinemia, and the risk of pancreatic cancer. Up to 80% of pancreatic cancer patients present with either new-onset type 2 diabetes or impaired glucose tolerance at the time of diagnosis. Recent population studies indicate that the incidence of pancreatic cancer is reduced among diabetics taking metformin. In this study, the effects of exposure of pancreatic cancer cells to high glucose levels on their growth and response to metformin were investigated. The human pancreatic cancer cell lines AsPC-1, BxPC-3, PANC-1 and MIAPaCa-2 were grown in normal (5 mM) or high (25 mM) glucose conditions, with or without metformin. The influence by metformin on proliferation, apoptosis and the AMPK and IGF-IR signalling pathways were evaluated in vitro. Metformin significantly reduced the proliferation of pancreatic cancer cells under normal glucose conditions. Hyperglycaemia however, protected against the metformin-induced growth inhibition. The anti-proliferative actions of metformin were associated with an activation of AMP-activated protein kinase AMPK Thr172 together with an inhibition of the insulin/insulin-like growth factor-I (IGF-I) receptor activation and downstream signalling mediators IRS-1 and phosphorylated Akt. Furthermore, exposure to metformin during normal glucose conditions led to increased apoptosis as measured by poly(ADP-ribose) polymerase (PARP) cleavage. In contrast, exposure to high glucose levels promoted a more robust IGF-I response and Akt activation which correlated to stimulated AMPK Ser485 phosphorylation and impaired AMPK Thr172 phosphorylation, resulting in reduced anti-proliferative and apoptotic effects by metformin. Our results indicate that metformin has direct anti-tumour activities in pancreatic cancer cells involving AMPK Thr172 activation and suppression of the insulin/IGF signalling pathways

  3. Fibroblast growth factor 21 is not required for glucose homeostasis, ketosis and tumour suppression associated to ketogenic diets in mice

    Science.gov (United States)

    Stemmer, Kerstin; Zani, Fabio; Habegger, Kirk M.; Neff, Christina; Kotzbeck, Petra; Bauer, Michaela; Yalamanchilli, Suma; Azad, Ali; Lehti, Maarit; Martins, Paulo J.F.; Müller, Timo D.; Pfluger, Paul T.; Seeley, Randy J.

    2016-01-01

    AIMS/HYPOTHESIS Ketogenic diets (KDs) increasingly gained attention as effective means for weight loss and potential adjunctive treatment of cancer. Metabolic benefits of KDs are regularly ascribed towards enhanced hepatic secretion of fibroblast growth factor (FGF) 21, and its systemic effects on fatty acid oxidation, energy expenditure and body weight. Ambiguous data from Fgf21 knockout strains and low FGF21 concentrations reported for humans in ketosis have nevertheless cast doubt regarding the endogenous function of FGF21. We here aimed to elucidate the causal role of FGF21 in mediating therapeutic benefits of KDs on metabolism and cancer. METHODS We established a dietary model of increased vs. decreased FGF21 by feeding C57BL/6J mice with KDs, either depleted or enriched with protein, respectively. We furthermore used wild type and Fgf21 knockout mice that were subjected to the respective diets, and monitored energy and glucose homeostasis as well as tumor growth after transplantation of Lewis-Lung-Carcinoma cells. RESULTS Hepatic and circulating but not adipose tissue FGF21 levels were profoundly increased by protein starvation and independent of the state of ketosis. We demonstrate that endogenous FGF21 is not essential for the maintenance of normoglycemia upon protein and carbohydrate starvation and is dispensable for the effects of KDs on energy expenditure. Furthermore, the tumor-suppressing effects of KDs were independent from FGF21, and rather driven by concomitant protein and carbohydrate starvation. CONCLUSION/INTERPRETATION Our data indicate that multiple systemic effects of KDs exposure in mice that were previously ascribed towards increased FGF21 secretion are rather a consequence of protein malnutrition. PMID:26099854

  4. On the Controllability Principles and the Construction of Uncontrollability

    DEFF Research Database (Denmark)

    Friis, Ivar; Gevoll, Linn; Hansen, Allan

    A key challenge when it comes to coping with the controllability principle is to understand why and how uncontrollability occurs. In this paper we draw on the Actor-Network Theory to provide more insight to why and how uncontrollability emerges in organizations. By means of an in-depth case study...... of a wide range of heterogeneous actors that connects in multiple ways and that in combination forms a complex network of relations which affect delivery time performance. Our study adds to research on the controllability principle. Whereas prior research has characterized uncontrollability as determined...... uncontrollability more specifically is about. Thus, our study adds to as well as elaborates on prior research. We illustrate how uncontrollability arise in the intersects of several heterogeneous elements such as the product information systems, quality management, incentive systems, outsourcing and customers. We...

  5. Andrographolide inhibits hypoxia-inducible factor-1 through phosphatidylinositol 3-kinase/AKT pathway and suppresses breast cancer growth

    Directory of Open Access Journals (Sweden)

    Li J

    2015-02-01

    Full Text Available Jie Li,1 Chao Zhang,1 Hongchuan Jiang,1 Jiao Cheng21Department of General Surgery, 2Department of Gynaecology and Obstetrics, Beijing Chao-Yang Hospital, Beijing, People’s Republic of ChinaAbstract: Hypoxia-inducible factor-1 (HIF-1 is a master regulator of the transcriptional response to hypoxia. HIF-1α is one of the most compelling anticancer targets. Andrographolide (Andro was newly identified to inhibit HIF-1 in T47D cells (a half maximal effective concentration [EC50] of 1.03×10-7 mol/L, by a dual-luciferase reporter assay. It suppressed HIF-1α protein and gene accumulation, which was dependent on the inhibition of upstream phosphatidylinositol 3-kinase (PI3K/AKT pathway. It also abrogated the expression of HIF-1 target vascular endothelial growth factor (VEGF gene and protein. Further, Andro inhibited T47D and MDA-MB-231 cell proliferation and colony formation. In addition, it exhibited significant in vivo efficacy and antitumor potential against the MDA-MB-231 xenograft in nude mice. In conclusion, these results highlighted the potential effects of Andro, which inhibits HIF-1, and hence may be developed as an antitumor agent for breast cancer therapy in future.Keywords: Andrographolide (Andro, HIF-1α, inhibit, breast cancer, hypoxia, PI3k/AKT/mTOR pathway

  6. siRNA-mediated Erc gene silencing suppresses tumor growth in Tsc2 mutant renal carcinoma model.

    Science.gov (United States)

    Imamura, Osamu; Okada, Hiroaki; Takashima, Yuuki; Zhang, Danqing; Kobayashi, Toshiyuki; Hino, Okio

    2008-09-18

    Silencing of gene expression by small interfering RNAs (siRNAs) is rapidly becoming a powerful tool for genetic analysis and represents a potential strategy for therapeutic product development. However, there are no reports of systemic delivery of siRNAs for stable treatment except short hairpin RNAs (shRNAs). On the other hand, there are many reports of systemic delivery of siRNAs for transient treatment using liposome carriers and others. With regard to shRNAs, a report showed fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Therefore, we decided to use original siRNA microspheres instead of shRNA for stable treatment of disease. In this study, we designed rat-specific siRNA sequences for Erc/mesothelin, which is a tumor-specific gene expressed in the Eker (Tsc2 mutant) rat model of hereditary renal cancer and confirmed the efficacy of gene silencing in vitro. Then, by using siRNA microspheres, we found that the suppression of Erc/mesothelin caused growth inhibition of Tsc2 mutant renal carcinoma cells in tumor implantation experiments in mice.

  7. GSK3 is required for rapalogs to induce degradation of some oncogenic proteins and to suppress cancer cell growth.

    Science.gov (United States)

    Koo, Junghui; Wang, Xuerong; Owonikoko, Taofeek K; Ramalingam, Suresh S; Khuri, Fadlo R; Sun, Shi-Yong

    2015-04-20

    The single-agent activity of rapalogs (rapamycin and its analogues) in most tumor types has been modest at best. The underlying mechanisms are largely unclear. In this report, we have uncovered a critical role of GSK3 in regulating degradation of some oncogenic proteins induced by rapalogs and cell sensitivity to rapalogs. The basal level of GSK3 activity was positively correlated with cell sensitivity of lung cancer cell lines to rapalogs. GSK3 inhibition antagonized rapamycin's growth inhibitory effects both in vitro and in vivo, while enforced activation of GSK3β sensitized cells to rapamycin. GSK3 inhibition rescued rapamcyin-induced reduction of several oncogenic proteins such as cyclin D1, Mcl-1 and c-Myc, without interfering with the ability of rapamycin to suppress mTORC1 signaling and cap binding. Interestingly, rapamycin induces proteasomal degradation of these oncogenic proteins, as evidenced by their decreased stabilities induced by rapamcyin and rescue of their reduction by proteasomal inhibition. Moreover, acute or short-time rapamycin treatment dissociated not only raptor, but also rictor from mTOR in several tested cell lines, suggesting inhibition of both mTORC1 and mTORC2. Thus, induction of GSK3-dependent degradation of these oncogenic proteins is likely secondary to mTORC2 inhibition; this effect should be critical for rapamycin to exert its anticancer activity.

  8. Bone morphogenetic protein-9 suppresses growth of myeloma cells by signaling through ALK2 but is inhibited by endoglin

    International Nuclear Information System (INIS)

    Olsen, O E; Wader, K F; Misund, K; Våtsveen, T K; Rø, T B; Mylin, A K; Turesson, I; Størdal, B F; Moen, S H; Standal, T; Waage, A; Sundan, A; Holien, T

    2014-01-01

    Multiple myeloma is a malignancy of plasma cells predominantly located in the bone marrow. A number of bone morphogenetic proteins (BMPs) induce apoptosis in myeloma cells in vitro, and with this study we add BMP-9 to the list. BMP-9 has been found in human serum at concentrations that inhibit cancer cell growth in vitro. We here show that the level of BMP-9 in serum was elevated in myeloma patients (median 176 pg/ml, range 8–809) compared with healthy controls (median 110 pg/ml, range 8–359). BMP-9 was also present in the bone marrow and was able to induce apoptosis in 4 out of 11 primary myeloma cell samples by signaling through ALK2. BMP-9-induced apoptosis in myeloma cells was associated with c-MYC downregulation. The effects of BMP-9 were counteracted by membrane-bound (CD105) or soluble endoglin present in the bone marrow microenvironment, suggesting a mechanism for how myeloma cells can evade the tumor suppressing activity of BMP-9 in multiple myeloma

  9. UNCONTROLLED PHOTOMULTIPLIER CURRENT IN PHOTOEMISSION ANALYSIS

    Directory of Open Access Journals (Sweden)

    K. A. Viazava

    2016-01-01

    Full Text Available The dependence of photon energy from energy of photoelectron is base of photoemission radiation analysis. In such photoemission measurements except current of photocathode is always exist a reverse current from the collector of electrons to the photocathode in two-electrode sensors. There are various ways of reverse and uncontrolled current eliminating or reducing their influence. The constructive method is based on creating an electron-optical system of photoelectronic device, which would be a photoelectron energy analyzer. The second method – technological. However, it requires the manufacture of the photocathode and the dynode system in different vacuum chamber with subsequent connection to a single device in vacuum environment without exposure to the atmosphere. The purpose of this article is to determinate the effect of photoemission from photocathode chamber and the first dynode of photomultiplier on energy distribution of the photoelectrons from photocathode. To solve this problem authors obtained calibration curves for measuring pyrometer module ПИФ 4/2 with ФЭУ-114 as a sensor at supply voltage 1350 V and different decelerating voltages. The effect of illumination on the value of modulation coefficient on temperature k(T and wavelength k(λ is shown. In temperature measurements, this effect is evident in fact that at temperatures below 1400 K linear dependence ln k – T-1 is broken. Still this linear dependence is a necessary consequence of the fact that the measured temperature is color temperature. However, this calibration curve can be used to measure low temperature if the target measurements condition and calibration conditions are identical. In wavelength calibration, curve k(λ at λ > 760 nm is two-valued, that doesn’t allow to identify monochromatic radiation by this method and bring in errors in temperature measurements. 

  10. Suppression subtractive hybridization profiles of radial growth phase and metastatic melanoma cell lines reveal novel potential targets

    International Nuclear Information System (INIS)

    Sousa, Josane F; Espreafico, Enilza M

    2008-01-01

    Melanoma progression occurs through three major stages: radial growth phase (RGP), confined to the epidermis; vertical growth phase (VGP), when the tumor has invaded into the dermis; and metastasis. In this work, we used suppression subtractive hybridization (SSH) to investigate the molecular signature of melanoma progression, by comparing a group of metastatic cell lines with an RGP-like cell line showing characteristics of early neoplastic lesions including expression of the metastasis suppressor KISS1, lack of αvβ3-integrin and low levels of RHOC. Two subtracted cDNA collections were obtained, one (RGP library) by subtracting the RGP cell line (WM1552C) cDNA from a cDNA pool from four metastatic cell lines (WM9, WM852, 1205Lu and WM1617), and the other (Met library) by the reverse subtraction. Clones were sequenced and annotated, and expression validation was done by Northern blot and RT-PCR. Gene Ontology annotation and searches in large-scale melanoma expression studies were done for the genes identified. We identified 367 clones from the RGP library and 386 from the Met library, of which 351 and 368, respectively, match human mRNA sequences, representing 288 and 217 annotated genes. We confirmed the differential expression of all genes selected for validation. In the Met library, we found an enrichment of genes in the growth factors/receptor, adhesion and motility categories whereas in the RGP library, enriched categories were nucleotide biosynthesis, DNA packing/repair, and macromolecular/vesicular trafficking. Interestingly, 19% of the genes from the RGP library map to chromosome 1 against 4% of the ones from Met library. This study identifies two populations of genes differentially expressed between melanoma cell lines from two tumor stages and suggests that these sets of genes represent profiles of less aggressive versus metastatic melanomas. A search for expression profiles of melanoma in available expression study databases allowed us to point to a

  11. Overexpression of p53 activated by small activating RNA suppresses the growth of human prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Ge Q

    2016-01-01

    Full Text Available Qiangqiang Ge,1,* Chenghe Wang,2,* Yajun Ruan,1,* Zhong Chen,1 Jihong Liu,1 Zhangqun Ye1 1Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 2Department of Urology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Previous research has reported that a particular double-stranded RNA, named dsP53-285, has the capacity to induce expression of the tumor suppressor gene TP53 in chimpanzee cells by targeting its promoter. Usually, it is the wild-type p53 protein, rather than mutants, which exhibits potent cancer-inhibiting effects. In addition, nonhuman primates, such as chimpanzees, share almost identical genome sequences with humans. This prompted us to speculate whether dsP53-285 can trigger wild-type p53 protein expression in human prostate cancer (PCa cells and consequently suppress cell growth. The human PCa cell lines LNCaP and DU145 were transfected with dsP53-285 for 72 hours. Compared with the dsControl and mock transfection groups, expression of both p53 messenger RNA and p53 protein was significantly enhanced after dsP53-285 transfection, and this enhancement was followed by upregulation of p21, which indirectly indicated that dsP53-285 induced wild-type p53 expression. Moreover, overexpression of wild-type p53 mediated by dsP53-285 downregulated the expression of Cyclin D1 and cyclin-dependent kinase 4/6, thereby inducing PCa cell cycle arrest in G0/G1 phase and then inhibiting cell proliferation and clonogenicity. More importantly, dsP53-285 suppressed PCa cells mainly by modulating wild-type p53 expression. In conclusion, our study provides evidence that dsP53-285 can significantly stimulate wild-type p53 expression in the human PCa cell lines LNCaP and DU145 and can exert potent antitumor effects. Keywords: p53, small activating RNA, prostate

  12. Growth hormone suppression test

    Science.gov (United States)

    ... Acromegaly - blood test; Gigantism - blood test Images Blood test References Kaiser U, Ho KKY. Pituitary physiology and diagnostic evaluation. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology . 13th ed. Philadelphia, PA: Elsevier; ...

  13. ASC-J9 Suppresses Castration-Resistant Prostate Cancer Growth through Degradation of Full-length and Splice Variant Androgen Receptors

    Directory of Open Access Journals (Sweden)

    Shinichi Yamashita

    2012-01-01

    Full Text Available Early studies suggested androgen receptor (AR splice variants might contribute to the progression of prostate cancer (PCa into castration resistance. However, the therapeutic strategy to target these AR splice variants still remains unresolved. Through tissue survey of tumors from the same patients before and after castration resistance, we found that the expression of AR3, a major AR splice variant that lacks the AR ligand-binding domain, was substantially increased after castration resistance development. The currently used antiandrogen, Casodex, showed little growth suppression in CWR22Rv1 cells. Importantly, we found that AR degradation enhancer ASC-J9 could degrade both full-length (fAR and AR3 in CWR22Rv1 cells as well as in C4-2 and C81 cells with addition of AR3. The consequences of such degradation of both fAR and AR3 might then result in the inhibition of AR transcriptional activity and cell growth in vitro. More importantly, suppression of AR3 specifically by short-hairpin AR3 or degradation of AR3 by ASC-J9 resulted in suppression of AR transcriptional activity and cell growth in CWR22Rv1-fARKD (fAR knockdown cells in which DHT failed to induce, suggesting the importance of targeting AR3. Finally, we demonstrated the in vivo therapeutic effects of ASC-J9 by showing the inhibition of PCa growth using the xenografted model of CWR22Rv1 cells orthotopically implanted into castrated nude mice with undetectable serum testosterone. These results suggested that targeting both fAR- and AR3-mediated PCa growth by ASC-J9 may represent the novel therapeutic approach to suppress castration-resistant PCa. Successful clinical trials targeting both fAR and AR3 may help us to battle castration-resistant PCa in the future.

  14. CDK2 and mTOR are direct molecular targets of isoangustone A in the suppression of human prostate cancer cell growth

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Eunjung; Son, Joe Eun; Byun, Sanguine; Lee, Seung Joon; Kim, Yeong A [WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 151-921 (Korea, Republic of); Liu, Kangdong [The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912 (United States); Kim, Jiyoung [WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 151-921 (Korea, Republic of); Lim, Soon Sung; Park, Jung Han Yoon [Department of Food Science and Nutrition, College of Natural Science, Hallym University, Chuncheon, 200-702 (Korea, Republic of); Dong, Zigang [The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912 (United States); Lee, Ki Won, E-mail: kiwon@snu.ac.kr [WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 151-921 (Korea, Republic of); Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270 (Korea, Republic of); Lee, Hyong Joo, E-mail: leehyjo@snu.ac.kr [WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 151-921 (Korea, Republic of); Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270 (Korea, Republic of)

    2013-10-01

    Licorice extract which is used as a natural sweetener has been shown to possess inhibitory effects against prostate cancer, but the mechanisms responsible are poorly understood. Here, we report a compound, isoangustone A (IAA) in licorice that potently suppresses the growth of aggressive prostate cancer and sought to clarify its mechanism of action. We analyzed its inhibitory effects on the growth of PTEN-deleted human prostate cancer cells, in vitro and in vivo. Administration of IAA significantly attenuated the growth of prostate cancer cell cultures and xenograft tumors. These effects were found to be attributable to inhibition of the G1/S phase cell cycle transition and the accumulation of p27{sup kip1}. The elevated p27{sup kip1} expression levels were concurrent with the decrease of its phosphorylation at threonine 187 through suppression of CDK2 kinase activity and the reduced phosphorylation of Akt at Serine 473 by diminishing the kinase activity of the mammalian target of rapamycin (mTOR). Further analysis using recombinant proteins and immunoprecipitated cell lysates determined that IAA exerts suppressive effects against CDK2 and mTOR kinase activity by direct binding with both proteins. These findings suggested that the licorice compound IAA is a potent molecular inhibitor of CDK2 and mTOR, with strong implications for the treatment of prostate cancer. Thus, licorice-derived extracts with high IAA content warrant further clinical investigation for nutritional sources for prostate cancer patients. - Highlights: • Isoangustone A suppresses growth of PC3 and LNCaP prostate cancer cells. • Administration of isoangustone A inhibits tumor growth in mice. • Treatment of isoangustone A induces cell cycle arrest and accumulation of p27{sup kip1}. • Isoangustone A inhibits CDK2 and mTOR activity. • Isoangustone A directly binds with CDK2 and mTOR complex in prostate cancer cells.

  15. Targeting mesothelin receptors with drug-loaded bacterial nanocells suppresses human mesothelioma tumour growth in mouse xenograft models.

    Directory of Open Access Journals (Sweden)

    Mohamed A Alfaleh

    Full Text Available Human malignant mesothelioma is a chemoresistant tumour that develops from mesothelial cells, commonly associated with asbestos exposure. Malignant mesothelioma incidence rates in European countries are still rising and Australia has one of the highest burdens of malignant mesothelioma on a population basis in the world. Therapy using systemic delivery of free cytotoxic agents is associated with many undesirable side effects due to non-selectivity, and is thus dose-limited which limits its therapeutic potential. Therefore, increasing the selectivity of anti-cancer agents has the potential to dramatically enhance drug efficacy and reduce toxicity. EnGeneIC Dream Vectors (EDV are antibody-targeted nanocells which can be loaded with cytotoxic drugs and delivered to specific cancer cells via bispecific antibodies (BsAbs which target the EDV and a cancer cell-specific receptor, simultaneously. BsAbs were designed to target doxorubicin-loaded EDVs to cancer cells via cell surface mesothelin (MSLN. Flow cytometry was used to investigate cell binding and induction of apoptosis, and confocal microscopy to visualize internalization. Mouse xenograft models were used to assess anti-tumour effects in vivo, followed by immunohistochemistry for ex vivo evaluation of proliferation and necrosis. BsAb-targeted, doxorubicin-loaded EDVs were able to bind to and internalize within mesothelioma cells in vitro via MSLN receptors and induce apoptosis. In mice xenografts, the BsAb-targeted, doxorubicin-loaded EDVs suppressed the tumour growth and also decreased cell proliferation. Thus, the use of MSLN-specific antibodies to deliver encapsulated doxorubicin can provide a novel and alternative modality for treatment of mesothelioma.

  16. Accelerated development in Johnsongrass seedlings (Sorghum halepense suppresses the growth of native grasses through size-asymmetric competition.

    Directory of Open Access Journals (Sweden)

    Susanne Schwinning

    Full Text Available Invasive plant species often dominate native species in competition, augmenting other potential advantages such as release from natural enemies. Resource pre-emption may be a particularly important mechanism for establishing dominance over competitors of the same functional type. We hypothesized that competitive success of an exotic grass against native grasses is mediated by establishing an early size advantage. We tested this prediction among four perennial C4 warm-season grasses: the exotic weed Johnsongrass (Sorghum halepense, big bluestem (Andropogon gerardii, little bluestem (Schizachyrium scoparius and switchgrass (Panicum virgatum. We predicted that a the competitive effect of Johnsongrass on target species would be proportional to their initial biomass difference, b competitive effect and response would be negatively correlated and c soil fertility would have little effect on competitive relationships. In a greenhouse, plants of the four species were grown from seed either alone or with one Johnsongrass neighbor at two fertilizer levels and periodically harvested. The first two hypotheses were supported: The seedling biomass of single plants at first harvest (50 days after seeding ranked the same way as the competitive effect of Johnsongrass on target species: Johnsongrass < big bluestem < little bluestem/switchgrass, while Johnsongrass responded more strongly to competition from Johnsongrass than from native species. At final harvest, native plants growing with Johnsongrass attained between 2-5% of their single-plant non-root biomass, while Johnsongrass growing with native species attained 89% of single-plant non-root biomass. Fertilization enhanced Johnsongrass' competitive effects on native species, but added little to the already severe competitive suppression. Accelerated early growth of Johnsongrass seedlings relative to native seedlings appeared to enable subsequent resource pre-emption. Size-asymmetric competition and resource

  17. Suppression of the epidermal growth factor receptor inhibits epithelial-mesenchymal transition in human pancreatic cancer PANC-1 cells.

    Science.gov (United States)

    Chang, Zhi-Gang; Wei, Jun-Min; Qin, Chang-Fu; Hao, Kun; Tian, Xiao-Dong; Xie, Kun; Xie, Xue-Hai; Yang, Yin-Mo

    2012-05-01

    Aberrant expression of epidermal growth factor receptor (EGFR) has been detected in pancreatic cancer; however, the mechanisms of EGFR in inducing pancreatic cancer development have not been adequately elucidated. The objective of this study was to determine the role of EGFR in mediating epithelial-mesenchymal transition (EMT) in pancreatic cancer cells. Pancreatic cancer cell line PANC-1 was transfected with small interfering RNA of EGFR by use of a lentiviral expression vector to establish an EGFR-knockdown cell line (si-PANC-1). PANC-1 cells transfected with lentiviral vector expressing negative control sequence were used as negative control (NC-PANC-1). Scratch assay and transwell study were used to analyze cell migration and invasion. Real-time PCR and Western blotting were used to detect the expression of EMT markers E-cadherin, N-cadherin, vimentin, and fibronectin and transcription factors snail, slug, twist1, and sip1 in PANC-1, NC-PANC-1, and si-PANC-1 cells. Immunofluorescent staining with these antibodies and confocal microscopy were used to observe their cellular location and morphologic changes. After RNA interference of EGFR, the migration and invasion ability of si-PANC-1 cells decreased significantly. The expression of epithelial phenotype marker E-cadherin increased and the expression of mesenchymal phenotype markers N-cadherin, vimentin, and fibronectin decreased, indicating reversion of EMT. We also observed intracellular translocation of E-cadherin. Expression of transcription factors snail and slug in si-PANC-1 cells decreased significantly. Suppression of EGFR expression can significantly inhibit EMT of pancreatic cancer PANC-1 cells. The mechanism may be related with the down-regulation of the expression of transcription factors snail and slug.

  18. Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth.

    Directory of Open Access Journals (Sweden)

    Xiaohong Wang

    2008-07-01

    Full Text Available MicroRNAs (miRNAs play important roles in cancer development. By cloning and sequencing of a HPV16(+ CaSki cell small RNA library, we isolated 174 miRNAs (including the novel miR-193c which could be grouped into 46 different miRNA species, with miR-21, miR-24, miR-27a, and miR-205 being most abundant. We chose for further study 10 miRNAs according to their cloning frequency and associated their levels in 10 cervical cancer- or cervical intraepithelial neoplasia-derived cell lines. No correlation was observed between their expression with the presence or absence of an integrated or episomal HPV genome. All cell lines examined contained no detectable miR-143 and miR-145. HPV-infected cell lines expressed a different set of miRNAs when grown in organotypic raft cultured as compared to monolayer cell culture, including expression of miR-143 and miR-145. This suggests a correlation between miRNA expression and tissue differentiation. Using miRNA array analyses for age-matched normal cervix and cervical cancer tissues, in combination with northern blot verification, we identified significantly deregulated miRNAs in cervical cancer tissues, with miR-126, miR-143, and miR-145 downregulation and miR-15b, miR-16, miR-146a, and miR-155 upregulation. Functional studies showed that both miR-143 and miR-145 are suppressive to cell growth. When introduced into cell lines, miR-146a was found to promote cell proliferation. Collectively, our data indicate that downregulation of miR-143 and miR-145 and upregulation of miR-146a play a role in cervical carcinogenesis.

  19. Enhanced suppression of tumor growth by concomitant treatment of human lung cancer cells with suberoylanilide hydroxamic acid and arsenic trioxide

    International Nuclear Information System (INIS)

    Chien, Chia-Wen; Yao, Ju-Hsien; Chang, Shih-Yu; Lee, Pei-Chih; Lee, Te-Chang

    2011-01-01

    The efficacy of arsenic trioxide (ATO) against acute promyelocytic leukemia (APL) and relapsed APL has been well documented. ATO may cause DNA damage by generating reactive oxygen intermediates. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, modulates gene and protein expression via histone-dependent or -independent pathways that may result in chromatin decondensation, cell cycle arrest, differentiation, and apoptosis. We investigated whether ATO and SAHA act synergistically to enhance the death of cancer cells. Our current findings showed that combined treatment with ATO and SAHA resulted in enhanced suppression of non-small-cell lung carcinoma in vitro in H1299 cells and in vivo in a xenograft mouse model. Flow cytometric analysis of annexin V+ cells showed that apoptotic cell death was significantly enhanced after combined treatment with ATO and SAHA. At the doses used, ATO did not interfere with cell cycle progression, but SAHA induced p21 expression and led to G1 arrest. A Comet assay demonstrated that ATO, but not SAHA, induced DNA strand breaks in H1299 cells; however, co-treatment with SAHA significantly increased ATO-induced DNA damage. Moreover, SAHA enhanced acetylation of histone H3 and sensitized genomic DNA to DNase I digestion. Our results suggest that SAHA may cause chromatin relaxation and increase cellular susceptibility to ATO-induced DNA damage. Combined administration of SAHA and ATO may be an effective approach to the treatment of lung cancer. -- Highlights: ► ATO and SAHA are therapeutic agents with different action modes. ► Combination of ATO and SAHA synergistically inhibits tumor cell growth. ► SAHA loosens chromatin structure resulting in increased sensitivity to DNase I. ► ATO-induced DNA damage and apoptosis are enhanced by co-treatment with SAHA.

  20. Abrogation of Gli3 expression suppresses the growth of colon cancer cells via activation of p53

    International Nuclear Information System (INIS)

    Kang, Han Na; Oh, Sang Cheul; Kim, Jun Suk; Yoo, Young A.

    2012-01-01

    p53, the major human tumor suppressor, appears to be related to sonic hedgehog (Shh)–Gli-mediated tumorigenesis. However, the role of p53 in tumor progression by the Shh–Gli signaling pathway is poorly understood. Herein we investigated the critical regulation of Gli3–p53 in tumorigenesis of colon cancer cells and the molecular mechanisms underlying these effects. RT-PCR analysis indicated that the mRNA level of Shh and Gli3 in colon tumor tissues was significantly higher than corresponding normal tissues (P < 0.001). The inhibition of Gli3 by treatment with Gli3 siRNA resulted in a clear decrease in cell proliferation and enhanced the level of expression of p53 proteins compared to treatment with control siRNA. The half-life of p53 was dramatically increased by treatment with Gli3 siRNA. In addition, treatment with MG132 blocked MDM2-mediated p53 ubiquitination and degradation, and led to accumulation of p53 in Gli3 siRNA-overexpressing cells. Importantly, ectopic expression of p53 siRNA reduced the ability of Gli3 siRNA to suppress proliferation of those cells compared with the cells treated with Gli3 siRNA alone. Moreover, Gli3 siRNA sensitized colon cancer cells to treatment with anti-cancer agents (5-FU and bevacizumab). Taken together, our studies demonstrate that loss of Gli3 signaling leads to disruption of the MDM2–p53 interaction and strongly potentiate p53-dependent cell growth inhibition in colon cancer cells, indicating a basis for the rational use of Gli3 antagonists as a novel treatment option for colon cancer.

  1. Trehalose Liposomes Suppress the Growth of Tumors on Human Lung Carcinoma-bearing Mice by Induction of Apoptosis In Vivo.

    Science.gov (United States)

    Ichihara, Hideaki; Kuwabara, Keiji; Matsumoto, Yoko

    2017-11-01

    Previous evidence demonstrates that trehalose liposomes (DMTreC14) composed of L-α-dimyristoylphosphatidylcholine (DMPC) and α-D-glycopyranosyl-α-D-glucopyranoside monomyristate (TreC14) inhibit proliferation and invasion on lung carcinoma (A549 cells) in vitro. Here, we aimed to investigate suppressive effects of DMTreC14 on the growth of tumor on human lung carcinoma bearing mice. DMTreC14 composed of 30 mol% DMPC and 70 mol% TreC14 were prepared by the sonication method. Anti-tumor activities of DMTreC14 using the subcutaneous and orthotopic graft-bearing mice of A549 cells were investigated in vivo. The remarkable reduction of volume and weight in subcutaneous tumors on subcutaneous lung carcinoma-bearing mice topically administrated with DMTreC14 were obtained. Apoptotic-positive cells in the subcutaneous tumor slice of subcutaneous lung carcinoma-bearing mice topically administrated with DMTreC14 were observed using TUNEL staining. Lung weights on the orthotopic graft-bearing mice of lung carcinoma intravenously administrated with DMTreC14 were markedly decreased compared to those of the control group. Remarkable decrease in dimensions of tumor area of lung on the orthotopic graft-bearing mice of lung carcinoma intravenously administrated with DMTreC14 was obtained in histological analysis using the hematoxylin and eosin staining. Remarkably high anti-tumor activities of DMTreC14 for the subcutaneous and orthotopic graft-bearing mice of lung carcinoma accompanied with apoptosis were revealed for the first time in vivo. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  2. Polo-like kinase 1 (PLK1) inhibition suppresses cell growth and enhances radiation sensitivity in medulloblastoma cells

    International Nuclear Information System (INIS)

    Harris, Peter S; Foreman, Nicholas K; Vibhakar, Rajeev; Venkataraman, Sujatha; Alimova, Irina; Birks, Diane K; Donson, Andrew M; Knipstein, Jeffrey; Dubuc, Adrian; Taylor, Michael D; Handler, Michael H

    2012-01-01

    Medulloblastoma is the most common malignant brain tumor in children and remains a therapeutic challenge due to its significant therapy-related morbidity. Polo-like kinase 1 (PLK1) is highly expressed in many cancers and regulates critical steps in mitotic progression. Recent studies suggest that targeting PLK1 with small molecule inhibitors is a promising approach to tumor therapy. We examined the expression of PLK1 mRNA in medulloblastoma tumor samples using microarray analysis. The impact of PLK1 on cell proliferation was evaluated by depleting expression with RNA interference (RNAi) or by inhibiting function with the small molecule inhibitor BI 2536. Colony formation studies were performed to examine the impact of BI 2536 on medulloblastoma cell radiosensitivity. In addition, the impact of depleting PLK1 mRNA on tumor-initiating cells was evaluated using tumor sphere assays. Analysis of gene expression in two independent cohorts revealed that PLK1 mRNA is overexpressed in some, but not all, medulloblastoma patient samples when compared to normal cerebellum. Inhibition of PLK1 by RNAi significantly decreased medulloblastoma cell proliferation and clonogenic potential and increased cell apoptosis. Similarly, a low nanomolar concentration of BI 2536, a small molecule inhibitor of PLK1, potently inhibited cell growth, strongly suppressed the colony-forming ability, and increased cellular apoptosis of medulloblastoma cells. Furthermore, BI 2536 pretreatment sensitized medulloblastoma cells to ionizing radiation. Inhibition of PLK1 impaired tumor sphere formation of medulloblastoma cells and decreased the expression of SRY (sex determining region Y)-box 2 (SOX2) mRNA in tumor spheres indicating a possible role in targeting tumor inititiating cells. Our data suggest that targeting PLK1 with small molecule inhibitors, in combination with radiation therapy, is a novel strategy in the treatment of medulloblastoma that warrants further investigation

  3. Hydrogen sulfide-releasing naproxen suppresses colon cancer cell growth and inhibits NF-κB signaling

    Directory of Open Access Journals (Sweden)

    Kodela R

    2015-08-01

    Full Text Available Ravinder Kodela,1 Niharika Nath,2 Mitali Chattopadhyay,1 Diandra E Nesbitt,1 Carlos A Velázquez-Martínez,3 Khosrow Kashfi11Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, 2Department of Life Sciences, New York Institute of Technology, New York, NY, USA; 3Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada Abstract: Colorectal cancer (CRC is the second leading cause of death due to cancer and the third most common cancer in men and women in the USA. Nuclear factor kappa B (NF-κB is known to be activated in CRC and is strongly implicated in its development and progression. Therefore, activated NF-κB constitutes a bona fide target for drug development in this type of malignancy. Many epidemiological and interventional studies have established nonsteroidal anti-inflammatory drugs (NSAIDs as a viable chemopreventive strategy against CRC. Our previous studies have shown that several novel hydrogen sulfide-releasing NSAIDs are promising anticancer agents and are safer derivatives of NSAIDs. In this study, we examined the growth inhibitory effect of a novel H2S-releasing naproxen (HS-NAP, which has a repertoire as a cardiovascular-safe NSAID, for its effects on cell proliferation, cell cycle phase transitions, and apoptosis using HT-29 human colon cancer cells. We also investigated its effect as a chemopreventive agent in a xenograft mouse model. HS-NAP suppressed the growth of HT-29 cells by induction of G0/G1 arrest and apoptosis and downregulated NF-κB. Tumor xenografts in mice were significantly reduced in volume. The decrease in tumor mass was associated with a reduction of cell proliferation, induction of apoptosis, and decreases in NF-κB levels in vivo. Therefore, HS-NAP demonstrates strong anticancer potential in CRC. Keywords: nonsteroidal anti-inflammatory drugs, cell cycle, apoptosis, xenograft, NF

  4. MicroRNA-9 suppresses the growth, migration, and invasion of malignant melanoma cells via targeting NRP1

    Directory of Open Access Journals (Sweden)

    Xu D

    2016-11-01

    Full Text Available Dan Xu,1 Xiaofeng Chen,2 Quanyong He,1 Chengqun Luo1 1Department of Plastic Surgery, Third Xiangya Hospital of Central South University, 2Department of Neurosurgery, Brain Hospital of Hunan Province, Changsha, Hunan, People’s Republic of China Abstract: MicroRNAs (miRs are a class of small noncoding RNAs that negatively regulate the gene expression by directly binding to the 3' untranslated region of their target mRNA, thus resulting in mRNA degradation or translational repression. miR-9 has recently been demonstrated to play a role in the development and progression of malignant melanoma (MM, but the regulatory mechanism of miR-9 in the malignant phenotypes of MM still remains largely unknown. In this study, a total of 73 pairs of MM tissues and adjacent normal tissues were collected. Real-time reverse transcription polymerase chain reaction and Western blot were used to detect the mRNA and protein expression of miR-9. MTT assay, wound healing assay, and transwell assay were conducted to determine the cell proliferation, migration, and invasion. Luciferase reporter assay was used to determine the targeting relationship between miR-9 and NRP1. Our data demonstrated that miR-9 expression was significantly downregulated in MM tissues compared with that in adjacent normal tissues. The decreased miR-9 level was significantly associated with the tumor stage and metastasis of MM. We also found that the expression level of miR-9 was decreased in MM cell lines (G361, B16, A375, and HME1 compared with normal skin HACAT cells. Ectopic expression of miR-9 led to a significant decrease in the ability of proliferation, migration, and invasion in A375 cells. NRP1 was further identified as a direct target gene of miR-9, and the protein expression of NRP1 was negatively regulated by miR-9 in A375 cells. Furthermore, overexpression of NRP1 reversed the suppressive effects of miR-9 on the malignant phenotypes of A375 cells. In vivo study revealed that miR-9

  5. Endophytic Association of Trichoderma asperellum within Theobroma cacao Suppresses Vascular Streak Dieback Incidence and Promotes Side Graft Growth.

    Science.gov (United States)

    Rosmana, Ade; Nasaruddin, Nasaruddin; Hendarto, Hendarto; Hakkar, Andi Akbar; Agriansyah, Nursalim

    2016-09-01

    Trichoderma species are able to persist on living sapwood and leaves of cacao ( Theobroma cacao ) in an endophytic relationship. In this research, we evaluated the ability of Trichodema asperellum introduced at the incision site in the bark for side grafting with the concentration of 4 g/10 mL, 4 g/100 mL, and 4 g/1,000 mL (suspended in water) in suppressing vascular streak dieback (VSD) incidence and promoting growth of side grafts in the field. The incidence of VSD in two local clones of cacao, MCC1 and M04, without application of T. asperellum was 71.2% and 70.1% at 21 wk after grafting, respectively. However, when the two clones were treated with a concentration of 4 g/10 mL T. asperellum , the incidence was 20.6% and 21.7%, respectively, compared to 29.1% and 20.9% at 4 g/100 mL and 18.2% and 15.6% at 4 g/1,000 mL. By comparing to the control, the treatment with the same concentrations of T. asperellum listed above, the total number of stomata in MCC1 decreased by 41.9%, 30.2%, and 14.0% and in M04 by 30.5%, 21.9%, and -2.5% (exception), respectively. Otherwise, the total area of stomata opening increased by 91.4%, 99.7%, and 28.6% in MCC1 and by 203.8%, 253.5%, and 35.9% in M04, respectively. Furthermore, the number of buds and branches treated with a mixture concentration on the the two clones increased by 90.7% and 21.7%, respectively. These data showed that the application of T. asperellum to cacao scions while grafting can decrease VSD incidence in side grafts and increase growth of grafts in addition to decreasing total number of stomata, increasing total area of opened stomata, and increasing number of buds and branches.

  6. Isolation, characterization, and evaluation of multi-trait plant growth promoting rhizobacteria for their growth promoting and disease suppressing effects on ginger.

    Science.gov (United States)

    Dinesh, Raghavan; Anandaraj, Muthuswamy; Kumar, Aundy; Bini, Yogiyar Kundil; Subila, Kizhakke Purayil; Aravind, Ravindran

    2015-04-01

    In this study, 100 PGPR strains isolated from different varieties of ginger (Zingiber officinale Rosc.) were first characterized for their morphological, biochemical, and nutrient mobilization traits in vitro. The PGPR were also screened in vitro for inhibition of Pythium myriotylum causing soft rot in ginger. Results revealed that only five PGPR showed >70% suppression of P. myriotylum. These 5 PGPR viz., GRB (Ginger rhizobacteria) 25--Burkholderia cepacia, GRB35--Bacillus amyloliquefaciens; GRB58--Serratia marcescens; GRB68--S. marcescens; GRB91--Pseudomonas aeruginosa were used for further growth promotion and biocontrol studies in the green house and field. The green house study revealed that GRB35 (B. amyloliquefaciens) and GRB68 (S. marcescens) registered markedly higher sprouting (96.3%) and lower disease incidence (48.1%) and greater rhizome yield (365.6 g pot(-1) and 384.4 g pot(-1), respectively), while control registered the lowest sprouting (66%), maximum soft rot incidence (100%) and lowest rhizome yield (134.4 g pot(-1)). In the field experiments also, GRB68 (S. marcescens) and GRB35 (B. amyloliquefaciens) registered the greatest sprouting (80% each), markedly lower soft rot incidence (5.2% and 7.3%, respectively) and higher yield (5.0 and 4.3 kg(3)m(-2), respectively) compared to chemicals like Streptomycin sulphate (73.0%, 18.5% and 2.3 kg(3)m(-2), respectively), Metalaxyl-Mancozeb (73.0%, 14.0% and 3.8 kg(3)m(-2), respectively) and control (73.0%, 25.1% and 2.2 kg 3m(-2), respectively). Overall, the results suggested that for growth promotion and management of soft rot disease in ginger, GRB35 B. amyloliquefaciens and GRB68 S. marcescens could be good alternatives to chemical measures. Since, the latter has been reported to be an opportunistic human pathogen, we recommend the use of B. amyloliquefaciens for integration into nutrient and disease management schedules for ginger cultivation. Copyright © 2015 Elsevier GmbH. All rights reserved.

  7. Growth responses of young Douglas-fir and tanoak 11 years after various levels of hardwood removal and understory suppression in southwestern Oregon, USA

    Science.gov (United States)

    Harrington, T.B.; Tappeiner, John C.

    1997-01-01

    At two sites in southwestern Oregon, height, diameter, and crown width of young Douglas-fir (Pseudotsuga menziesii) and sprout-origin tanoak (Lithocarpus densiflorus) were measured 1–11 years after reducing the density of a 2-year-old tanoak stand to 0%, 25%, 50%, and 100% of its initial cover. Some plots also included suppression of understory vegetation. Tanoak cover developed linearly with time, with steepness of the growth trajectory increasing at a diminishing rate with increasing percentage of initial tanoak cover. Fifth-year cover of understory vegetation declined linearly with increasing percentage of initial tanoak cover (R2 = 0.29). Survival of Douglas-fir (96–100%) differed little among initial abundances of tanoak, while growth trajectories for its size became increasingly exponential with decreasing percentage of initial tanoak cover. Eleventh-year heights of Douglas-fir were similar for 0%, 25%, and 50% of initial tanoak cover; however, diameter increased linearly with decreasing percentage of initial tanoak cover (R2 = 0.73), and the slope of the relationship steepened with understory suppression. Our results indicate that young stands exhibiting a wide range of stand compositions and productivities can be established by early manipulations of tanoak and understory abundance. Complete removal of tanoak plus understory suppression are necessary to maximize Douglas-fir growth, while productive, mixed stands can be achieved by removing 50% or more of tanoak cover.

  8. 3-bromopyruvate and sodium citrate target glycolysis, suppress survivin, and induce mitochondrial-mediated apoptosis in gastric cancer cells and inhibit gastric orthotopic transplantation tumor growth.

    Science.gov (United States)

    Wang, Ting-An; Zhang, Xiao-Dong; Guo, Xing-Yu; Xian, Shu-Lin; Lu, Yun-Fei

    2016-03-01

    Glycolysis is the primary method utilized by cancer cells to produce the energy (adenosine triphosphate, ATP) required for cell proliferation. Therefore, inhibition of glycolysis may inhibit tumor growth. We previously found that both 3-bromopyruvate (3-BrPA) and sodium citrate (SCT) can inhibit glycolysis in vitro; however, the underlying inhibitory mechanisms remain unclear. In the present study, we used a human gastric cancer cell line (SGC-7901) and an orthotopic transplantation tumor model in nude mice to explore the specific mechanisms of 3-BrPA and SCT. We found that both 3-BrPA and SCT effectively suppressed cancer cell proliferation, arrested the cell cycle, induced apoptosis, and decreased the production of lactate and ATP. 3-BrPA significantly reduced the glycolytic enzyme hexokinase activity, while SCT selectively inhibited phosphofructokinase-1 activity. Furthermore, 3-BrPA and SCT upregulated the expression of pro-apoptotic proteins (Bax, cytochrome c, and cleaved caspase-3) and downregulated the expression of anti-apoptotic proteins (Bcl-2 and survivin). Finally, our animal model of gastric cancer indicated that intraperitoneal injection of 3-BrPA and SCT suppressed orthotopic transplantation tumor growth and induced tumor apoptosis. Taken together, these results suggest that 3-BrPA and SCT selectively suppress glycolytic enzymes, decrease ATP production, induce mitochondrial-mediated apoptosis, downregulate survivin, and inhibit tumor growth. Moreover, an intraperitoneal injection is an effective form of administration of 3-BrPA and SCT.

  9. Inhibition of Calcium-Activated Chloride Channel ANO1/TMEM16A Suppresses Tumor Growth and Invasion in Human Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Linghan Jia

    Full Text Available Lung cancer or pulmonary carcinoma is primarily derived from epithelial cells that are thin and line on the alveolar surfaces of the lung for gas exchange. ANO1/TMEM16A, initially identified from airway epithelial cells, is a member of Ca2+-activated Cl- channels (CaCCs that function to regulate epithelial secretion and cell volume for maintenance of ion and tissue homeostasis. ANO1/TMEM16A has recently been shown to be highly expressed in several epithelium originated carcinomas. However, the role of ANO1 in lung cancer remains unknown. In this study, we show that inhibition of calcium-activated chloride channel ANO1/TMEM16A suppresses tumor growth and invasion in human lung cancer. ANO1 is upregulated in different human lung cancer cell lines. Knocking-down ANO1 by small hairpin RNAs inhibited proliferation, migration and invasion of GLC82 and NCI-H520 cancel cells evaluated by CCK-8, would-healing, transwell and 3D soft agar assays. ANO1 protein is overexpressed in 77.3% cases of human lung adenocarcinoma tissues detected by immunohistochemistry. Furthermore, the tumor growth in nude mice implanted with GLC82 cells was significantly suppressed by ANO1 silencing. Taken together, our findings provide evidence that ANO1 overexpression contributes to tumor growth and invasion of lung cancer; and suppressing ANO1 overexpression may have therapeutic potential in lung cancer therapy.

  10. MAZ-binding G4-decoy with locked nucleic acid and twisted intercalating nucleic acid modifications suppresses KRAS in pancreatic cancer cells and delays tumor growth in mice

    DEFF Research Database (Denmark)

    Cogoi, Susanna; Zorzet, Sonia; Rapozzi, Valentina

    2013-01-01

    and stability, two polycyclic aromatic hydrocarbon units (TINA or AMANY) were inserted internally, to cap the quadruplex. The most active G4-decoy (2998), which had two para-TINAs, strongly suppressed KRAS expression in Panc-1 cells. It also repressed their metabolic activity (IC50 = 520 nM), and it inhibited...... cell growth and colony formation by activating apoptosis. We finally injected 2998 and control oligonucleotides 5153, 5154 (2 nmol/mouse) intratumorally in SCID mice bearing a Panc-1 xenograft. After three treatments, 2998 reduced tumor xenograft growth by 64% compared with control and increased...

  11. Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression.

    Science.gov (United States)

    Campochiaro, Peter A; Khanani, Arshad; Singer, Michael; Patel, Sunil; Boyer, David; Dugel, Pravin; Kherani, Saleema; Withers, Barbara; Gambino, Laura; Peters, Kevin; Brigell, Mitchell

    2016-08-01

    with a ≥2-step change was 11.4% in all AKB-9778-treated subjects compared with 4.2% in the ranibizumab monotherapy group. AKB-9778 was well tolerated, with no clear by-treatment differences in adverse events. Activation of Tie2 by subcutaneous injections of AKB-9778 combined with suppression of vascular endothelial growth factor (VEGF) causes a significantly greater reduction in DME than that seen with suppression of VEGF alone. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

  12. Omalizumab in Japanese children with severe allergic asthma uncontrolled with standard therapy.

    Science.gov (United States)

    Odajima, Hiroshi; Ebisawa, Motohiro; Nagakura, Toshikazu; Fujisawa, Takao; Akasawa, Akira; Ito, Komei; Doi, Satoru; Yamaguchi, Koichi; Katsunuma, Toshio; Kurihara, Kazuyuki; Kondo, Naomi; Sugai, Kazuko; Nambu, Mitsuhiko; Hoshioka, Akira; Yoshihara, Shigemi; Sato, Norio; Seko, Noriko; Nishima, Sankei

    2015-10-01

    Omalizumab has demonstrated clinical benefits in children with moderate to severe allergic asthma. However, no studies have been performed in Japanese asthmatic children. The aim of this study was to evaluate the efficacy including free IgE suppression and safety of omalizumab in Japanese children with severe allergic asthma. The primary objective was to examine whether omalizumab decreases serum free IgE levels to less than 25 ng/ml (target level of suppression). Thirty-eight Japanese children (6-15 years) with uncontrolled severe allergic asthma despite inhaled corticosteroids (>200 μg/day fluticasone propionate or equivalent) and two or more controller therapies received add-on treatment with omalizumab in a 24-week, multicenter, uncontrolled, open-label study. The geometric mean serum free IgE level at 24 weeks was 15.6 ng/mL. Compared with baseline, total asthma symptom scores, daily activity scores and nocturnal sleep scores at 24 weeks were significantly improved. The rates of asthma exacerbation and hospitalization due to asthma were reduced by 69.2% and 78.2%, respectively (p omalizumab decreased free IgE levels to less than 25 ng/mL. Omalizumab improved asthma control and was well-tolerated, as well. Copyright © 2015 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

  13. Multiple roles of glyoxalase 1-mediated suppression of methylglyoxal glycation in cancer biology-Involvement in tumour suppression, tumour growth, multidrug resistance and target for chemotherapy.

    Science.gov (United States)

    Rabbani, Naila; Xue, Mingzhan; Weickert, Martin O; Thornalley, Paul J

    2018-04-01

    Glyoxalase 1 (Glo1) is part of the glyoxalase system in the cytoplasm of all human cells. It catalyses the glutathione-dependent removal of the endogenous reactive dicarbonyl metabolite, methylglyoxal (MG). MG is formed mainly as a side product of anaerobic glycolysis. It modifies protein and DNA to form mainly hydroimidazolone MG-H1 and imidazopurinone MGdG adducts, respectively. Abnormal accumulation of MG, dicarbonyl stress, increases adduct levels which may induce apoptosis and replication catastrophe. In the non-malignant state, Glo1 is a tumour suppressor protein and small molecule inducers of Glo1 expression may find use in cancer prevention. Increased Glo1 expression is permissive for growth of tumours with high glycolytic activity and is thereby a biomarker of tumour growth. High Glo1 expression is a cause of multi-drug resistance. It is produced by over-activation of the Nrf2 pathway and GLO1 amplification. Glo1 inhibitors are antitumour agents, inducing apoptosis and necrosis, and anoikis. Tumour stem cells and tumours with high flux of MG formation and Glo1 expression are sensitive to Glo1 inhibitor therapy. It is likely that MG-induced cell death contributes to the mechanism of action of current antitumour agents. Common refractory tumours have high prevalence of Glo1 overexpression for which Glo1 inhibitors may improve therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Treatment Combining X-Irradiation and a Ribonucleoside Anticancer Drug, TAS106, Effectively Suppresses the Growth of Tumor Cells Transplanted in Mice

    International Nuclear Information System (INIS)

    Yasui, Hironobu; Inanami, Osamu; Asanuma, Taketoshi; Iizuka, Daisuke; Nakajima, Takayuki; Kon, Yasuhiro; Matsuda, Akira; Kuwabara, Mikinori

    2007-01-01

    Purpose: To examine the in vivo antitumor efficacy of X-irradiation combined with administration of a ribonucleoside anticancer drug, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (TAS106, ECyd), to tumor cell-transplanted mice. Methods and Materials: Colon26 murine rectum adenocarcinoma cells and MKN45 human gastric adenocarcinoma cells were inoculated into the footpad in BALB/c mice and severe combined immunodeficient mice, respectively. They were treated with a relatively low dose of X-irradiation (2 Gy) and low amounts of TAS106 (0.1 mg/kg and 0.5 mg/kg). The tumor growth was monitored by measuring the tumor volume from Day 5 to Day 16 for Colon26 and from Day 7 to Day 20 for MKN45. Histologic analyses for proliferative and apoptotic cells in the tumors were performed using Ki-67 immunohistochemical and terminal deoxynucleotidyl transferase-mediated nick end labeling staining. The expression of survivin, a key molecule related to tumor survival, was assessed by quantitative polymerase chain reaction and immunohistochemical analysis. Results: When X-irradiation and TAS106 treatment were combined, significant inhibition of tumor growth was observed in both types of tumors compared with mice treated with X-irradiation or TAS106 alone. Marked inhibition of tumor growth was observed in half of the mice that received the combined treatment three times at 2-day intervals. Parallel to these phenomena, the suppression of survivin expression and appearance of Ki-67-negative and apoptotic cells were observed. Conclusions: X-irradiation and TAS106 effectively suppress tumor growth in mice. The inhibition of survivin expression by TAS106 is thought to mainly contribute to the suppression of the tumor growth

  15. 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.

  16. Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth.

    Science.gov (United States)

    Cramer, Shira L; Saha, Achinto; Liu, Jinyun; Tadi, Surendar; Tiziani, Stefano; Yan, Wupeng; Triplett, Kendra; Lamb, Candice; Alters, Susan E; Rowlinson, Scott; Zhang, Yan Jessie; Keating, Michael J; Huang, Peng; DiGiovanni, John; Georgiou, George; Stone, Everett

    2017-01-01

    Cancer cells experience higher oxidative stress from reactive oxygen species (ROS) than do non-malignant cells because of genetic alterations and abnormal growth; as a result, maintenance of the antioxidant glutathione (GSH) is essential for their survival and proliferation. Under conditions of elevated ROS, endogenous L-cysteine (L-Cys) production is insufficient for GSH synthesis. This necessitates uptake of L-Cys that is predominantly in its disulfide form, L-cystine (CSSC), via the xCT(-) transporter. We show that administration of an engineered and pharmacologically optimized human cyst(e)inase enzyme mediates sustained depletion of the extracellular L-Cys and CSSC pool in mice and non-human primates. Treatment with this enzyme selectively causes cell cycle arrest and death in cancer cells due to depletion of intracellular GSH and ensuing elevated ROS; yet this treatment results in no apparent toxicities in mice even after months of continuous treatment. Cyst(e)inase suppressed the growth of prostate carcinoma allografts, reduced tumor growth in both prostate and breast cancer xenografts and doubled the median survival time of TCL1-Tg:p53 -/- mice, which develop disease resembling human chronic lymphocytic leukemia. It was observed that enzyme-mediated depletion of the serum L-Cys and CSSC pool suppresses the growth of multiple tumors, yet is very well tolerated for prolonged periods, suggesting that cyst(e)inase represents a safe and effective therapeutic modality for inactivating antioxidant cellular responses in a wide range of malignancies.

  17. The HLJ1-targeting drug screening identified Chinese herb andrographolide that can suppress tumour growth and invasion in non-small-cell lung cancer.

    Science.gov (United States)

    Lai, Yi-Hua; Yu, Sung-Liang; Chen, Hsuan-Yu; Wang, Chi-Chung; Chen, Huei-Wen; Chen, Jeremy J W

    2013-05-01

    HLJ1 is a novel tumour suppressor and is a potential druggable target for non-small-cell lung cancer (NSCLC). In this report, using a promoter-containing enhancer region as the HLJ1-targeting drug-screening platform, we identified several herbal compounds from a Chinese herbal bank with the capacity to enhance HLJ1 promoter activity and suppress tumour growth and invasion of NSCLC. Among the herbal drugs identified, the andrographolide (from Andrographis paniculata [Burm. f.] Nees.) most significantly induced HLJ1 expression and suppressed tumorigenesis both in vitro and in vivo. The andrographolide upregulates HLJ1 via JunB activation, which modulates AP-2α binding at the MMP-2 promoter and represses the expression of MMP-2. In addition, silencing of HLJ1 partially reverses the inhibition of cancer-cell invasion by andrographolide. Microarray transcriptomic analysis was performed to comprehensively depict the andrographolide-regulated signalling pathways. We showed that andrographolide can affect 939 genes (analysis of variance, false discovery rate andrographolide on anticancer invasion and proliferation. In conclusion, the HLJ1-targeting drug-screening platform is useful for screening of novel anticancer compounds. Using this platform, we identified andrographolide is a promising new anticancer agent that could suppress tumour growth and invasion in NSCLC.

  18. Suppression of emittance growth caused by mechanical vibrations of magnetic elements in presence of beam-beam effects in the SSC

    International Nuclear Information System (INIS)

    Lebedev, V.A.; Parkhomchuk, V.V.; Shil'tsev, V.D.; Skrinskij, A.N.

    1991-01-01

    A ground motion produces shifts of storage ring quadrupoles. It strongly influences on the beam behaviour in large proton (anti)proton colliders due to the closed orbit distortion and due to the transverse emittance growth. Calculations of both effects are presented in this paper. An active feedback system is useful for the emittance growth suppression. It is shown that in this case the main parameter which determines the emittance growth is the betatron tune spread due to the beam-beam effects. A simple analytical model is considered which results are in good coincidence with computer simulations. All calculations are adapted to the Superconducting Super Collider (SSC). 13 refs.; 9 figs.; 3 tabs

  19. Gleditsia Saponin C Induces A549 Cell Apoptosis via Caspase-Dependent Cascade and Suppresses Tumor Growth on Xenografts Tumor Animal Model

    Directory of Open Access Journals (Sweden)

    Ye Cheng

    2018-01-01

    Full Text Available Saponins are natural compounds and possess the most promising anti-cancer function. Here, a saponin gleditsia saponin C (GSC, extracted from gleditsiae fructus abnormalis, could induce apoptosis of lung tumor cell line A549 via caspase dependent cascade and this effect could be prevented by the caspase inhibitors. In addition, GSC induced cell death companied with an increase ratio of Bax:Bcl-2 and inhibition of ERK and Akt signaling pathways. Meanwhile, GSC suppressed TNFα inducing NF-κB activation and increased the susceptibility of lung cancer cell to TNFα induced apoptosis. Furthermore, on mouse xenograft model, GSC significantly suppressed tumor growth and induced cancer cell apoptosis, which validated the anti-tumor effect of GSC. Based on these results, GSC might be a promising drug candidate of anti-lung cancer for its potential clinical applications.

  20. Suppression of hyphal growth of soil-borne fungi by dune soils from vigorous and declining stands of Ammophila arenaria

    NARCIS (Netherlands)

    De Boer, W.; Klein Gunnewiek, P.J.A.; Woldendorp, J.W.

    1998-01-01

    A study was carried out to determine whether expansion of marram-grass stands (Ammophila arenaria (L.) Link) on acidic inner Dutch coastal dunes was caused by suppressiveness of soils from these stands against three potential pathogenic fungi of marram grass, namely Fusarium culmorum (W. G. Sm.)

  1. miR-129 suppresses tumor cell growth and invasion by targeting PAK5 in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zhai, Jian [Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438 (China); Qu, Shuping [Department II of Special Medical Care, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438 (China); Li, Xiaowei; Zhong, Jiaming; Chen, Xiaoxia [Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438 (China); Qu, Zengqiang, E-mail: drquzengqiang@163.com [Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438 (China); Wu, Dong, E-mail: wudongstc@126.com [Department II of Special Medical Care, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438 (China)

    2015-08-14

    Emerging evidence suggests that microRNAs (miRNAs) play important roles in regulating HCC development and progression; however, the mechanisms by which their specific functions and mechanisms remained to be further explored. miR-129 has been reported in gastric cancers, lung cancer and colon cancer. In this study, we disclosed a new tumor suppresser function of miR-129 in HCC. We also found the downregulation of miR-129 occurred in nearly 3/4 of the tumors examined (56/76) compared with adjacent nontumorous tissues, which was more importantly, correlated to the advanced stage and vascular invasion. We then demonstrated that miR-129 overexpression attenuated HCC cells proliferation and invasion, inducing apoptosis in vitro. Moreover, we used miR-129 antagonist and found that anti-miR-129 promoted HCC cells malignant phenotypes. Mechanistically, our further investigations revealed that miR-129 suppressed cell proliferation and invasion by targeting the 3’-untranslated region of PAK5, as well as miR-129 silencing up-regulated PAK5 expression. Moreover, miR-129 expression was inversely correlated with PAK5 expression in 76 cases of HCC samples. RNA interference of PAK5 attenuated anti-miR-129 mediated cell proliferation and invasion in HCC cells. Taken together, these results demonstrated that miR-129 suppressed tumorigenesis and progression by directly targeting PAK5, defining miR-129 as a potential treatment target for HCC. - Highlights: • Decreased of miR-129 is found in HCC and associated with advanced stage and metastasis. • miR-129 suppresses proliferation and invasion of HCC cells. • miR-129 directly targets the 3′ UTR of PAK5 and diminishes PAK5 expression. • PAK5 is involved in miR-129 mediated suppression functions.

  2. Association of Controlled and Uncontrolled Hypertension With Workplace Productivity.

    Science.gov (United States)

    Unmuessig, Victoria; Fishman, Paul A; Vrijhoef, Hubertus J M; Elissen, Arianne M J; Grossman, David C

    2016-03-01

    The authors estimated the lost productive time (LPT) due to absenteeism and presenteeism among employees at the Group Health Cooperative with controlled and uncontrolled hypertension compared with normotensive patients. The patients responded to a survey inquiring about health behaviors with links to their medical record to identify diagnoses, blood pressure measurement, and prescription drug dispenses. Individuals with controlled hypertension were more likely to report any LPT relative to individuals with uncontrolled hypertension (40.6% vs 32.6%, Pabsenteeism compared with normotensive individuals (1.04 vs 0.59 hours; P=.001). Individuals with uncontrolled hypertension were more likely to report LPT due to absenteeism compared with individuals with controlled hypertension (1.35 vs 0.72 hours; P=.001). There were no significant differences between individuals with hypertension whose blood pressure was controlled and normotensive individuals with respect to the likelihood of reporting any LPT or in the amounts of absenteeism and presenteeism. © 2015 Wiley Periodicals, Inc.

  3. The antagonistic regulation of abscisic acid-inhibited root growth by brassinosteroids is partially mediated via direct suppression of ABSCISIC ACID INSENSITIVE 5 expression by BRASSINAZOLE RESISTANT 1.

    Science.gov (United States)

    Yang, Xiaorui; Bai, Yang; Shang, Jianxiu; Xin, Ruijiao; Tang, Wenqiang

    2016-09-01

    Brassinosteroids (BRs) and abscisic acid (ABA) are plant hormones that antagonistically regulate many aspects of plant growth and development; however, the mechanisms that regulate the crosstalk of these two hormones are still not well understood. BRs regulate plant growth and development by activating BRASSINAZOLE RESISTANT 1 (BZR1) family transcription factors. Here we show that the crosstalk between BRs and ABA signalling is partially mediated by BZR1 regulated gene expression. bzr1-1D is a dominant mutant with enhanced BR signalling; our results showed that bzr1-1D mutant is less sensitive to ABA-inhibited primary root growth. By RNA sequencing, a subset of BZR1 regulated ABA-responsive root genes were identified. Of these genes, the expression of a major ABA signalling component ABA INSENSITIVE 5 (ABI5) was found to be suppressed by BR and by BZR1. Additional evidences showed that BZR1 could bind strongly with several G-box cis-elements in the promoter of ABI5, suppress the expression of ABI5 and make plants less sensitive to ABA. Our study demonstrated that ABI5 is a direct target gene of BZR1, and modulating the expression of ABI5 by BZR1 plays important roles in regulating the crosstalk between the BR and ABA signalling pathways. © 2016 John Wiley & Sons Ltd.

  4. Styrene maleic acid-encapsulated RL71 micelles suppress tumor growth in a murine xenograft model of triple negative breast cancer.

    Science.gov (United States)

    Martey, Orleans; Nimick, Mhairi; Taurin, Sebastien; Sundararajan, Vignesh; Greish, Khaled; Rosengren, Rhonda J

    2017-01-01

    Patients with triple negative breast cancer have a poor prognosis due in part to the lack of targeted therapies. In the search for novel drugs, our laboratory has developed a second-generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidine-4-one (RL71), that exhibits potent in vitro cytotoxicity. To improve the clinical potential of this drug, we have encapsulated it in styrene maleic acid (SMA) micelles. SMA-RL71 showed improved biodistribution, and drug accumulation in the tumor increased 16-fold compared to control. SMA-RL71 (10 mg/kg, intravenously, two times a week for 2 weeks) also significantly suppressed tumor growth compared to control in a xenograft model of triple negative breast cancer. Free RL71 was unable to alter tumor growth. Tumors from SMA-RL71-treated mice showed a decrease in angiogenesis and an increase in apoptosis. The drug treatment also modulated various cell signaling proteins including the epidermal growth factor receptor, with the mechanisms for tumor suppression consistent with previous work with RL71 in vitro. The nanoformulation was also nontoxic as shown by normal levels of plasma markers for liver and kidney injury following weekly administration of SMA-RL71 (10 mg/kg) for 90 days. Thus, we report clinical potential following encapsulation of a novel curcumin derivative, RL71, in SMA micelles.

  5. Peroxisome Proliferator-Activated Receptor-γ Inhibits Transformed Growth of Non-Small Cell Lung Cancer Cells through Selective Suppression of Snail

    Directory of Open Access Journals (Sweden)

    Rashmi Choudhary

    2010-03-01

    Full Text Available Work from our laboratory and others has demonstrated that activation of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ inhibits transformed growth of non-small cell lung cancer (NSCLC cell lines in vitro and in vivo. We have demonstrated that activation of PPARγ promotes epithelial differentiation of NSCLC by increasing expression of E-cadherin, as well as inhibiting expression of COX-2 and nuclear factor-κB. The Snail family of transcription factors, which includes Snail (Snail1, Slug (Snail2, and ZEB1, is an important regulator of epithelial-mesenchymal transition, as well as cell survival. The goal of this study was to determine whether the biological responses to rosiglitazone, a member of the thiazolidinedione family of PPARγ activators, are mediated through the regulation of Snail family members. Our results indicate that, in two independent NSCLC cell lines, rosiglitazone specifically decreased expression of Snail, with no significant effect on either Slug or ZEB1. Suppression of Snail using short hairpin RNA silencing mimicked the effects of PPARγ activation, in inhibiting anchorage-independent growth, promoting acinar formation in three-dimensional culture, and inhibiting invasiveness. This was associated with the increased expression of E-cadherin and decreased expression of COX-2 and matrix metaloproteinases. Conversely, overexpression of Snail blocked the biological responses to rosiglitazone, increasing anchorage-independent growth, invasiveness, and promoting epithelial-mesenchymal transition. The suppression of Snail expression by rosiglitazone seemed to be independent of GSK-3 signaling but was rather mediated through suppression of extracellular signal-regulated kinase activity. These findings suggest that selective regulation of Snail may be critical in mediating the antitumorigenic effects of PPARγ activators.

  6. Identification of growth phenotype-related genes in Aspergillus oryzae by heterologous macroarray and suppression subtractive hybridization

    NARCIS (Netherlands)

    Biesebeke, R. te; Levin, A.; Sagt, C.; Bartels, J.; Goosen, T.; Ram, A.; Hondel, C. van den; Punt, P.

    2005-01-01

    Aspergillus oryzae requires polarized growth for colonization of solid substrates, and this growth phenotype differs from that seen in liquid medium. Various experimental approaches were used to identify genes that are differentially expressed when A. oryzae is grown on wheat kernels and in a

  7. Attenuation of the beta-catenin/TCF4 complex in colorectal cancer cells induces several growth-suppressive microRNAs that target cancer promoting genes

    DEFF Research Database (Denmark)

    Schepeler, Troels; Holm, Anja; Halvey, P

    2012-01-01

    Aberrant activation of the Wnt signaling pathway is causally involved in the formation of most colorectal cancers (CRCs). Although detailed knowledge exists regarding Wnt-regulated protein-coding genes, much less is known about the possible involvement of non-coding RNAs. Here we used TaqMan Array......RNAs are upregulated as a consequence of forced attenuation of Wnt signaling in CRC cells, and some of these miRNAs inhibit cell growth with concomitant suppression of several growth-stimulatory cancer-related genes....... MicroRNA Cards, capable of detecting 664 unique human microRNAs (miRNAs), to describe changes of the miRNA transcriptome following disruption of beta-catenin/TCF4 activity in DLD1 CRC cells. Most miRNAs appeared to respond independent of host gene regulation and proximal TCF4 chromatin occupancy...

  8. Conditions that Influence Drivers' Yielding Behavior for Uncontrolled Crossings

    Science.gov (United States)

    Bourquin, Eugene; Emerson, Robert Wall; Sauerburger, Dona

    2011-01-01

    Pedestrians with visual impairments need to cross streets where traffic signals and traffic signage are not present. This study examined the influences of several interventions, including a pedestrian's use of a mobility cane, on the behavior of drivers when they were expected to yield to a pedestrian crossing at an uncontrolled crossing.…

  9. Processes on Uncontrolled Aerodromes and Safety Indicators - Part I

    Directory of Open Access Journals (Sweden)

    Vladimír Plos

    2013-09-01

    Full Text Available This article describes the processes that take place at the beginning of each duty of dispatcher at uncontrolled aerodromes.Thanks to modeling and analysis of these processes, there is a possible to find critical ones and implement precise targeted safety measures.

  10. Unpredictable and Uncontrollable Events: A New Perspective on Experimental Neurosis

    Science.gov (United States)

    Kihlstrom, John F.; Mineka, Susan

    1978-01-01

    Recent work has shown that unpredictable and/or uncontrollable events can produce a variety of cognitive, affective, and somatic disturbances to the organism. These disturbances are compared to and found to be quite similar to the symptoms of the classic cases of experimental neurosis described by Pavlov, Gantt, Liddell, Masserman, and Wolpe.…

  11. Term Based Comparison Metrics for Controlled and Uncontrolled Indexing Languages

    Science.gov (United States)

    Good, B. M.; Tennis, J. T.

    2009-01-01

    Introduction: We define a collection of metrics for describing and comparing sets of terms in controlled and uncontrolled indexing languages and then show how these metrics can be used to characterize a set of languages spanning folksonomies, ontologies and thesauri. Method: Metrics for term set characterization and comparison were identified and…

  12. Androgen receptor (AR) degradation enhancer ASC-J9® in an FDA-approved formulated solution suppresses castration resistant prostate cancer cell growth.

    Science.gov (United States)

    Cheng, Max A; Chou, Fu-Ju; Wang, Keliang; Yang, Rachel; Ding, Jie; Zhang, Qiaoxia; Li, Gonghui; Yeh, Shuyuan; Xu, Defeng; Chang, Chawnshang

    2018-03-28

    ASC-J9 ® is a recently-developed androgen receptor (AR)-degradation enhancer that effectively suppresses castration resistant prostate cancer (PCa) cell proliferation and invasion. The optimal half maximum inhibitory concentrations (IC 50 ) of ASC-J9 ® at various PCa cell confluences (20%, 50%, and 100%) were assessed via both short-term MTT growth assays and long-term clonogenic proliferation assays. Our results indicate that the IC 50 values for ASC-J9 ® increased with increasing cell confluency. The IC 50 values were significantly decreased in PCa AR-positive cells compared to PCa AR-negative cells or in normal prostate cells. This suggests that ASC-J9 ® may function mainly via targeting the AR-positive PCa cells with limited unwanted side-effects to suppress the surrounding normal prostate cells. Mechanism dissection indicated that ASC-J9 ® might function via altering the apoptosis signals to suppress the PCa AR-negative PC-3 cells. Preclinical studies using multiple in vitro PCa cell lines and an in vivo mouse model with xenografted castration-resistant PCa CWR22Rv1 cells demonstrated that ASC-J9 ® has similar AR degradation effects when dissolved in FDA-approved solvents, including DMSO, PEG-400:Tween-80 (95:5), DMA:Labrasol:Tween-80 (10:45:45), and DMA:Labrasol:Tween-20 (10:45:45). Together, results from preclinical studies suggest a potential new therapy with AR-degradation enhancer ASC-J9 ® may potentially be ready to be used in human clinical trials in order to better suppress PCa at later castration resistant stages. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Astragaloside IV suppresses transforming growth factor-β1 induced fibrosis of cultured mouse renal fibroblasts via inhibition of the MAPK and NF-κB signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Che, Xiajing; Wang, Qin; Xie, Yuanyuan; Xu, Weijia; Shao, Xinghua; Mou, Shan, E-mail: shan_mou@126.com; Ni, Zhaohui, E-mail: doctor_nzh@126.com

    2015-09-04

    Renal fibrosis, a progressive process characterized by the accumulation of extracellular matrix (ECM) leading to organ dysfunction, is a characteristic of chronic kidney diseases. Among fibrogenic factors known to regulate the renal fibrotic process, transforming growth factor-β (TGF-β) plays a central role. In the present study, we examined the effect of Astragaloside IV (AS-IV), a component of the traditional Chinese medicinal plant Astragalus membranaceus, on the processes associated with renal fibrosis in cultured mouse renal fibroblasts treated with TGF-β1. RT-PCR, western blotting, immunofluorescence staining and collagen assays showed that AS-IV suppressed TGF-β1 induced fibroblast proliferation, transdifferentiation, and ECM production in a dose-dependent manner. Examination of the underlying mechanisms showed that the effect of AS-IV on the inhibition of fibroblast differentiation and ECM formation were mediated by its modulation of the activity of the MAPK and NF-κB signaling pathways. Taken together, our results indicate that AS-IV alleviates renal interstitial fibrosis via a mechanism involving the MAPK and NF-κB signaling pathways and demonstrate the therapeutic potential of AS-IV for the treatment of chronic kidney diseases. - Highlights: • AS-IV suppressed TGF-β1 induced renal fibroblast proliferation. • AS-IV suppressed TGF-β1 induced renal fibroblast transdifferentiation. • AS-IV suppressed TGF-β1 induced ECM production. • AS-IV alleviates renal fibrosis via the MAPK and NF-κB signaling pathways.

  14. Suppression of cancer growth in mice by adeno-associated virus vector-mediated IFN-beta expression driven by hTERT promoter.

    Science.gov (United States)

    He, Ling Feng; Wang, Yi Gang; Xiao, Tian; Zhang, Kang Jiang; Li, Gong Chu; Gu, Jin Fa; Chu, Liang; Tang, Wen Hao; Tan, Wen-Song; Liu, Xin Yuan

    2009-12-28

    Adeno-associated virus (AAV) has rapidly become a promising gene delivery vehicle for its excellent advantages of non-immunogenic, low pathogenicity and long-term gene expression in vivo. However, a major obstacle in development of effective AAV vector is the lack of tissue specificity, which caused low efficiency of AAV transfer to target cells. The application of human telomerase reverse transcriptase (hTERT) promoter is a prior targeting strategy for AAV in cancer gene therapy as hTERT activity is transcriptionally upregulated in most cancer cells. In the present work, we investigated whether AAV-mediated human interferon beta (IFN-beta) gene driven by hTERT promoter could specifically express in tumor cells and suppress tumor cell growth. Our data demonstrated that hTERT promoter-driven IFN-beta expression was the tumor-specific, decreased the cell viability of tumor cells but not normal cells, and induced tumor cell apoptosis via activation of caspase pathway and release of cytochrome c. AAV-mediated IFN-beta expression driven by hTERT promoter significantly suppressed the growth of colorectal cancer and lung cancer xenograft in mice and resulted in tumor cells death in vivo. These data suggested that AAVs in combination with hTERT-mediated IFN-beta expression could exert potential antitumor activity and provide a novel targeting approach to clinical gene therapy of varieties of cancers.

  15. Honokiol inhibits sphere formation and xenograft growth of oral cancer side population cells accompanied with JAK/STAT signaling pathway suppression and apoptosis induction

    International Nuclear Information System (INIS)

    Huang, Jhy-Shrian; Yao, Chih-Jung; Chuang, Shuang-En; Yeh, Chi-Tai; Lee, Liang-Ming; Chen, Ruei-Ming; Chao, Wan-Ju; Whang-Peng, Jacqueline; Lai, Gi-Ming

    2016-01-01

    Eliminating cancer stem cells (CSCs) has been suggested for prevention of tumor recurrence and metastasis. Honokiol, an active compound of Magnolia officinalis, had been proposed to be a potential candidate drug for cancer treatment. We explored its effects on the elimination of oral CSCs both in vitro and in vivo. By using the Hoechst side population (SP) technique, CSCs-like SP cells were isolated from human oral squamous cell carcinoma (OSCC) cell lines, SAS and OECM-1. Effects of honokiol on the apoptosis and signaling pathways of SP-derived spheres were examined by Annexin V/Propidium iodide staining and Western blotting, respectively. The in vivo effectiveness was examined by xenograft mouse model and immunohistochemical tissue staining. The SP cells possessed higher stemness marker expression (ABCG2, Ep-CAM, Oct-4 and Nestin), clonogenicity, sphere formation capacity as well as tumorigenicity when compared to the parental cells. Treatment of these SP-derived spheres with honokiol resulted in apoptosis induction via Bax/Bcl-2 and caspase-3-dependent pathway. This apoptosis induction was associated with marked suppression of JAK2/STAT3, Akt and Erk signaling pathways in honokiol-treated SAS spheres. Consistent with its effect on JAK2/STAT3 suppression, honokiol also markedly inhibited IL-6-mediated migration of SAS cells. Accordingly, honokiol dose-dependently inhibited the growth of SAS SP xenograft and markedly reduced the immunohistochemical staining of PCNA and endothelial marker CD31 in the xenograft tumor. Honokiol suppressed the sphere formation and xenograft growth of oral CSC-like cells in association with apoptosis induction and inhibition of survival/proliferation signaling pathways as well as angiogenesis. These results suggest its potential as an integrative medicine for combating oral cancer through targeting on CSCs. The online version of this article (doi:10.1186/s12885-016-2265-6) contains supplementary material, which is available to

  16. EGCG Inhibits Proliferation, Invasiveness and Tumor Growth by Up-Regulation of Adhesion Molecules, Suppression of Gelatinases Activity, and Induction of Apoptosis in Nasopharyngeal Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Chih-Yeu Fang

    2015-01-01

    Full Text Available (−-Epigallocatechin-3-gallate (EGCG, a major green tea polyphenol, has been shown to inhibit the proliferation of a variety of tumor cells. Epidemiological studies have shown that drinking green tea can reduce the incidence of nasopharyngeal carcinoma (NPC, yet the underlying mechanism is not well understood. In this study, the inhibitory effect of EGCG was tested on a set of Epstein Barr virus-negative and -positive NPC cell lines. Treatment with EGCG inhibited the proliferation of NPC cells but did not affect the growth of a non-malignant nasopharyngeal cell line, NP460hTert. Moreover, EGCG treated cells had reduced migration and invasive properties. The expression of the cell adhesion molecules E-cadherin and β-catenin was found to be up-regulated by EGCG treatment, while the down-regulation of matrix metalloproteinases (MMP-2 and MMP-9 were found to be mediated by suppression of extracellular signal-regulated kinase (ERK phosphorylation and AP-1 and Sp1 transactivation. Spheroid formation by NPC cells in suspension was significantly inhibited by EGCG. Oral administration of EGCG was capable of suppressing tumor growth in xenografted mice bearing NPC tumors. Treatment with EGCG was found to elevate the expression of p53 and p21, and eventually led to apoptosis of NPC cells via caspase 3 activation. The nuclear translocation of NF-κB and β-catenin was also suppressed by EGCG treatment. These results indicate that EGCG can inhibit the proliferation and invasiveness, and induce apoptosis, of NPC cells, making it a promising agent for chemoprevention or adjuvant therapy of NPC.

  17. Prader-Willi region non-protein coding RNA 1 suppressed gastric cancer growth as a competing endogenous RNA of microRNA-425-5p.

    Science.gov (United States)

    Chen, Zihao; Ju, Hongping; Yu, Shan; Zhao, Ting; Jing, Xiaojie; Li, Ping; Jia, Jing; Li, Nan; Tan, Bibo; Li, Yong

    2018-03-13

    Gastric cancer (GC) is one of a major global health problem especially in Asia. Nowadays, long non-coding RNA has gained significantly attention in the current research climate such as carcinogenesis. This research desired to explore the mechanism of Prader-Willi region non-protein coding RNA 1 (PWRN1) on regulating GC process. Differentially expressed lncRNAs in GC tissues were screened out through microarray analysis. The RNA and protein expression level was detected by qRT-PCR and western blot. Cell proliferation, apoptosis rate, metastasis abilities were respectively determined by CCK8, flow cytometry, wound healing and transwell assay. The luciferase reporter system was used to verify the targeting relationships between PWRN1, miR-425-5p and PTEN RIP assay was performed to prove whether PWRN1 acted as a competitive endogenous RNA (ceRNA) of miR-425-5p. Tumor xenograft model and immunohistochemistry were developed to study the influence of PWRN1 on tumor growth in vivo Microarray analysis determined that PWRN1 was different expressed between GC tissues and adjacent tissues. QRT-PCR revealed PWRN1 low expression in GC tissues and cells. PWRN1 up-regulated could reduce proliferation and metastasis and increased apoptosis in GC cells, while miR-425-5p had reverse effects. The RIP assay indicated that PWRN1 may target an oncogene miR-425-5p. The tumor xenograft assay found that up-regulated PWRN1 suppressed the tumor growth. The bioinformatic analysis, luciferase assay and western blot indicated that PWRN1 affected PTEN/Akt/MDM2/p53 axis via suppressing miR-425-5p. Our findings suggested that PWRN1 functioned as a ceRNA targeting to miR-425-5p and suppressed GC development via p53 signaling pathway. ©2018 The Author(s).

  18. Cantharidin Inhibits the Growth of Triple-Negative Breast Cancer Cells by Suppressing Autophagy and Inducing Apoptosis in Vitro and in Vivo

    Directory of Open Access Journals (Sweden)

    Hong-chang Li

    2017-10-01

    Full Text Available Background/Aims: Cantharidin, a type of terpenoid secreted by the blister beetle Mylabris phalerata (Pallas, has attracted great attention in cancer therapy because of its potential anti-cancer activities. Here, we report the effects on apoptosis and autophagy in human triple-negative breast cancer (TNBC cell lines after treatment with cantharidin and attempt to elucidate the underlying mechanisms. Methods: MDA-MB-231 and MDA-MB-468 cells were treated with cantharidin and cell proliferation was examined using CCK-8 and clone formation assays. The expression of apoptosis- and autophagy-associated proteins was detected by western blotting. Cells were infected with lentivirus carrying the Beclin-1 gene, and MDA-MB-231-beclin1 (MB231-Bec and MDA-MB-468-beclin-1(MB468-Bec cells stably expressing Beclin-1 were established. Autophagic vacuoles in cells were observed with LC3 staining using fluorescence microscopy, and apoptotic cells were detected via flow cytometry. Tumor growth was assessed by subcutaneous inoculation of TNBC cells into BALB/c nude mice. Results: Cantharidin inhibited the proliferation of MDA-MB-231 and MDA-MB-468 cells, and induced cell apoptosis. Cantharidin additionally inhibited the conversion of LC3 I to LC3 II and autophagosome formation by suppressing the expression of Beclin-1. Furthermore, overexpression of Beclin-1 in TNBC cells attenuated the cytotoxicity of cantharidin. In vivo, cantharidin inhibited the growth of MDA-MB-231 and MDA-MB-468 xenografts in nude mice by suppressing autophagy and inducing apoptosis, and Beclin-1 overexpression in TNBC cells reduced the efficacy of cantharidin. Conclusions: Cantharidin inhibits autophagy by suppressing Beclin-1 expression and inducing apoptosis of TNBC cells in vitro and in vivo, thereby representing a potential strategy for the treatment of TNBC.

  19. Resveratrol inhibits transforming growth factor-β2-induced epithelial-to-mesenchymal transition in human retinal pigment epithelial cells by suppressing the Smad pathway

    Directory of Open Access Journals (Sweden)

    Chen CL

    2017-01-01

    Full Text Available Ching-Long Chen,1,2 Yi-Hao Chen,1,2 Ming-Cheng Tai,2 Chang-Min Liang,2 Da-Wen Lu,1,2 Jiann-Torng Chen1,2 1Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan; 2Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan Abstract: Proliferative vitreoretinopathy (PVR is the main cause of failure following retinal detachment surgery. Transforming growth factor (TGF-β2-induced epithelial-to-mesenchymal transition (EMT plays an important role in the development of PVR, and EMT inhibition decreases collagen gel contraction and fibrotic membrane formation, resulting in prevention of PVR. Resveratrol is naturally found in red wine and has inhibitory effects on EMT. Resveratrol is widely used in cardioprotection, neuroprotection, chemotherapy, and antiaging therapy. The purpose of this study was to investigate the effects of resveratrol on TGF-β2-induced EMT in ARPE-19 cells in vitro. We found that resveratrol suppressed the decrease of zona occludens-1 (ZO-1 and caused an increase of alpha-smooth muscle actin expression in TGF-β2-treated ARPE-19 cells, assessed using Western blots; moreover, it also suppressed the decrease in ZO-1 and the increase of vimentin expression, observed using immunocytochemistry. Resveratrol attenuated TGF-β2-induced wound closure and cell migration in ARPE-19 cells in a scratch wound test and modified Boyden chamber assay, respectively. We also found that resveratrol reduced collagen gel contraction – assessed by collagen matrix contraction assay – and suppressed the phosphorylation of Smad2 and Smad3 in TGF-β2-treated ARPE-19 cells. These results suggest that resveratrol mediates anti-EMT effects, which could be used in the prevention of PVR. Keywords: resveratrol, epithelial-to-mesenchymal transition, proliferative vitreoretinopathy, transforming growth factor-β2, retinal pigment epithelial cells

  20. Hepatic Radiofrequency Ablation–induced Stimulation of Distant Tumor Growth Is Suppressed by c-Met Inhibition

    Science.gov (United States)

    Kumar, Gaurav; Moussa, Marwan; Wang, Yuanguo; Rozenblum, Nir; Galun, Eithan; Goldberg, S. Nahum

    2016-01-01

    Purpose To elucidate how hepatic radiofrequency (RF) ablation affects distant extrahepatic tumor growth by means of two key molecular pathways. Materials and Methods Rats were used in this institutional animal care and use committee–approved study. First, the effect of hepatic RF ablation on distant subcutaneous in situ R3230 and MATBIII breast tumors was evaluated. Animals were randomly assigned to standardized RF ablation, sham procedure, or no treatment. Tumor growth rate was measured for 3½ to 7 days. Then, tissue was harvested for Ki-67 proliferative indexes and CD34 microvascular density. Second, hepatic RF ablation was performed for hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and c-Met receptor expression measurement in periablational rim, serum, and distant tumor 24 hours to 7 days after ablation. Third, hepatic RF ablation was combined with either a c-Met inhibitor (PHA-665752) or VEGF receptor inhibitor (semaxanib) and compared with sham or drug alone arms to assess distant tumor growth and growth factor levels. Finally, hepatic RF ablation was performed in rats with c-Met–negative R3230 tumors for comparison with the native c-Met–positive line. Tumor size and immunohistochemical quantification at day 0 and at sacrifice were compared with analysis of variance and the two-tailed Student t test. Tumor growth curves before and after treatment were analyzed with linear regression analysis to determine mean slopes of pre- and posttreatment growth curves on a per-tumor basis and were compared with analysis of variance and paired two-tailed t tests. Results After RF ablation of normal liver, distant R3230 tumors were substantially larger at 7 days compared with tumors treated with the sham procedure and untreated tumors, with higher growth rates and tumor cell proliferation. Similar findings were observed in MATBIII tumors. Hepatic RF ablation predominantly increased periablational and serum HGF and downstream distant tumor

  1. Total Saponin from Root of Actinidia valvata Dunn Inhibits Hepatoma 22 Growth and Metastasis In Vivo by Suppression Angiogenesis

    Directory of Open Access Journals (Sweden)

    Guo-Yin Zheng

    2012-01-01

    Full Text Available The root of Actinidia valvata dunn has been widely used in the treatment of hepatocellular carcinoma (HCC, proved to be beneficial for a longer and better life in China. In present work, total saponin from root of Actinidia valvata Dunn (TSAVD was extracted, and its effects on hepatoma H22-based mouse in vivo were observed. Primarily transplanted hypodermal hepatoma H22-based mice were used to observe TSAVD effect on tumor growth. The microvessel density (MVD, vascular endothelial growth factor (VEGF, basic fibroblast growth factor (bFGF are characterized factors of angiogenesis, which were compared between TSAVD-treated and control groups. Antimetastasis effect on experimental pulmonary metastasis hepatoma mice was also observed in the study. The results demonstrated that TSAVD can effectively inhibit HCC growth and metastasis in vivo, inhibit the formation of microvessel, downregulate expressions of VEGF and bFGF, and retrain angiogenesis of hepatoma 22 which could be one of the reasons.

  2. Inhibition of IL-17A suppresses enhanced-tumor growth in low dose pre-irradiated tumor beds.

    Directory of Open Access Journals (Sweden)

    Eun-Jung Lee

    Full Text Available Ionizing radiation induces modification of the tumor microenvironment such as tumor surrounding region, which is relevant to treatment outcome after radiotherapy. In this study, the effects of pre-irradiated tumor beds on the growth of subsequently implanted tumors were investigated as well as underlying mechanism. The experimental model was set up by irradiating the right thighs of C3H/HeN mice with 5 Gy, followed by the implantation of HCa-I and MIH-2. Both implanted tumors in the pre-irradiated bed showed accelerated-growth compared to the control. Tumor-infiltrated lymphocyte (TIL levels were increased, as well as pro-tumor factors such as IL-6 and transforming growth factor-beta1 (TGF-β1 in the pre-irradiated group. In particular, the role of pro-tumor cytokine interleukin-17A (IL-17A was investigated as a possible target mechanism because IL-6 and TGF-β are key factors in Th17 cells differentiation from naïve T cells. IL-17A expression was increased not only in tumors, but also in CD4+ T cells isolated from the tumor draining lymph nodes. The effect of IL-17A on tumor growth was confirmed by treating tumors with IL-17A antibody, which abolished the acceleration of tumor growth. These results indicate that the upregulation of IL-17A seems to be a key factor for enhancing tumor growth in pre-irradiated tumor beds.

  3. Styrene maleic acid-encapsulated RL71 micelles suppress tumor growth in a murine xenograft model of triple negative breast cancer

    Directory of Open Access Journals (Sweden)

    Martey O

    2017-10-01

    Full Text Available Orleans Martey,1 Mhairi Nimick,1 Sebastien Taurin,1 Vignesh Sundararajan,1 Khaled Greish,2 Rhonda J Rosengren1 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2Department of Molecular Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain Abstract: Patients with triple negative breast cancer have a poor prognosis due in part to the lack of targeted therapies. In the search for novel drugs, our laboratory has developed a second-generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene-1-methylpiperidine-4-one (RL71, that exhibits potent in vitro cytotoxicity. To improve the clinical potential of this drug, we have encapsulated it in styrene maleic acid (SMA micelles. SMA-RL71 showed improved biodistribution, and drug accumulation in the tumor increased 16-fold compared to control. SMA-RL71 (10 mg/kg, intravenously, two times a week for 2 weeks also significantly suppressed tumor growth compared to control in a xenograft model of triple negative breast cancer. Free RL71 was unable to alter tumor growth. Tumors from SMA-RL71-treated mice showed a decrease in angiogenesis and an increase in apoptosis. The drug treatment also modulated various cell signaling proteins including the epidermal growth factor receptor, with the mechanisms for tumor suppression consistent with previous work with RL71 in vitro. The nanoformulation was also nontoxic as shown by normal levels of plasma markers for liver and kidney injury following weekly administration of SMA-RL71 (10 mg/kg for 90 days. Thus, we report clinical potential following encapsulation of a novel curcumin derivative, RL71, in SMA micelles. Keywords: curcumin derivatives, nanomedicine, EGFR, biodistribution

  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. Berberine suppresses tumorigenicity and growth of nasopharyngeal carcinoma cells by inhibiting STAT3 activation induced by tumor associated fibroblasts

    International Nuclear Information System (INIS)

    Tsang, Chi Man; Cheung, Yuk Chun; Lui, Vivian Wai-Yan; Yip, Yim Ling; Zhang, Guitao; Lin, Victor Weitao; Cheung, Kenneth Chat-Pan; Feng, Yibin; Tsao, Sai Wah

    2013-01-01

    Cortidis rhizoma (Huanglian) and its major therapeutic component, berberine, have drawn extensive attention in recent years for their anti-cancer properties. Growth inhibitory effects of berberine on multiple types of human cancer cells have been reported. Berberine inhibits invasion, induces cell cycle arrest and apoptosis in human cancer cells. The anti-inflammatory property of berberine, involving inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) activation, has also been documented. In this study, we have examined the effects of berberine on tumorigenicity and growth of nasopharyngeal carcinoma (NPC) cells and their relationship to STAT3 signaling using both in vivo and in vitro models. Berberine effectively inhibited the tumorigenicity and growth of an EBV-positive NPC cell line (C666-1) in athymic nude mice. Inhibition of tumorigenic growth of NPC cells in vivo was correlated with effective inhibition of STAT3 activation in NPC cells inside the tumor xenografts grown in nude mice. In vitro, berberine inhibited both constitutive and IL-6-induced STAT3 activation in NPC cells. Inhibition of STAT3 activation by berberine induced growth inhibition and apoptotic response in NPC cells. Tumor-associated fibroblasts were found to secret IL-6 and the conditioned medium harvested from the fibroblasts also induced STAT3 activation in NPC cells. Furthermore, STAT3 activation by conditioned medium of tumor-associated fibroblasts could be blocked by berberine or antibodies against IL-6 and IL-6R. Our observation that berberine effectively inhibited activation of STAT3 induced by tumor-associated fibroblasts suggests a role of berberine in modulating the effects of tumor stroma on the growth of NPC cells. The effective inhibition of STAT3 activation in NPC cells by berberine supports its potential use in the treatment of NPC

  6. Suppression of growth and invasive behavior of human prostate cancer cells by ProstaCaid™: mechanism of activity.

    Science.gov (United States)

    Jiang, Jiahua; Eliaz, Isaac; Sliva, Daniel

    2011-06-01

    Since the use of dietary supplements as alternative treatments or adjuvant therapies in cancer treatment is growing, a scientific verification of their biological activity and the detailed mechanisms of their action are necessary for the acceptance of dietary supplements in conventional cancer treatments. In the present study we have evaluated the anti-cancer effects of dietary supplement ProstaCaid™ (PC) which contains mycelium from medicinal mushrooms (Ganoderma lucidum, Coriolus versicolor, Phellinus linteus), saw palmetto berry, pomegranate, pumpkin seed, green tea [40% epigallocatechin-3-gallate (EGCG)], Japanese knotweed (50% resveratrol), extracts of turmeric root (BCM-95®), grape skin, pygeum bark, sarsaparilla root, Scutellaria barbata, eleuthero root, Job's tears, astragalus root, skullcap, dandelion, coptis root, broccoli, and stinging nettle, with purified vitamin C, vitamin D3, selenium, quercetin, citrus bioflavonoid complex, β sitosterolzinc, lycopene, α lipoic acid, boron, berberine and 3.3'-diinodolymethane (DIM). We show that PC treatment resulted in the inhibition of cell proliferation of the highly invasive human hormone refractory (independent) PC-3 prostate cancer cells in a dose- and time-dependent manner with IC50 56.0, 45.6 and 39.0 µg/ml for 24, 48 and 72 h, respectively. DNA-microarray analysis demonstrated that PC inhibits proliferation through the modulation of expression of CCND1, CDK4, CDKN1A, E2F1, MAPK6 and PCNA genes. In addition, PC also suppresses metastatic behavior of PC-3 by the inhibition of cell adhesion, cell migration and cell invasion, which was associated with the down-regulation of expression of CAV1, IGF2, NR2F1, and PLAU genes and suppressed secretion of the urokinase plasminogen activator (uPA) from PC-3 cells. In conclusion, the dietary supplement PC is a promising natural complex with the potency to inhibit invasive human prostate cancer.

  7. Selective suppression of autocatalytic caspase-3 driven by two-step transcriptional amplified human telomerase reverse transcriptase promoter on ovarian carcinoma growth in vitro and in mice.

    Science.gov (United States)

    Song, Yue; Xin, Xing; Xia, Zhijun; Zhai, Xingyue; Shen, Keng

    2014-07-01

    The objective of our study was to construct recombinant adenovirus (rAd) AdHTVP2G5-rev-casp3, which expresses autocatalytic caspase-3 driven by human telomerase reverse transcriptase promoter (hTERTp) with a two-step transcription amplification (TSTA) system and investigate its antitumor effects on ovarian cancer in vitro and in vivo. Fluorescent detection was used to detect EGFP expression in various cells. Cell viabilities were determined using the Cell Counting Kit-8 and flow cytometry. RT-PCR and immunoblotting assays were used to detect cellular apoptotic activities. Tumor growth and survival of tumor-bearing mice were studied. The hTERTp-TSTA system showed the strongest activity in hTERT-positive cancer cells when compared with hTERTp and cytomeglovirus promoter (CMVp). In contrast, it showed no activity in hTERT‑negative HUVECs. AdHTVP2G5‑rev-casp3 markedly suppressed the survival of AO cells in a dose-dependent modality with a viability rate of 17.8 ± 3.5% at an MOI of 70, which was significantly lower than that by AdHT-rev-casp3 and Ad-rev-casp3 (rAds which express rev-caspase-3 driven by hTERTp and CMVp, respectively). In contrast, AdHTVP2G5‑rev-casp3 induced little HUVEC death with a viability rate of 92.7 ± 5.2% at the same MOI. Additionally, AdHTVP2G5-rev-casp3 (MOI=70) caused significant apoptosis in AO cells with an apoptotic rate of 42%. The tumor growth suppression rate of AdHTVP2G5-rev-casp3 was 81.52%, significantly higher than that of AdHT-rev-casp3 (54.94%) or Ad-rev-casp3 (21.35%). AdHTVP2G5-rev-casp3 significantly improved the survival of tumor-bearing mice with little liver damage, with a mean survival of 258 ± 28 days. These results showed that AdHTVP2G5-rev-casp3 caused effective apoptosis with significant tumor selectivity, strongly suppressed tumor growth and improved mouse survival with little liver toxicity. It can be a potent therapeutic agent for tumor targeted treatment of ovarian cancer.

  8. 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

  9. EGFR-targeted plasmonic magnetic nanoparticles suppress lung tumor growth by abrogating G2/M cell-cycle arrest and inducing DNA damage

    Directory of Open Access Journals (Sweden)

    Kuroda S

    2014-08-01

    G2/M checkpoint by inhibiting BRCA1, Chk1, and phospho-Cdc2/CDK1 protein expression. In vivo therapy studies showed 225-NP treatment reduced EGFR phosphorylation, increased γH2AX foci, and induced tumor cell apoptosis, resulting in suppression of tumor growth. Conclusion: The 225-NP treatment induces DNA damage and abrogates G2/M phase of the cell cycle, leading to cellular apoptosis and suppression of lung tumor growth both in vitro and in vivo. Our findings provide a rationale for combining 225-NP with other DNA-damaging agents for achieving enhanced anticancer activity. Keywords: lung cancer, epidermal growth factor receptor, autophagy

  10. Local uncontrollability for affine control systems with jumps

    Science.gov (United States)

    Treanţă, Savin

    2017-09-01

    This paper investigates affine control systems with jumps for which the ideal If(g1, …, gm) generated by the drift vector field f in the Lie algebra L(f, g1, …, gm) can be imbedded as a kernel of a linear first-order partial differential equation. It will lead us to uncontrollable affine control systems with jumps for which the corresponding reachable sets are included in explicitly described differentiable manifolds.

  11. Mucormycosis and Myiasis in Uncontrolled Diabetes: A Double Whammy

    Directory of Open Access Journals (Sweden)

    Om Prakash D Toshniwal

    2011-01-01

    Full Text Available Mucormycosis is a rare, often fatal opportunistic fungal infection that is caused by an aerobic saprophytic fungus belonging to the order mucorales and class zygomycetes. Myiasis is caused by the members of the Diptera fly family that lay eggs or larvae on food, necrotic tissue, open wounds, and unbroken skin or mucosa. We report a rare case of mucormycosis coexisting with oral myiasis in a 50-year-old woman with uncontrolled diabetes mellitus.

  12. Injury due to uncontrolled acceleration of an electric wheelchair.

    Science.gov (United States)

    Becker, D G; Washington, B V; Devlin, P M; Zook, J E; Edlich, R F

    1991-01-01

    Approximately 750,000 disabled individuals use electrical platform mobility aids (wheelchairs) for adaptive transportation. Because there are no mandatory standards for platform mobility aids and wheelchairs, these adaptive transportation aids are prone to potential design and maintenance problems. An injury caused by uncontrolled acceleration of a platform mobility aid is reported. Examination of the platform mobility aid identified a defect in its speed control regulator that has been subsequently corrected by the manufacturer.

  13. Vanillin Analogues o-Vanillin and 2,4,6-Trihydroxybenzaldehyde Inhibit NFĸB Activation and Suppress Growth of A375 Human Melanoma.

    Science.gov (United States)

    Marton, Annamária; Kúsz, Erzsébet; Kolozsi, Csongor; Tubak, Vilmos; Zagotto, Giuseppe; Buzás, Krisztina; Quintieri, Luigi; Vizler, Csaba

    2016-11-01

    Constitutive activation of nuclear factor kappa-B (NFĸB) is a hallmark of various cancer types, including melanoma. Chemotherapy may further increase tumour NFĸB activity, a phenomenon that, in turn, exacerbates drug resistance. This study aimed at preliminary screening of a panel of aromatic aldehydes, including vanillin, for cytotoxicity and suppression of tumour cell NFĸB activity. The cytotoxic and NFĸB-inhibitory effects of 10 aromatic aldehydes, including vanillin, were investigated in cultured A375 human melanoma cells. Each compound was assayed alone and in combination with the model NFĸB-activating drug doxorubicin. The most promising analogues were then tested alone and in combination with 4-hydroperoxycyclophosphamide in vitro, and with cyclophosphamide in mice bearing A375 xenografts. The vanillin analogues o-vanillin and 2,4,6-trihydroxybenzaldehyde exhibited cytotoxicity against cultured A375 cells, and inhibited doxorubicin- and 4-hydroperoxycyclophosphamide-induced NFĸB activation. They also suppressed A375 cell growth in mice. o-vanillin and 2,4,6-trihydroxybenzaldehyde deserve further evaluation as potential anticancer drugs. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  14. Bone Marrow Suppression by c-Kit Blockade Enhances Tumor Growth of Colorectal Metastases through the Action of Stromal Cell-Derived Factor-1

    Directory of Open Access Journals (Sweden)

    Kathrin Rupertus

    2012-01-01

    Full Text Available Background. Mobilization of c-Kit+ hematopoietic cells (HCs contributes to tumor vascularization. Whereas survival and proliferation of HCs are regulated by binding of the stem cell factor to its receptor c-Kit, migration of HCs is directed by stromal cell-derived factor (SDF-1. Therefore, targeting migration of HCs provides a promising new strategy of anti-tumor therapy. Methods. BALB/c mice (=16 were pretreated with an anti-c-Kit antibody followed by implantation of CT26.WT-GFP colorectal cancer cells into dorsal skinfold chambers. Animals (=8 additionally received a neutralizing anti-SDF-1 antibody. Animals (=8 treated with a control antibody served as controls. Investigations were performed using intravital fluorescence microscopy, immunohistochemistry, flow cytometry and western blot analysis. Results. Blockade of c-Kit significantly enhanced tumor cell engraftment compared to controls due to stimulation of tumor cell proliferation and invasion without markedly affecting tumor vascularization. C-Kit blockade significantly increased VEGF and CXCR4 expression within the growing tumors. Neutralization of SDF-1 completely antagonized this anti-c-Kit-associated tumor growth by suppression of tumor neovascularization, inhibition of tumor cell proliferation and reduction of muscular infiltration. Conclusion. Our study indicates that bone marrow suppression via anti-c-Kit pretreatment enhances tumor cell engraftment of colorectal metastases due to interaction with the SDF-1/CXCR4 pathway which is involved in HC-mediated tumor angiogenesis.

  15. Prepubertal exposure to arsenic(III) suppresses circulating insulin-like growth factor-1 (IGF-1) delaying sexual maturation in female rats.

    Science.gov (United States)

    Reilly, Michael P; Saca, James C; Hamilton, Alina; Solano, Rene F; Rivera, Jesse R; Whitehouse-Innis, Wendy; Parsons, Jason G; Dearth, Robert K

    2014-04-01

    Arsenic (As) is a prevalent environmental toxin readily accessible for human consumption and has been identified as an endocrine disruptor. However, it is not known what impact As has on female sexual maturation. Therefore, in the present study, we investigated the effects of prepubertal exposure on mammary gland development and pubertal onset in female rats. Results showed that prepubertal exposure to 10 mg/kg of arsenite (As(III)) delayed vaginal opening (VO) and prepubertal mammary gland maturation. We determined that As accumulates in the liver, disrupts hepatocyte function and suppresses serum levels of the puberty related hormone insulin-like growth factor 1 (IGF-1) in prepubertal animals. Overall, this is the first study to show that prepubertal exposure to As(III) acts peripherally to suppress circulating levels of IGF-1 resulting in delayed sexual maturation. Furthermore, this study identifies a critical window of increased susceptibility to As(III) that may have a lasting impact on female reproductive function. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Sema4D, the ligand for Plexin B1, suppresses c-Met activation and migration and promotes melanocyte survival and growth.

    Science.gov (United States)

    Soong, Joanne; Chen, Yulin; Shustef, Elina M; Scott, Glynis A

    2012-04-01

    Semaphorins are secreted and membrane-bound proteins involved in neural pathfinding, organogenesis, and tumor progression, through Plexin and neuropilin receptors. We recently reported that Plexin B1, the Semaphorin 4D (Sema4D) receptor, is a tumor-suppressor protein for melanoma, which functions, in part, through inhibition of the oncogenic c-Met tyrosine kinase receptor. In this report, we show that Sema4D is a protective paracrine factor for normal human melanocyte survival in response to UV irradiation, and that it stimulates proliferation and regulates the activity of the c-Met receptor. c-Met receptor signaling stimulates melanocyte migration, partly through downregulation of the cell adhesion molecule E-cadherin. Sema4D suppressed activation of c-Met in response to its ligand, hepatocyte growth factor (HGF), and partially blocked the suppressive effects of HGF on E-cadherin expression in melanocytes and HGF-dependent migration. These data demonstrate a role for Plexin B1 in maintenance of melanocyte survival and proliferation in the skin, and suggest that Sema4D and Plexin B1 act cooperatively with HGF and c-Met to regulate c-Met-dependent effects in human melanocytes. Because our data show that Plexin B1 is profoundly downregulated by UVB in melanocytes, loss of Plexin B1 may accentuate HGF-dependent effects on melanocytes, including melanocyte migration.

  17. Mechanism of Cancer Growth Suppression of Alpha-Fetoprotein Derived Growth Inhibitory Peptides (GIP): Comparison of GIP-34 versus GIP-8 (AFPep). Updates and Prospects

    Energy Technology Data Exchange (ETDEWEB)

    Mizejewski, Gerald J. [Division of Translational Medicine, Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY 12201 (United States)

    2011-06-20

    The Alpha-fetoprotein (AFP) derived Growth Inhibitory Peptide (GIP) is a 34-amino acid segment of the full-length human AFP molecule that inhibits tumor growth and metastasis. The GIP-34 and its carboxy-terminal 8-mer segment, termed GIP-8, were found to be effective as anti-cancer therapeutic peptides against nine different human cancer types. Following the uptake of GIP-34 and GIP-8 into the cell cytoplasm, each follows slightly different signal transduction cascades en route to inhibitory pathways of tumor cell growth and proliferation. The parallel mechanisms of action of GIP-34 versus GIP-8 are demonstrated to involve interference of signaling transduction cascades that ultimately result in: (1) cell cycle S-phase/G2-phase arrest; (2) prevention of cyclin inhibitor degradation; (3) protection of p53 from inactivation by phosphorylation; and (4) blockage of K{sup +} ion channels opened by estradiol and epidermal growth factor (EGF). The overall mechanisms of action of both peptides are discussed in light of their differing modes of cell attachment and uptake fortified by RNA microarray analysis and electrophysiologic measurements of cell membrane conductance and resistance. As a chemotherapeutic adjunct, the GIPs could potentially aid in alleviating the negative side effects of: (1) tamoxifen resistance, uterine hyperplasia/cancer, and blood clotting; (2) Herceptin antibody resistance and cardiac (arrest) arrhythmias; and (3) doxorubicin's bystander cell toxicity.

  18. Current-horn suppression for reduced coherent-synchrotron-radiation-induced emittance growth in strong bunch compression

    Directory of Open Access Journals (Sweden)

    T. K. Charles

    2017-03-01

    Full Text Available Control of coherent synchrotron radiation (CSR-induced emittance growth is essential in linear accelerators designed to deliver very high brightness electron beams. Extreme current values at the head and tail of the electron bunch, resulting from strong bunch compression, are responsible for large CSR production leading to significant transverse projected emittance growth. The Linac Coherent Light Source (LCLS truncates the head and tail current spikes which greatly improves free electron laser (FEL performance. Here we consider the underlying dynamics that lead to formation of current spikes (also referred to as current horns, which has been identified as caustics forming in electron trajectories. We present a method to analytically determine conditions required to avoid the caustic formation and therefore prevent the current spikes from forming. These required conditions can be easily met, without increasing the transverse slice emittance, through inclusion of an octupole magnet in the middle of a bunch compressor.

  19. Ozone-induced growth suppression in radish plants in relation to pre- and post-fumigation temperatures. [Raphanus sativus L

    Energy Technology Data Exchange (ETDEWEB)

    Adedipe, N.O.; Ormrod, D.P.

    1974-01-01

    Two cultivars of Raphanus sativus L. (radish) were fumigated with ozone at a concentration of 25 parts per hundred million (pphm) for 3 h, before or after subjecting the plants to two growth temperature regimes. In the cultivar ''Cavalier'' ozone decreased leaf weight at the lower pre-fumigation day/night growth temperature regime of 20/15/sup 0/, but had no significant effect when the plants were either pre- or post-fumigation conditioned at the high temperatures of 30/25/sup 0/. In the cultivar ''Cherry Belle'', ozone decreased the leaf weight of only low temperature post-fumigation conditioned plants. Ozone had no significant effect on the total soluble carbohydrate concentration of ''Cherry Belle'', while it increased that of pre-fumigation conditioned ''Cavalier'' plants.

  20. Suppression of DHT-induced paracrine stimulation of endothelial cell growth by estrogens via prostate cancer cells.

    Science.gov (United States)

    Wen, Juan; Zhao, Yuan; Li, Jinghe; Weng, Chunyan; Cai, Jingjing; Yang, Kan; Yuan, Hong; Imperato-McGinley, Julianne; Zhu, Yuan-Shan

    2013-07-01

    Androgen modulation of angiogenesis in prostate cancer may be not directly mediated by androgen receptor (AR) as AR is not detected in the prostatic endothelial cells. We examined the paracrine stimulation of cell proliferation by prostate tumor cells and its modulation by androgen and estrogens in a murine endothelial cell line (MEC) that does not express AR. Tumor cell conditioned media (TCM) collected from LAPC-4 or LNCaP prostatic tumor cells produced a time- and concentration-dependent induction of cell growth in MECs, which was parallel to the VEGF concentration in the TCM. This TCM-induced cell growth in MECs was enhanced by the treatment of prostatic tumor cells with dihydrotestosterone (DHT). Both the TCM-stimulation and DHT-enhancement effects in MECs were completely blocked by SU5416, a specific VEGF receptor antagonist. Co-administration of 17α-estradiol or 17β-estradiol with DHT in prostatic tumor cells completely inhibited the DHT-enhancement effect while treatment with DHT, 17α-estradiol or 17β-estradiol did not produce any significant direct effect in MECs. Moreover, administration of 17α-estradiol or 17β-estradiol in xenograft animals with LAPC-4 or LNCaP prostate tumor significantly decreased the microvessel number in the tumor tissues. Our study indicated that prostate tumor cells regulate endothelial cell growth through a paracrine mechanism, which is mainly mediated by VEGF; and DHT is able to modulate endothelial cell growth via tumor cells, which is inhibited by 17α-estradiol and 17β-estradiol. Thus, both17α-estradiol and 17β-estradiol are potential agents for anti-angiogenesis therapy in androgen-responsive prostate cancer. Copyright © 2013 Wiley Periodicals, Inc.

  1. Bortezomib induces apoptosis and suppresses cell growth and metastasis by inactivation of Stat3 signaling in chondrosarcoma.

    Science.gov (United States)

    Bao, Xing; Ren, Tingting; Huang, Yi; Ren, Chongmin; Yang, Kang; Zhang, Hongliang; Guo, Wei

    2017-02-01

    Bortezomib, formerly known as PS341, is a novel proteasome inhibitor with in vitro and in vivo antineoplastic effects in many malignancies. However, diverse antitumor mechanisms of bortezomib have been identified in many investigations and preclinical studies. Understanding the molecular and cellular mechanisms through which bortezomib acts will improve the therapeutic utility of this drug in different cancer types. In the present study, we investigated the in vitro and in vivo effects of bortezomib on chondrosarcoma. Bortezomib selectively inhibited cell growth in chondrosarcoma cells but not in normal articular cartilage cells. In addition to growth inhibition, apoptosis and cell cycle arrest, bortezomib triggered alleviation of migratory and invasive properties of chondrosarcoma cells. Mechanistically, signal transducer and activator of transcription 3 (Stat3) and its downstream targets Bcl-2, cyclin D1 and c-Myc was inactivated by bortezomib treatment. Accordingly, small interfering RNA (siRNA)-mediated Stat3 knockdown enhanced bortezomib-induced apoptosis, and concomitantly enhanced the inhibitory effect of bortezomib on cell viability, migration and invasion. Moreover, while Slug, MMP9, MMP2, CD44, N-cadherin and vimentin, the mesenchymal cell markers, were repressed by bortezomib concomitant increased expression of E-cadherin was observed. In vivo, bortezomib downregulated Stat3 activity and mesenchymal cell marker expression, induced apoptosis and inhibition of metastasis and tumor growth. Together, inactivation of Stat3 signaling contributes to bortezomib-induced inhibition of tumor growth, migration and invation on chondrosarcoma. Bortezomib demonstrates an antineoplastic role on chondrosarcoma both in vitro and in vivo. These beneficial effects can be explained by bortezomib-mediated Stat3 supression. The present study suggests a promising therapeutics target in chondrosarcoma and probably in other kinds of metastatic malignant tumors.

  2. Suppression of FAT/CD36 mRNA by human growth hormone in pancreatic β-cells

    DEFF Research Database (Denmark)

    Dalgaard, Louise Torp; Thams, Peter Grevsen; Gaarn, Louise Winkel

    2011-01-01

    of this study was to examine the effect of human growth hormone (hGH) on mRNAs of fatty acid transport and binding proteins expressed in pancreatic β-cells, and to examine this in relation to β-cell survival after exposure to fatty acids. hGH decreased mRNA levels of FAT/CD36, whereas mRNAs of GPR40, FASN, FABP...

  3. Suppression of FAT/CD36 mRNA by human growth hormone in pancreatic ß-cells

    DEFF Research Database (Denmark)

    Dalgaard, Louise Torp; Thams, Peter Grevsen; Gaarn, Louise Winkel

    2011-01-01

    of this study was to examine the effect of human growth hormone (hGH) on mRNAs of fatty acid transport and binding proteins expressed in pancreatic ß-cells, and to examine this in relation to ß-cell survival after exposure to fatty acids. hGH decreased mRNA levels of FAT/CD36, whereas mRNAs of GPR40, FASN, FABP...

  4. Effects of octreotide infusion, surgery and estrogen on suppression of height increase and 20K growth hormone ratio in a girl with gigantism due to a growth hormone-secreting macroadenoma.

    Science.gov (United States)

    Minagawa, M; Yasuda, T; Someya, T; Kohno, Y; Saeki, N; Hashimoto, Y

    2000-01-01

    We treated an extremely tall 13-year-old girl with a growth hormone (GH)-secreting macroadenoma and GH levels of 120-495 ng/ml with a combination of preoperative octreotide infusion, surgery and postoperative octreotide infusion plus estrogen, which resulted in reduced tumor size prior to surgery, reduced GH levels and completely suppressed growth after surgery. 20K GH is produced by alternative splicing of 22K GH mRNA and the ratio of 20K GH to 22K GH is within a small range in the normal population and high in a GH-secreting tumor. The 20K/22K GH ratio in this patient was persistently elevated during each phase of the treatment and may serve as a sensitive index of tumor-derived GH secretion. Copyright 2000 S. Karger AG, Basel.

  5. Angiopoietin-2 impairs collateral artery growth associated with the suppression of the infiltration of macrophages in mouse hindlimb ischaemia

    Directory of Open Access Journals (Sweden)

    Xiaoyong Tan

    2016-10-01

    Full Text Available Abstract Background Angiopoietin-2 (Ang-2, a ligand of the Tie-2 receptor, plays an important role in maintaining endothelial cells and in destabilizing blood vessels. Collateral artery growth (arteriogenesis is a key adaptive response to arterial occlusion. It is unknown whether the destabilization of blood vessels by Ang-2 can affect arteriogenesis and modulate mononuclear cell function. This study aimed to investigate the effects of Ang-2 on collateral artery growth. Methods Hindlimb ischaemia model was produced in C57BL/6 mice by femoral artery ligation. Blood flow perfusion was measured using a laser Doppler perfusion imager quantitative RT-PCR analysis was applied to identify the level of angiogenic factors. Results After the induction of hindlimb ischaemia, blood flow recovery was impaired in mice treated with recombinant Ang-2 protein; this was accompanied by a reduction of peri-collateral macrophage infiltration. In addition, quantitative RT-PCR analysis revealed that Ang-2 treatment decreased monocyte chemotactic protein-1 (MCP-1, platelet-derived growth factor-BB (PDGF-BB mRNA levels in ischaemic adductor muscles. Ang-2 can lead to macrophage M1/M2 polarization shift inhibition in the ischaemic muscles. Furthermore, Ang-2 reduced the in vitro inflammatory response in macrophages and vascular cells involved in arteriogenesis. Conclusions Our results demonstrate that Ang-2 is essential for efficient arteriogenesis, which controls macrophage infiltration.

  6. miR-214 down-regulates ARL2 and suppresses growth and invasion of cervical cancer cells

    International Nuclear Information System (INIS)

    Peng, Ruiqing; Men, Jianlong; Ma, Rui; Wang, Qian; Wang, Yang; Sun, Ying; Ren, Jing

    2017-01-01

    Increasing evidence has shown that miRNAs are implicated in carcinogenesis and can function as oncogenes or tumor suppressor genes in human cancers. In this study, we confirmed that miR-214 is frequently down-regulated in cervical cancer compared with normal cervical tissues. Ectopic expression of miR-214 suppressed proliferation, migration and invasion of HeLa and C33A cervical cancer cells. Bioinformatics analysis revealed that ADP ribosylation factor like 2 (ARL2) was a potential target of miR-214 and was remarkably up-regulated in cervical cancer. Knockdown of ARL2 markedly inhibited cervical cancer cell proliferation, migration and invasion, similarly to over-expression of miR-214, indicating that ARL2 may function as an oncogene in cervical cancer. In conclusion, our study revealed that miR-214 acts as a tumor suppressor via inhibiting proliferation, migration and invasion of cervical cancer cells through targeting ARL2, and that both miR-214 and ARL2 may serve as prognostic or therapeutic targets for cervical cancer. - Highlights: • miR-214 targets ARL2. • ARL2 maybe an oncogene in cervical cancer. • ARL2 rescues miR-214.

  7. Boswellic acid suppresses growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model through modulation of multiple targets.

    Directory of Open Access Journals (Sweden)

    Byoungduck Park

    Full Text Available Pancreatic cancer (PaCa is one of the most lethal cancers, with an estimated 5-year survival of <5% even when patients are given the best treatment available. In addition, these treatments are often toxic and expensive, thus new agents which are safe, affordable and effective are urgently needed. We describe here the results of our study with acetyl-11-keto-β-boswellic acid (AKBA, an agent obtained from an Ayurvedic medicine, gum resin of Boswellia serrata. Whether AKBA has an activity against human PaCa, was examined in in vitro models and in an orthotopic nude mouse model of PaCa. We found that AKBA inhibited the proliferation of four different PaCa cell lines (AsPC-1, PANC-28, and MIA PaCa-2 with K-Ras and p53 mutations, and BxPC-3 with wild-type K-Ras and p53 mutation. These effects correlated with an inhibition of constitutively active NF-κB and suppression of NF-κB regulating gene expression. AKBA also induced apoptosis, and sensitized the cells to apoptotic effects of gemcitabine. In the orthotopic nude mouse model of PaCa, p.o. administration of AKBA alone (100 mg/kg significantly inhibited the tumor growth; this activity was enhanced by gemcitabine. In addition, AKBA inhibited the metastasis of the PaCa to spleen, liver, and lungs. This correlated with decreases in Ki-67, a biomarker of proliferation, and CD31, a biomarker of microvessel density, in the tumor tissue. AKBA produced significant decreases in the expression of NF-κB regulating genes in the tissues. Immunohistochemical analysis also showed AKBA downregulated the expression of COX-2, MMP-9, CXCR4, and VEGF in the tissues. Overall these results demonstrate that AKBA can suppress the growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model that correlates with modulation of multiple targets.

  8. Iron oxide magnetic nanoparticles combined with actein suppress non-small-cell lung cancer growth in a p53-dependent manner

    Directory of Open Access Journals (Sweden)

    Wang MS

    2017-10-01

    Full Text Available Ming-Shan Wang,1 Liang Chen,2 Ya-Qiong Xiong,2 Jing Xu,2 Ji-Peng Wang,2 Zi-Li Meng2 1Department of Oncology, Huaiyin Hospital of Huai’an City, Huai’an, China; 2Department of Respiration, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China Abstract: Actein (AT is a triterpene glycoside isolated from the rhizomes of Cimicifuga foetida that has been investigated for its antitumor effects. AT treatment leads to apoptosis in various cell types, including breast cancer cells, by regulating different signaling pathways. Iron oxide (Fe3O4 magnetic nanoparticles (MNPs are nanomaterials with biocompatible activity and low toxicity. In the present study, the possible benefits of AT in combination with MNPs on non-small-cell lung cancer (NSCLC were explored in in vitro and in vivo studies. AT-MNP treatment contributed to apoptosis in NSCLC cells, as evidenced by activation of the caspase 3-signaling pathway, which was accompanied by downregulation of the antiapoptotic proteins Bcl2 and BclXL, and upregulation of the proapoptotic signals Bax and Bad. The death receptors of TRAIL were also elevated following AT-MNP treatment in a p53-dependent manner. Furthermore, a mouse xenograft model in vivo revealed that AT-MNP treatment exhibited no toxicity and suppressed NSCLC growth compared to either AT or MNP monotherapies. In conclusion, this study suggests a novel therapy to induce apoptosis in suppressing NSCLC growth in a p53-dependent manner by combining AT with Fe3O4 MNPs. Keywords: actein, Fe3O4 magnetic nanoparticles, NSCLC, apoptosis, p53

  9. XIAP BIR domain suppresses miR-200a expression and subsequently promotes EGFR protein translation and anchorage-independent growth of bladder cancer cell

    Directory of Open Access Journals (Sweden)

    Chao Huang

    2017-01-01

    Full Text Available Abstract Background The X-linked inhibitor of apoptosis protein (XIAP is a well-known potent apoptosis suppressor and also participates in cancer cell biological behaviors, therefore attracting great attentions as a potential antineoplastic therapeutic target for past years. Anti-IAP therapy is reported to be closely related to epidermal growth factor receptor (EGFR expression level. However, whether and how XIAP modulates EGFR expression remains largely unknown. Methods Human XIAP was knockdown with short-hairpin RNA in two different bladder cancer cell lines, T24T and UMUC3. Two XIAP mutants, XIAP ∆BIR (deletion of N-terminal three BIR domains and XIAP ∆RING (deletion of C-terminal RING domain and keeping the function of BIR domains, were generated to determine which domain is involved in regulating EGFR. Results We found here that lacking of XIAP expression resulted in a remarkable suppression of EGFR expression, consequently leading to the deficiency of anchorage-independent cell growth. Further study demonstrated that BIR domain of XIAP was crucial for regulating the EGFR translation by suppressing the transcription and expression of miR-200a. Mechanistic studies indicated that BIR domain activated the protein phosphatase 2 (PP2A activity by decreasing the phosphorylation of PP2A at Tyr307 in its catalytic subunit, PP2A-C. Such activated PP2A prevented the deviant phosphorylation and activation of MAPK kinases/MAPKs, their downstream effector c-Jun, and in turn inhibiting transcription of c-Jun-regulated the miR-200a. Conclusions Our study uncovered a novel function of BIR domain of XIAP in regulating the EGFR translation, providing significant insight into the understanding of the XIAP overexpression in the cancer development and progression, further offering a new theoretical support for using XIAP BIR domain and EGFR as targets for cancer therapy.

  10. IMMUNOLOGICAL MARKERS OF UNCONTROLLED ATOPIC BRONCHIAL ASTHMA IN CHILDREN

    Directory of Open Access Journals (Sweden)

    M. V. Smolnikova

    2017-01-01

    Full Text Available Bronchial asthma is a prevalent chronic allergic disease of lungs at early ages. A priority  task in allergology  is to search  biological  markers  related  to uncontrolled atopic  bronchial asthma. Cytokines fulfill their distinct function in pathogenesis of atopic  bronchial asthma, participating at the initiation, development and persistence of allergic inflammation in airways, causing different  variations of clinical course of the disease (with  respect  to its acuteness, severity, frequency of exacerbations. The  present  work has studied  indices  of cellular  and  humoral links of immunity, as well as levels of some  pro and  anti-inflammatory cytokines in peripheral blood serum (IL-4, IL-10, IL-2 and TNFα, aiming to determine potential markers of uncontrolled atopic bronchial asthma in children. A group of Caucasian (European children was involved into the research: Cohort 1, moderate atopic  bronchial asthma with controlled course during the last 3 months (n = 59; Cohort 2, severe/moderate-severe atopic bronchial asthma with uncontrolled course of the disease within last 3 months (n = 51,  Cohort 3 – control, practically healthy  children without signs of atopy  (n = 33. All the  children included in the group with atopic  bronchial asthma underwent regular mono/combined basic therapy  at high/ intermediate therapeutic doses.  We performed a comparative analysis  of cell  population indices  reflecting certain cellular  immunity links,  and  determined significantly  lower  levels of CD3+   lymphocytes, as well as decrease in relative  and  absolute  contents of CD4+  and  CD8+  cells in the  cohort with  uncontrolled course of atopic  bronchial asthma, as compared with controlled-course cohort. When  evaluating concentrations  of cytokines in peripheral blood serum of the patients with controlled and uncontrolled atopic  bronchial asthma, we revealed  significantly  higher

  11. 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

  12. The Natural Product Osthole Attenuates Yeast Growth by Extensively Suppressing the Gene Expressions of Mitochondrial Respiration Chain.

    Science.gov (United States)

    Wang, Zhe; Shen, Yan

    2017-03-01

    The fast growing evidences have indicated that the natural product osthole is a promising drug candidate for fighting several serious human diseases, for example, cancer and inflammation. However, the mode-of-action (MoA) of osthole remains largely incomplete. In this study, we investigated the growth inhibition activity of osthole using fission yeast as a model, with the goal of understanding the osthole's mechanism of action, especially from the molecular level. Microarray analysis indicated that osthole has significant impacts on gene transcription levels (In total, 214 genes are up-regulated, and 97 genes are down-regulated). Gene set enrichment analysis (GSEA) indicated that 11 genes belong to the "Respiration module" category, especially including the components of complex III and V of mitochondrial respiration chain. Based on GSEA and network analysis, we also found that 54 up-regulated genes belong to the "Core Environmental Stress Responses" category, particularly including many transporter genes, which suggests that the rapidly activated nutrient exchange between cell and environment is part of the MoA of osthole. In summary, osthole can greatly impact on fission yeast transcriptome, and it primarily represses the expression levels of the genes in respiration chain, which next causes the inefficiency of ATP production and thus largely explains osthole's growth inhibition activity in Schizosaccharomyces pombe (S. pombe). The complexity of the osthole's MoA shown in previous studies and our current research demonstrates that the omics approach and bioinformatics tools should be applied together to acquire the complete landscape of osthole's growth inhibition activity.

  13. 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...

  14. Paris polyphylla Suppresses Proliferation and Vasculogenic Mimicry of Human Osteosarcoma Cells and Inhibits Tumor Growth In Vivo.

    Science.gov (United States)

    Yao, Nan; Ren, Ke; Wang, Yimin; Jin, Qiaomei; Lu, Xiao; Lu, Yan; Jiang, Cuihua; Zhang, Dongjian; Lu, Jun; Wang, Chen; Huo, Jiege; Chen, Yong; Zhang, Jian

    2017-01-01

    Paris polyphylla, a traditional antipyretic-detoxicate chinese medicinal herb, has been applied extensively in cancer treatments for nearly 2000 years. The purpose of the present study is to evaluate the potential anti-osteosarcoma effects of Paris polyphylla ethanol extract (PPEE) and to investigate its underlying mechanisms. The antiproliferation activity of PPEE was tested on 143B, MG-63, U-2 OS and hFOB1.19 cells using MTT assay. The pro-apoptotic and cell cycle arrest effects of PPEE were confirmed by Hoechst 33342 staining and flow cytometry. The antimigratory, anti-invasive and antivasculogenic mimicry (VM) effects of PPEE were investigated by wound healing, Transwell and 3D culture assays. Mouse xenograft model was used to examine its anti-osteosarcoma efficacy in vivo. Hematologic profiles and hepatorenal functions were evaluated to assess the toxicity of PPEE. PPEE evidently suppressed cell proliferation of 143B, MG-63 and U-2 OS with IC50 values of 10-60[Formula: see text][Formula: see text]g/mL, but showed little cytotoxicity against normal osteoblastic cell. PPEE promoted apoptosis in 143B cell via caspase activation, increased Bax/Bcl-2 ratio and PARP cleavage. It also induced G2/M phase arrest associated with elevated phosphorylation of CDK1, Cdc25C, Chk2 and down-regulation of cyclin B1, CDK1, Cdc25C expression. Additionally, PPEE inhibited 143B cell migration, invasion and VM formation at noncytotoxic concentrations through decreasing the expression of FAK, Mig-7, MMP2 and MMP9. Finally, daily oral administration of PPEE for four weeks exhibits potent antitumor and anti-VM activity in 143B xenograft model with low toxicity. Taken together, these findings demonstrated PPEE possesses anti-osteosarcoma and anti-VM activity in vitro and in vivo, and therefore is a potential candidate for osteosarcoma treatment.

  15. CX4945 suppresses the growth of castration-resistant prostate cancer cells by reducing AR-V7 expression.

    Science.gov (United States)

    Deng, Chuangzhong; Chen, Jieping; Guo, Shengjie; Wang, Yanjun; Zhou, Qianghua; Li, Zaishang; Yang, Xingping; Yu, Xingsu; Zhang, Zhenfeng; Zhou, Fangjian; Han, Hui; Yao, Kai

    2017-08-01

    The aberrant expression of casein kinase 2 (CK2) has been reported to be involved in the tumorigenesis and progression of prostate cancer. The inhibition of CK2 activity represses androgen-dependent prostate cancer cells by attenuating the androgen receptor (AR) signaling pathway. In this study, we examined the effect of CK2 inhibition in castration-resistant prostate cancer (CRPC) cells, in which AR variants (ARVs) play a predominant role. A newly synthetic CK2 selective inhibitor CX4945 was utilized to study the effect of CK2 inhibition in CRPC cells by CCK8 assay and colony formation assay. Protein and mRNA levels of full-length AR (AR-FL) and AR-V7 were determined by qPCR and western blot, respectively. The nuclear translocation of p50 and p65 was assessed to reflect the activity of the NF-κB pathway. CX4945 reduced the proliferation of CRPC cells in a dose-dependent and time-dependent manner. AR-V7 rather than AR-FL was downregulated by CX4945 in both the mRNA and protein level. Furthermore, CX4945 could restore the sensitivity of CRPC cells to bicalutamide. The analysis of possible mechanisms demonstrated that the inhibition of CK2 diminished the phosphorylation of p65 at ser529 and thus attenuated the activity of the NF-κB pathway. The inhibition of CK2 by CX4945 can repress the viability of CRPC cells and restore their sensitivity to anti-androgen therapy by suppressing AR-V7. This finding presents a potential option for the treatment of prostate cancer, especially CRPC.

  16. Enhancing plant productivity while suppressing biofilm growth in a windowfarm system using beneficial bacteria and ultraviolet irradiation.

    Science.gov (United States)

    Lee, Seungjun; Ge, Chongtao; Bohrerova, Zuzana; Grewal, Parwinder S; Lee, Jiyoung

    2015-07-01

    Common problems in a windowfarm system (a vertical and indoor hydroponic system) are phytopathogen infections in plants and excessive buildup of biofilms. The objectives of this study were (i) to promote plant health by making plants more resistant to infection by using beneficial biosurfactant-producing Pseudomonas chlororaphis around the roots and (ii) to minimize biofilm buildup by ultraviolet (UV) irradiation of the water reservoir, thereby extending the lifespan of the whole system with minimal maintenance. Pseudomonas chlororaphis-treated lettuce grew significantly better than nontreated lettuce, as indicated by enhancement of color, mass, length, and number of leaves per head (p < 0.05). The death rate of the lettuce was reduced by ∼ 50% when the lettuce was treated with P. chlororaphis. UV irradiation reduced the bacteria (4 log reduction) and algae (4 log reduction) in the water reservoirs and water tubing systems. Introduction of P. chlororaphis into the system promoted plant growth and reduced damage caused by the plant pathogen Pythium ultimum. UV irradiation of the water reservoir reduced algal and biofilm growth and extended the lifespan of the system.

  17. Splenectomy suppresses growth and metastasis of hepatocellular carcinoma through decreasing myeloid-derived suppressor cells in vivo.

    Science.gov (United States)

    Long, Xin; Wang, Jian; Zhao, Jian-Ping; Liang, Hui-Fang; Zhu, Peng; Cheng, Qi; Chen, Qian; Wu, Yan-Hui; Zhang, Zhan-Guo; Zhang, Bi-Xiang; Chen, Xiao-Ping

    2016-10-01

    The function of the spleen in tumor development has been investigated for years. The relationship of the spleen with hepatocellular carcinoma (HCC), a huge health burden worldwide, however, remains unknown. The present study aimed to examine the effect of splenectomy on the development of HCC and the possible mechanism. Mouse hepatic carcinoma lines H22 and Hepa1-6 as well as BALB/c and C57 mice were used to establish orthotopic and metastatic mouse models of liver cancer. Mice were divided into four groups, including control group, splenectomy control group (S group), tumor group (T group) and tumor plus splenectomy group (T+S group). Tumor growth, metastases and overall survival were assessed at determined time points. Meanwhile, myeloid-derived suppressor cells (MDSCs) were isolated from the peripheral blood (PB), the spleen and liver tumors, and then measured by flow cytometery. It was found that liver cancer led to splenomegaly, and increased the percentage of MDSCs in the PB and spleen in the mouse models. Splenectomy inhibited the growth and progression of liver cancer and prolonged the overall survival time of orthotopic and metastatic models, which was accompanied by decreased proportion of MDSCs in the PB and tumors of liver cancer-bearing mouse. It was suggested that splenectomy could be considered an adjuvant therapy to treat liver cancer.

  18. PET measurements of hyperthermia-induced suppression of protein synthesis in tumors in relation to effects on tumor growth

    International Nuclear Information System (INIS)

    Daemen, B.J.; Elsinga, P.H.; Mooibroek, J.; Paans, A.M.; Wieringa, A.R.; Konings, A.W.; Vaalburg, W.

    1991-01-01

    Hyperthermia-induced metabolic changes in tumor tissue have been monitored by PET. Uptake of L-[1-11C]tyrosine in rhabdomyosarcoma tissue of Wag/Rij rats was dose-dependently reduced after local hyperthermia treatment at 42, 45, or 47 degrees C. Tumor blood flow, as measured by PET with 13NH3, appeared to be unchanged. The L-[1-11C]tyrosine uptake data were compared to uptake data of L-[1-14C]tyrosine and with data on the incorporation of L-[1-14C]tyrosine into tumor proteins. After intravenous injection, the 14C data were obtained from dissected tumor tissue. Heat-induced inhibition of the incorporation of L-[1-14C]tyrosine into tumor proteins tallied with the L-[1-11C]tyrosine uptake data. Heat-induced inhibition of amino acid uptake in the tumor correlated well with regression of tumor growth. It is concluded that PET using L-[1-11C]tyrosine is eligible for monitoring the effect of hyperthermia on tumor growth

  19. 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

  20. Silencing of RhoA and RhoC expression by RNA interference suppresses human colorectal carcinoma growth in vivo

    Directory of Open Access Journals (Sweden)

    Wang Haibo

    2010-09-01

    Full Text Available Abstract Background RhoA and RhoC have been proved to be over-expressed in many solid cancers, including colorectal cancer. The reduction of RhoA and RhoC expression by RNA interference (RNAi resulted growth inhibition of cancer cells. The present study was to evaluate the effect of silencing of RhoA and RhoC expression by RNAi on growth of human colorectal carcinoma (CRC in tumor-bearing nude mice in vivo. Methods To establish HCT116 cell transplantable model, the nude mice were subcutaneously inoculated with 1.0 × 107 HCT116 cells and kept growing till the tumor xenografts reached 5-7 mm in diameter. Then the mice were randomly assigned to three groups(seven mice in each group: (1 normal saline(NS group, (2replication-defective recombinant adenovirus carrying the negative control shRNA (Ad-HK group and (3replication-defective recombinant adenovirus carrying the 4-tandem linked RhoA and RhoC shRNAs (Ad-RhoA-RhoC group. Ad-HK (4 × 108 pfu, 30 ul/mouse, Ad-RhoA-RhoC (4 × 108 pfu, 30 ul/mouse or PBS (30 ul/mouse was injected intratumorally four times once every other day. The weight and volumes of tumor xenografts were recorded. The levels of RhoA and RhoC mRNA transcripts and proteins in tumor xenografts were detected by reverse quantitative transcription polymerase chain reaction (QRT-PCR and immunohistochemical staining respectively. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL assay was used to detect the death of cells. Results The xenografts in mice could be seen at 5th day from the implantation of HCT116 cells and all had reached 5-7 mm in size at 9th day. After injection intratumorally, the growth speed of tumor xenografts in Ad-RhoA-RhoC group was significantly delayed compared with those in NS and Ad-HK group(P RhoA and RhoC reduced more in Ad-RhoA-RhoC group than those in NS and Ad-HK group. The relative RhoA and RhoC mRNA transcripts were decreased to 48% and 43% respectively (P RhoA and Rho

  1. Schistosoma mansoni infection suppresses the growth of Plasmodium yoelii parasites in the liver and reduces gametocyte infectivity to mosquitoes.

    Directory of Open Access Journals (Sweden)

    Taeko Moriyasu

    2018-01-01

    Full Text Available Malaria and schistosomiasis are major parasitic diseases causing morbidity and mortality in the tropics. Epidemiological surveys have revealed coinfection rates of up to 30% among children in Sub-Saharan Africa. To investigate the impact of coinfection of these two parasites on disease epidemiology and pathology, we carried out coinfection studies using Plasmodium yoelii and Schistosoma mansoni in mice. Malaria parasite growth in the liver following sporozoite inoculation is significantly inhibited in mice infected with S. mansoni, so that when low numbers of sporozoites are inoculated, there is a large reduction in the percentage of mice that go on to develop blood stage malaria. Furthermore, gametocyte infectivity is much reduced in mice with S. mansoni infections. These results have profound implications for understanding the interactions between Plasmodium and Schistosoma species, and have implications for the control of malaria in schistosome endemic areas.

  2. Evaluation of transforming growth factor-β1 suppress Pokemon/epithelial-mesenchymal transition expression in human bladder cancer cells.

    Science.gov (United States)

    Li, Wei; Kidiyoor, Amritha; Hu, Yangyang; Guo, Changcheng; Liu, Min; Yao, Xudong; Zhang, Yuanyuan; Peng, Bo; Zheng, Junhua

    2015-02-01

    Transforming growth factor-β1 (TGF-β1) plays a dual role in apoptosis and in proapoptotic responses in the support of survival in a variety of cells. The aim of this study was to determine the function of TGF-β1 in bladder cancer cells and the relationship with POK erythroid myeloid ontogenic factor (Pokemon). TGF-β1 and its receptors mediate several tumorigenic cascades that regulate cell proliferation, migration, and survival of bladder cancer cells. Bladder cancer cells T24 were treated with different levels of TGF-β1. Levels of Pokemon, E-cadherin, Snail, MMP2, MMP9, Twist, VEGF, and β-catenin messenger RNA (mRNA) and protein were examined by real-time quantitative fluorescent PCR and Western blot analysis, respectively. The effects of TGF-β1 on epithelial-mesenchymal transition of T24 cells were evaluated with wound-healing assay, proliferation of T24 was evaluated with reference to growth curves with MTT assay, and cell invasive ability was investigated by Transwell assay. Data show that Pokemon was inhibited by TGF-β1 treatment; the gene and protein of E-cadherin and β-catenin expression level showed decreased markedly after TGF-β1 treatment (P Pokemon, β-catenin, and E-cadherin. The high expression of TGF-β1 leads to an increase in the phenotype and apical-base polarity of epithelial cells. These changes of cells may result in the recurrence and progression of bladder cancer at last. Related mechanism is worthy of further investigation.

  3. In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by CRISPR/Cas9

    International Nuclear Information System (INIS)

    Zhen, Shuai; Hua, Ling; Takahashi, Y.; Narita, S.; Liu, Yun-Hui; Li, Yan

    2014-01-01

    Highlights: • Established CRISPR/Cas9 targeting promoter of HPV 16 and targeting E6, E7 transcript. • CRISPR/Cas9 resulted in accumulation of p53 and p21, reduced the proliferation of cervical cancer cells. • Finding inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9. • CRISPR/Cas9 will be a new treatment strategy, in cervical and other HPV-associated cancer therapy. - Abstract: Deregulated expression of high-risk human papillomavirus oncogenes (E6 and E7) is a pivotal event for pathogenesis and progression in cervical cancer. Both viral oncogenes are therefore regarded as ideal therapeutic targets. In the hope of developing a gene-specific therapy for HPV-related cancer, we established CRISPR/Cas9 targeting promoter of HPV 16 E6/E7 and targeting E6, E7 transcript, transduced the CRISPR/Cas9 into cervical HPV-16-positive cell line SiHa. The results showed that CRISPR/Cas9 targeting promoter, as well as targeting E6 and E7 resulted in accumulation of p53 and p21 protein, and consequently remarkably reduced the abilities of proliferation of cervical cancer cells in vitro. Then we inoculated subcutaneously cells into nude mice to establish the transplanted tumor animal models, and found dramatically inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9 targeting (promoter+E6+E7)-transcript. Our results may provide evidence for application of CRISPR/Cas9 targeting HR-HPV key oncogenes, as a new treatment strategy, in cervical and other HPV-associated cancer therapy

  4. In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by CRISPR/Cas9

    Energy Technology Data Exchange (ETDEWEB)

    Zhen, Shuai [Baoji Maternal and Child Health Hospital, 2 Xinjian Road East, WeiBin District, Baoji City, 721000, Shanxi Province (China); Xijing Hospital, Fourth Military Medical University, Xi’an (China); Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Kyoto University, Kyoto 606-8507 (Japan); Hua, Ling [Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Takahashi, Y.; Narita, S. [Kyoto University, Kyoto 606-8507 (Japan); Liu, Yun-Hui [Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Li, Yan [Baoji Hospital of Traditional Chinese Medicine, No 43, BaoFu Road, Baoji City, Shanxi Province (China)

    2014-08-08

    Highlights: • Established CRISPR/Cas9 targeting promoter of HPV 16 and targeting E6, E7 transcript. • CRISPR/Cas9 resulted in accumulation of p53 and p21, reduced the proliferation of cervical cancer cells. • Finding inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9. • CRISPR/Cas9 will be a new treatment strategy, in cervical and other HPV-associated cancer therapy. - Abstract: Deregulated expression of high-risk human papillomavirus oncogenes (E6 and E7) is a pivotal event for pathogenesis and progression in cervical cancer. Both viral oncogenes are therefore regarded as ideal therapeutic targets. In the hope of developing a gene-specific therapy for HPV-related cancer, we established CRISPR/Cas9 targeting promoter of HPV 16 E6/E7 and targeting E6, E7 transcript, transduced the CRISPR/Cas9 into cervical HPV-16-positive cell line SiHa. The results showed that CRISPR/Cas9 targeting promoter, as well as targeting E6 and E7 resulted in accumulation of p53 and p21 protein, and consequently remarkably reduced the abilities of proliferation of cervical cancer cells in vitro. Then we inoculated subcutaneously cells into nude mice to establish the transplanted tumor animal models, and found dramatically inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9 targeting (promoter+E6+E7)-transcript. Our results may provide evidence for application of CRISPR/Cas9 targeting HR-HPV key oncogenes, as a new treatment strategy, in cervical and other HPV-associated cancer therapy.

  5. 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.

  6. Stable RNA interference of ErbB-2 gene synergistic with epirubicin suppresses breast cancer growth in vitro and in vivo

    International Nuclear Information System (INIS)

    Hu Xiaoqu; Su Fengxi; Qin Li; Jia Weijuan; Gong Chang; Yu Fengyan; Guo Jujiang; Song Erwei

    2006-01-01

    Overexpression of human epidermal growth factor receptor-2 (Her2, ErbB-2) contributes to the progression and metastasis of breast cancer, implying that Her2 gene is a suitable target of RNA interference (RNAi) for breast cancer therapy. Here, we employed plasmid-mediated expression of 2 different Her2-shRNAs (pU6-Her2shRNAs) efficiently silenced the target gene expression on Her2 expressing SKBR-3 breast cancer cells in both mRNA and protein levels. Consequently, pU6-Her2shRNA increased apoptosis and reduced proliferation of SKBR-3 cells assayed by TUNEL and MTT, respectively. In vivo, intra-tumor injection of pU6-Her2shRNA inhibited the growth of SKBR-3 tumors inoculated subcutaneously in nude mice. Furthermore, pU6-Her2shRNA synergized the tumor suppression effect of epirubicin to SKBR-3 cells in vitro and implanted subcutaneously in nude mice. Therefore, we concluded that stable silencing of Her2 gene expression with plasmid expressing shRNA may hold great promise as a novel therapy for Her2 expressing breast cancers alone or in combination with anthracycline chemotherapy

  7. Adiponectin deficiency suppresses lymphoma growth in mice by modulating NK cells, CD8 T cells, and myeloid-derived suppressor cells.

    Science.gov (United States)

    Han, Sora; Jeong, Ae Lee; Lee, Sunyi; Park, Jeong Su; Kim, Kwang Dong; Choi, Inpyo; Yoon, Suk Ran; Lee, Myung Sok; Lim, Jong-Seok; Han, Seung Hyun; Yoon, Do Young; Yang, Young

    2013-05-01

    Previously, we found that adiponectin (APN) suppresses IL-2-induced NK cell activation by downregulating the expression of the IFN-γ-inducible TNF-related apoptosis-inducing ligand and Fas ligand. Although the antitumor function of APN has been reported in several types of solid tumors, with few controversial results, no lymphoma studies have been conducted. In this study, we assessed the role of APN in immune cell function, including NK cells, CTLs, and myeloid-derived suppressor cells, in EL4 and B16F10 tumor-bearing APN knockout (KO) mice. We observed attenuated EL4 growth in the APNKO mice. Increased numbers of splenic NK cells and splenic CTLs were identified under naive conditions and EL4-challenged conditions, respectively. In APNKO mice, splenic NK cells showed enhanced cytotoxicity with and without IL-2 stimulation. Additionally, there were decreased levels of myeloid-derived suppressor cell accumulation in the EL4-bearing APNKO mice. Enforced MHC class I expression on B16F10 cells led to attenuated growth of these tumors in APNKO mice. Thus, our results suggest that EL4 regression in APNKO mice is not only due to an enhanced antitumor immune response but also to a high level of MHC class I expression.

  8. Growth differentiation factor-15 (GDF-15) suppresses in vitro angiogenesis through a novel interaction with connective tissue growth factor (CCN2).

    Science.gov (United States)

    Whitson, Ramon J; Lucia, Marshall Scott; Lambert, James R

    2013-06-01

    Growth differentiation factor-15 (GDF-15) and the CCN family member, connective tissue growth factor (CCN2), are associated with cardiac disease, inflammation, and cancer. The precise role and signaling mechanism for these factors in normal and diseased tissues remains elusive. Here we demonstrate an interaction between GDF-15 and CCN2 using yeast two-hybrid assays and have mapped the domain of interaction to the von Willebrand factor type C domain of CCN2. Biochemical pull down assays using secreted GDF-15 and His-tagged CCN2 produced in PC-3 prostate cancer cells confirmed a direct interaction between these proteins. To investigate the functional consequences of this interaction, in vitro angiogenesis assays were performed. We demonstrate that GDF-15 blocks CCN2-mediated tube formation in human umbilical vein endothelial (HUVEC) cells. To examine the molecular mechanism whereby GDF-15 inhibits CCN2-mediated angiogenesis, activation of αV β3 integrins and focal adhesion kinase (FAK) was examined. CCN2-mediated FAK activation was inhibited by GDF-15 and was accompanied by a decrease in αV β3 integrin clustering in HUVEC cells. These results demonstrate, for the first time, a novel signaling pathway for GDF-15 through interaction with the matricellular signaling molecule CCN2. Furthermore, antagonism of CCN2 mediated angiogenesis by GDF-15 may provide insight into the functional role of GDF-15 in disease states. Copyright © 2012 Wiley Periodicals, Inc.

  9. Targeting of GIT1 by miR-149* in breast cancer suppresses cell proliferation and metastasis in vitro and tumor growth in vivo

    Directory of Open Access Journals (Sweden)

    Dong Y

    2017-12-01

    the tumor growth, while restored GIT1 accelerated the tumor growth in nude mice after 35 days of tumor xenograft. Collectively, these findings concluded that miR-149* might exert a tumor suppressive role in breast cancer by targeting GIT1. Keywords: microRNA 149*, miR-149*, G protein-coupled receptor kinase interacting protein 1, GIT1, tumor suppressive role, breast cancer

  10. Suppression of Retinal Neovascularization in vivo by Inhibition of Vascular Endothelial Growth Factor (VEGF) Using Soluble VEGF-Receptor Chimeric Proteins

    Science.gov (United States)

    Aiello, Lloyd Paul; Pierce, Eric A.; Foley, Eliot D.; Takagi, Hitoshi; Chen, Helen; Riddle, Lavon; Ferrara, Napoleone; King, George L.; Smith, Lois E. H.

    1995-11-01

    The majority of severe visual loss in the United States results from complications associated with retinal neovascularization in patients with ischemic ocular diseases such as diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity. Intraocular expression of the angiogenic protein vascular endothelial growth factor (VEGF) is closely correlated with neovascularization in these human disorders and with ischemia-induced retinal neovascularization in mice. In this study, we evaluated whether in vivo inhibition of VEGF action could suppress retinal neovascularization in a murine model of ischemic retinopathy. VEGF-neutralizing chimeric proteins were constructed by joining the extracellular domain of either human (Flt) or mouse (Flk) high-affinity VEGF receptors with IgG. Control chimeric proteins that did not bind VEGF were also used. VEGF-receptor chimeric proteins eliminated in vitro retinal endothelial cell growth stimulation by either VEGF (P hypoxic conditioned medium (P < 0.005) without affecting growth under nonstimulated conditions. Control proteins had no effect. To assess in vivo response, animals with bilateral retinal ischemia received intravitreal injections of VEGF antagonist in one eye and control protein in the contralateral eye. Retinal neovascularization was quantitated histologically by a masked protocol. Retinal neovascularization in the eye injected with human Flt or murine Flk chimeric protein was reduced in 100% (25/25; P < 0.0001) and 95% (21/22; P < 0.0001) of animals, respectively, compared to the control treated eye. This response was evident after only a single intravitreal injection and was dose dependent with suppression of neovascularization noted after total delivery of 200 ng of protein (P < 0.002). Reduction of histologically evident neovascular nuclei per 6-um section averaged 47% ± 4% (P < 0.001) and 37% ± 2% (P < 0.001) for Flt and Flk chimeric proteins with maximal inhibitory effects of 77% and 66

  11. CAUSES OF UNCONTROLLED BLOOD PRESSURE IN THE OVER-65 POPULATION

    Directory of Open Access Journals (Sweden)

    A Khosravi

    2010-12-01

    Full Text Available Abstract  INTRODUCTION: Hypertension is a major cause of cardiovascular disease and the prevalence of hypertension shows a linear increase with aging so that it increases by 10 percent every 10 years. This study was conducted to investigate the causes of uncontrolled blood pressure in people aged over 65 years. methods: This descriptive case-control study was conducted at Isfahan Amin Hospital in 2003 on two-hundred over-65 subjects diagnosed with hypertension through a routine travel check-up for Mecca pilgrimage. After medical examinations and blood pressure measurement according to WHO standards, the subjects were divided into a case group (controlled blood pressure and a control group (uncontrolled blood pressure, respectively. A questionnaire was filled in for each subject and the data were analyzed with χ2 and t-student test. results: The case and control groups had mean ages of 70.7±5.2 and 69.5±4.9 years, respectively. In the case group, less than half of the subjects were taking their antihypertensive medications regularly and 12.5% engaged in self-therapy. Fifty-five percent of subjects in the case group expressed a lack of motivation as the reason for discontinuing therapy. Their knowledge and practice were also found to be significantly lower than the control group (P<0.05. Discussion: In comparison with other studies, it was observed that the most common causes of uncontrolled blood pressure are poor knowledge, inappropriate practice in avoiding risk factors, and the discontinuation of pharmaceutical antihypertensive therapy.Keywords . Hypertension . Cardiovascular diseases . Antihypertensive agents . Diet therapy

  12. Essential uncontrollability of discrete linear, time-invariant, dynamical systems

    Science.gov (United States)

    Cliff, E. M.

    1975-01-01

    The concept of a 'best approximating m-dimensional subspace' for a given set of vectors in n-dimensional whole space is introduced. Such a subspace is easily described in terms of the eigenvectors of an associated Gram matrix. This technique is used to approximate an achievable set for a discrete linear time-invariant dynamical system. This approximation characterizes the part of the state space that may be reached using modest levels of control. If the achievable set can be closely approximated by a proper subspace of the whole space then the system is 'essentially uncontrollable'. The notion finds application in studies of failure-tolerant systems, and in decoupling.

  13. Pediatric intensive care treatment of uncontrolled status epilepticus.

    Science.gov (United States)

    Wilkes, Ryan; Tasker, Robert C

    2013-04-01

    The critically ill mechanically ventilated child with ongoing seizures that are refractory to any treatment presents a distinct challenge in pediatric neurocritical care. The evidence base from randomized controlled trials on which anti-epileptic drug (AED) strategy should be used is inadequate. This review of refractory and super-refractory status epilepticus summarizes recent pediatric case series regarding definitions, the second-tier AED therapies once initial anticonvulsants have failed, and the experience of high-dose midazolam, barbiturate anesthesia, and volatile anesthetics for uncontrolled status epilepticus. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Calculation of research reactor RA power at uncontrolled reactivity changes

    International Nuclear Information System (INIS)

    Cupac, S.

    1978-01-01

    The safety analysis of research reactor RA involves also the calculation of reactor power at uncontrolled reactivity changes. The corresponding computer code, based on Point Kinetics Model has been made. The short review of method applied for solving kinetic equations is given and several examples illustrating the reactor behaviour at various reactivity changes are presented. The results already obtained are giving rather rough picture of reactor behaviour in considered situations. This is the consequence of using simplified feed back and reactor cooling models, as well as temperature reactivity coefficients, which do not correspond to the actual reactor RA structure (which is now only partly fulfilled with 80% enriched uranium fuel). (author) [sr

  15. 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.

  16. The Growth Suppressing Effects of Girinimbine on Hepg2 Involve Induction of Apoptosis and Cell Cycle Arrest

    Directory of Open Access Journals (Sweden)

    Tang Sook Wah

    2011-08-01

    Full Text Available Murraya koenigii is an edible herb widely used in folk medicine. Here we report that girinimbine, a carbazole alkaloid isolated from this plant, inhibited the growth and induced apoptosis in human hepatocellular carcinoma, HepG2 cells. The MTT and LDH assay results showed that girinimbine decreased cell viability and increased cytotoxicity in a dose-and time-dependent manner selectively. Girinimbine-treated HepG2 cells showed typical morphological features of apoptosis, as observed from normal inverted microscopy and Hoechst 33342 assay. Furthermore, girinimbine treatment resulted in DNA fragmentation and elevated levels of caspase-3 in HepG2 cells. Girinimbine treatment also displayed a time-dependent accumulation of the Sub-G0/G1 peak (hypodiploid and caused G0/G1-phase arrest. Together, these results demonstrated for the first time that girinimbine could effectively induce programmed cell death in HepG2 cells and suggests the importance of conducting further investigations in preclinical human hepatocellular carcinoma models, especially on in vivo efficacy, to promote girinimbine for use as an anticancer agent against hepatocellular carcinoma.

  17. Salinomycin inhibits proliferation and induces apoptosis of human nasopharyngeal carcinoma cell in vitro and suppresses tumor growth in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Danxin; Zhang, Yu; Huang, Jie; Fan, Zirong; Shi, Fengrong; Wang, Senming, E-mail: wsenming@126.com

    2014-01-10

    Highlight: •We first evaluated the effect of salinomycin on nasopharyngeal carcinoma (NPC). •Salinomycin could inhibit Wnt/β-catenin signaling and induce apoptosis in NPC. •So salinomycin may be a good potential candidate for the chemotherapy of NPC. -- Abstract: Salinomycin (Sal) is a polyether ionophore antibiotic that has recently been shown to induce cell death in various human cancer cells. However, whether salinomycin plays a functional role in nasopharyngeal carcinoma (NPC) has not been determined to date. The present study investigated the chemotherapeutic efficacy of salinomycin and its molecular mechanisms of action in NPC cells. Salinomycin efficiently inhibited proliferation and invasion of 3 NPC cell lines (CNE-1, CNE-2, and CNE-2/DDP) and activated a extensive apoptotic process that is accompanied by activation of caspase-3 and caspase-9, and decreased mitochondrial membrane potential. Meanwhile, the protein expression level of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and β-catenin was down-regulated, which showed that the Wnt/β-catenin signaling was involved in salinomycin-induced apoptosis of NPC cells. In a nude mouse NPC xenograft model, the anti-tumor effect of salinomycin was associated with the downregulation of β-catenin expression. The present study demonstrated that salinomycin can effectively inhibit proliferation and invasion, and induce apoptosis of NPC cells in vitro and inhibit tumor growth in vivo, probably via the inhibition of Wnt/β-catenin signaling, suggesting salinomycin as a potential candidate for the chemotherapy of NPC.

  18. Derricin and derricidin inhibit Wnt/β-catenin signaling and suppress colon cancer cell growth in vitro.

    Directory of Open Access Journals (Sweden)

    Barbara F Fonseca

    Full Text Available Overactivation of the Wnt/β-catenin pathway in adult tissues has been implicated in many diseases, such as colorectal cancer. Finding chemical substances that can prevent this phenomenon is an emerging problem. Recently, several natural compounds have been described as Wnt/β-catenin inhibitors and might be promising agents for the control of carcinogenesis. Here, we describe two natural substances, derricin and derricidin, belonging to the chalcone subclass, that show potent transcriptional inhibition of the Wnt/β-catenin pathway. Both chalcones are able to affect the cell distribution of β-catenin, and inhibit Wnt-specific reporter activity in HCT116 cells and in Xenopus embryos. Derricin and derricidin also strongly inhibited canonical Wnt activity in vitro, and rescued the Wnt-induced double axis phenotype in Xenopus embryos. As a consequence of Wnt/β-catenin inhibition, derricin and derricidin treatments reduce cell viability and lead to cell cycle arrest in colorectal cancer cell lines. Taken together, our results strongly support these chalcones as novel negative modulators of the Wnt/β-catenin pathway and colon cancer cell growth in vitro.

  19. Cystatin C deficiency suppresses tumor growth in a breast cancer model through decreased proliferation of tumor cells.

    Science.gov (United States)

    Završnik, Janja; Butinar, Miha; Prebanda, Mojca Trstenjak; Krajnc, Aleksander; Vidmar, Robert; Fonović, Marko; Grubb, Anders; Turk, Vito; Turk, Boris; Vasiljeva, Olga

    2017-09-26

    Cysteine cathepsins are proteases that, in addition to their important physiological functions, have been associated with multiple pathologies, including cancer. Cystatin C (CstC) is a major endogenous inhibitor that regulates the extracellular activity of cysteine cathepsins. We investigated the role of cystatin C in mammary cancer using CstC knockout mice and a mouse model of breast cancer induced by expression of the polyoma middle T oncoprotein (PyMT) in the mammary epithelium. We showed that the ablation of CstC reduced the rate of mammary tumor growth. Notably, a decrease in the proliferation of CstC knockout PyMT tumor cells was demonstrated ex vivo and in vitro , indicating a role for this protease inhibitor in signaling pathways that control cell proliferation. An increase in phosphorylated p-38 was observed in CstC knockout tumors, suggesting a novel function for cystatin C in cancer development, independent of the TGF-β pathway. Moreover, proteomic analysis of the CstC wild-type and knockout PyMT primary cell secretomes revealed a decrease in the levels of 14-3-3 proteins in the secretome of knock-out cells, suggesting a novel link between cysteine cathepsins, cystatin C and 14-3-3 proteins in tumorigenesis, calling for further investigations.

  20. Evaluation of putative allelochemicals in rice root exudates for their role in the suppression of arrowhead root growth.

    Science.gov (United States)

    Seal, Alexa N; Haig, Terry; Pratley, James E

    2004-08-01

    In previous studies, 15 putative allelopathic compounds detected in rice root exudates were quantified by GC/MS/MS. In this study, multiple regression analysis on these compounds determined that five selected phenolics, namely caffeic, p-hydroxybenzoic, vanillic, syringic, and p-coumaric acids, from rice exudates were best correlated with the observed allelopathic effect on arrowhead (Sagittaria montevidensis) root growth. Despite this positive association, determination of the phenolic acid dose-response curve established that the amount quantified in the exudates was much lower than the required threshold concentration for arrowhead inhibition. A similar dose-response curve resulted from a combination of all 15 quantified compounds. Significant differences between the amounts of trans-ferulic acid, abietic acid, and an indole also existed between allelopathic and non-allelopathic rice cultivars. The potential roles of these three compounds in rice allelopathy were examined by chemoassay. Overall, neither the addition of trans-ferulic acid nor 5-hydroxyindole-3-acetic acid to the phenolic mix significantly contributed to phytotoxicity, although at higher concentrations, trans-ferulic acid appeared to act antagonistically to the phytotoxic effects of the phenolic mix. The addition of abietic acid also decreased the inhibitory effect of the phenolic mix. These studies indicate that the compounds quantified are not directly responsible for the observed allelopathic response. It is possible that the amount of phenolic acids may be indirectly related to the chemicals finally responsible for the observed allelopathic effect.

  1. Resveratrol (trans-3,5,4'-trihydroxystilbene) suppresses EL4 tumor growth by induction of apoptosis involving reciprocal regulation of SIRT1 and NF-κB.

    Science.gov (United States)

    Singh, Narendra P; Singh, Udai P; Hegde, Venkatesh L; Guan, Hongbing; Hofseth, Lorne; Nagarkatti, Mitzi; Nagarkatti, Prakash S

    2011-08-01

    Understanding the molecular mechanisms through which natural products and dietary supplements exhibit anticancer properties is crucial and can lead to drug discovery and chemoprevention. The current study sheds new light on the mode of action of resveratrol (RES), a plant-derived polyphenolic compound, against EL-4 lymphoma growth. Immuno-compromised NOD/SCID mice injected with EL-4 tumor cells and treated with RES (100 mg/kg body weight) showed delayed development and progression of tumor growth and increased mean survival time. RES caused apoptosis in EL4 cells through activation of aryl hydrocarbon receptor (AhR) and upregulation of Fas and FasL expression in vitro. Blocking of RES-induced apoptosis in EL4 cells by FasL mAb, cleavage of caspases and PARP, and release of cytochorme c, demonstrated the participation of both extrinsic and intrinsic pathways of apoptosis. RES also induced upregulation of silent mating type information regulation 2 homolog, 1 (SIRT1) and downregulation of nuclear factor kappa B (NF-κB) in EL4 cells. siRNA-mediated downregulation of SIRT1 in EL4 cells increased the activation of NF-κB but decreased RES-mediated apoptosis, indicating the critical role of SIRT1 in apoptosis via blocking activation of NF-κB. These data suggest that RES-induced SIRT1 upregulation promotes tumor cell apoptosis through negative regulation of NF-κB, leading to suppression of tumor growth. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Impaired compensation to femoral artery ligation in diet-induced obese mice is primarily mediated via suppression of collateral growth by Nox2 and p47phox.

    Science.gov (United States)

    DiStasi, Matthew R; Mund, Julie A; Bohlen, H Glenn; Miller, Steven J; Ingram, David A; Dalsing, Michael C; Unthank, Joseph L

    2015-10-01

    The present study was undertaken to establish the role of NADPH oxidase (Nox) in impaired vascular compensation to arterial occlusion that occurs in the presence of risk factors associated with oxidative stress. Diet-induced obese (DIO) mice characterized by multiple comorbidities including diabetes and hyperlipidemia were used as a preclinical model. Arterial occlusion was induced by distal femoral artery ligation in lean and DIO mice. Proximal collateral arteries were identified as the site of major (∼70%) vascular resistance to calf perfusion by distal arterial pressures, which decreased from ∼80 to ∼30 mmHg with ligation in both lean and DIO mice. Two weeks after ligation, significant vascular compensation occurred in lean but not DIO mice as evidenced by increased perfusion (147 ± 48% vs. 49 ± 29%) and collateral diameter (151 ± 30% vs. 44 ± 17%). Vascular mRNA expression of p22(phox), Nox2, Nox4, and p47(phox) were all increased in DIO mice. Treatment of DIO mice with either apocynin or Nox2ds-tat or with whole body ablation of either Nox2 or p47(phox) ameliorated the impairment in both collateral growth and hindlimb perfusion. Multiparametric flow cytometry analysis demonstrated elevated levels of circulating monocytes in DIO mice without impaired mobilization and demargination after femoral artery ligation. These results establish collateral resistance as the major limitation to calf perfusion in this preclinical model, demonstrate than monocyte mobilization and demarginatin is not suppressed, implicate Nox2-p47(phox) interactions in the impairment of vascular compensation to arterial occlusion in DIO mice, and suggest that selective Nox component suppression/inhibition may be effective as either primary or adjuvant therapy for claudicants. Copyright © 2015 the American Physiological Society.

  3. Prostaglandin E2 and Transforming Growth Factor-β Play a Critical Role in Suppression of Allergic Airway Inflammation by Adipose-Derived Stem Cells.

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    Kyu-Sup Cho

    Full Text Available The role of soluble factors in the suppression of allergic airway inflammation by adipose-derived stem cells (ASCs remains to be elucidated. Moreover, the major soluble factors responsible for the immunomodulatory effects of ASCs in allergic airway diseases have not been well documented. We evaluated the effects of ASCs on allergic inflammation in asthmatic mice treated with a prostaglandin E2 (PGE2 inhibitor or transforming growth factor-β (TGF-β neutralizing antibodies.Asthmatic mice were injected intraperitoneally with a PGE2 inhibitor or TGF-β neutralizing antibodies at approximately the same time as ASCs injection and were compared with non-treated controls. In asthmatic mice, ASCs significantly reduced airway hyperresponsiveness, the number of total inflammatory cells and eosinophils in the bronchoalveolar lavage fluid (BALF, eosinophilic inflammation, goblet cell hyperplasia, and serum total and allergen-specific IgE and IgG1. ASCs significantly inhibited Th2 cytokines, such as interleukin (IL-4, IL-5, and IL-13, and enhanced the Th1 cytokine (Interferon-γ and regulatory cytokines (IL-10 and TGF-β in the BALF and lung draining lymph nodes (LLNs. ASCs engraftment caused significant increases in the regulatory T cell (Treg and IL-10+ T cell populations in LLNs. However, blocking PGE2 or TGF-β eliminated the immunosuppressive effect of ASCs in allergic airway inflammation.ASCs are capable of secreting PGE2 and TGF-β, which may play a role in inducing Treg expansion. Furthermore, treatment with a PGE2 inhibitor or TGF-β neutralizing antibodies eliminated the beneficial effect of ASCs treatment in asthmatic mice, suggesting that PGE2 and TGF-β are the major soluble factors responsible for suppressing allergic airway inflammation.

  4. Inhibition of polo-like kinase 1 leads to the suppression of osteosarcoma cell growth in vitro and in vivo.

    Science.gov (United States)

    Liu, Xianzhe; Choy, Edwin; Harmon, David; Yang, Shuhua; Yang, Cao; Mankin, Henry; Hornicek, Francis J; Duan, Zhenfeng

    2011-06-01

    Osteosarcoma is the most common type of primary bone cancer in children and adolescents. Treatment options for osteosarcoma may include surgery, chemotherapy, and radiotherapy. Unfortunately, many patients eventually relapse, resulting in an unsatisfactory outcome. The serine/threonine-specific polo-like kinase 1 (PLK1) is a kinase that plays an important role in mitosis and the maintenance of genomic stability. PLK1 has been found to be highly expressed in the malignant cells of osteosarcoma. Here, we describe the in-vitro and in-vivo effects of BI 2536, a small-molecule inhibitor of PLK1, which through inhibiting PLK1 enzymatic activity, causes mitotic arrest and eventually induces cancer cell apoptosis. In this study, we show that the PLK1 inhibitor, BI 2536, inhibits proliferation and induces apoptosis in two-dimensional and three-dimensional cultures of osteosarcoma cell lines, KHOS and U-2OS. A proliferation assay performed both in two-dimensional and three-dimensional culture showed that the growth of both cell lines was inhibited by BI 2536. Cell cycle analysis showed that the cells treated with BI 2536 were mainly arrested in the G2/M phase. Immunofluorescence and western blotting analysis confirmed that the administration of BI 2536 led to significant decrease of PLK1 and Mcl-1 protein expression levels in dose-dependent and time-dependent manners. Furthermore, BI 2536-induced apoptosis in the osteosarcoma cell lines was shown by poly (ADP-ribose) polymerase cleavage and caspase assay. Finally, in mouse osteosarcoma xenografts, BI 2536-treated mice had significantly smaller tumors compared with the control mice. These findings offer evidence of the potential role for targeting PLK1 in osteosarcoma therapy.

  5. Apamin inhibits hepatic fibrosis through suppression of transforming growth factor β1-induced hepatocyte epithelial-mesenchymal transition.

    Science.gov (United States)

    Lee, Woo-Ram; Kim, Kyung-Hyun; An, Hyun-Jin; Kim, Jung-Yeon; Lee, Sun-Jae; Han, Sang-Mi; Pak, Sok Cheon; Park, Kwan-kyu

    2014-07-18

    Apamin is an integral part of bee venom, as a peptide component. It has long been known as a highly selective block Ca(2+)-activated K(+) (SK) channels. However, the cellular mechanism and anti-fibrotic effect of apamin in TGF-β1-induced hepatocytes have not been explored. In the present study, we investigated the anti-fibrosis or anti-EMT mechanism by examining the effect of apamin on TGF-β1-induced hepatocytes. AML12 cells were seeded at ∼60% confluence in complete growth medium. Twenty-four hours later, the cells were changed to serum free medium containing the indicated concentrations of apamin. After 30 min, the cells were treated with 2 ng/ml of TGF-β1 and co-cultured for 48 h. Also, we investigated the effects of apamin on the CCl4-induced liver fibrosis animal model. Treatment of AML12 cells with 2 ng/ml of TGF-β1 resulted in loss of E-cadherin protein at the cell-cell junctions and concomitant increased expression of vimentin. In addition, phosphorylation levels of ERK1/2, Akt, Smad2/3 and Smad4 were increased by TGF-β1 stimulation. However, cells treated concurrently with TGF-β1 and apamin retained high levels of localized expression of E-cadherin and showed no increase in vimentin. Specifically, treatment with 2 μg/ml of apamin almost completely blocked the phosphorylation of ERK1/2, Akt, Smad2/3 and Smad4 in AML12 cells. In addition, apamin exhibited prevention of pathological changes in the CCl4-injected animal models. These results demonstrate the potential of apamin for the prevention of EMT progression induced by TGF-β1 in vitro and CCl4-injected in vivo. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Contrasting spatial patterns in active-fire and fire-suppressed Mediterranean climate old-growth mixed conifer forests.

    Science.gov (United States)

    Fry, Danny L; Stephens, Scott L; Collins, Brandon M; North, Malcolm P; Franco-Vizcaíno, Ernesto; Gill, Samantha J

    2014-01-01

    In Mediterranean environments in western North America, historic fire regimes in frequent-fire conifer forests are highly variable both temporally and spatially. This complexity influenced forest structure and spatial patterns, but some of this diversity has been lost due to anthropogenic disruption of ecosystem processes, including fire. Information from reference forest sites can help management efforts to restore forests conditions that may be more resilient to future changes in disturbance regimes and climate. In this study, we characterize tree spatial patterns using four-ha stem maps from four old-growth, Jeffrey pine-mixed conifer forests, two with active-fire regimes in northwestern Mexico and two that experienced fire exclusion in the southern Sierra Nevada. Most of the trees were in patches, averaging six to 11 trees per patch at 0.007 to 0.014 ha(-1), and occupied 27-46% of the study areas. Average canopy gap sizes (0.04 ha) covering 11-20% of the area were not significantly different among sites. The putative main effects of fire exclusion were higher densities of single trees in smaller size classes, larger proportion of trees (≥ 56%) in large patches (≥ 10 trees), and decreases in spatial complexity. While a homogenization of forest structure has been a typical result from fire exclusion, some similarities in patch, single tree, and gap attributes were maintained at these sites. These within-stand descriptions provide spatially relevant benchmarks from which to manage for structural heterogeneity in frequent-fire forest types.

  7. Contrasting spatial patterns in active-fire and fire-suppressed Mediterranean climate old-growth mixed conifer forests.

    Directory of Open Access Journals (Sweden)

    Danny L Fry

    Full Text Available In Mediterranean environments in western North America, historic fire regimes in frequent-fire conifer forests are highly variable both temporally and spatially. This complexity influenced forest structure and spatial patterns, but some of this diversity has been lost due to anthropogenic disruption of ecosystem processes, including fire. Information from reference forest sites can help management efforts to restore forests conditions that may be more resilient to future changes in disturbance regimes and climate. In this study, we characterize tree spatial patterns using four-ha stem maps from four old-growth, Jeffrey pine-mixed conifer forests, two with active-fire regimes in northwestern Mexico and two that experienced fire exclusion in the southern Sierra Nevada. Most of the trees were in patches, averaging six to 11 trees per patch at 0.007 to 0.014 ha(-1, and occupied 27-46% of the study areas. Average canopy gap sizes (0.04 ha covering 11-20% of the area were not significantly different among sites. The putative main effects of fire exclusion were higher densities of single trees in smaller size classes, larger proportion of trees (≥ 56% in large patches (≥ 10 trees, and decreases in spatial complexity. While a homogenization of forest structure has been a typical result from fire exclusion, some similarities in patch, single tree, and gap attributes were maintained at these sites. These within-stand descriptions provide spatially relevant benchmarks from which to manage for structural heterogeneity in frequent-fire forest types.

  8. Robust Crop and Weed Segmentation under Uncontrolled Outdoor Illumination

    Directory of Open Access Journals (Sweden)

    Hong Y. Jeon

    2011-06-01

    Full Text Available An image processing algorithm for detecting individual weeds was developed and evaluated. Weed detection processes included were normalized excessive green conversion, statistical threshold value estimation, adaptive image segmentation, median filter, morphological feature calculation and Artificial Neural Network (ANN. The developed algorithm was validated for its ability to identify and detect weeds and crop plants under uncontrolled outdoor illuminations. A machine vision implementing field robot captured field images under outdoor illuminations and the image processing algorithm automatically processed them without manual adjustment. The errors of the algorithm, when processing 666 field images, ranged from 2.1 to 2.9%. The ANN correctly detected 72.6% of crop plants from the identified plants, and considered the rest as weeds. However, the ANN identification rates for crop plants were improved up to 95.1% by addressing the error sources in the algorithm. The developed weed detection and image processing algorithm provides a novel method to identify plants against soil background under the uncontrolled outdoor illuminations, and to differentiate weeds from crop plants. Thus, the proposed new machine vision and processing algorithm may be useful for outdoor applications including plant specific direct applications (PSDA.

  9. Predictability of uncontrollable multifocal seizures - towards new treatment options

    Science.gov (United States)

    Lehnertz, Klaus; Dickten, Henning; Porz, Stephan; Helmstaedter, Christoph; Elger, Christian E.

    2016-04-01

    Drug-resistant, multifocal, non-resectable epilepsies are among the most difficult epileptic disorders to manage. An approach to control previously uncontrollable seizures in epilepsy patients would consist of identifying seizure precursors in critical brain areas combined with delivering a counteracting influence to prevent seizure generation. Predictability of seizures with acceptable levels of sensitivity and specificity, even in an ambulatory setting, has been repeatedly shown, however, in patients with a single seizure focus only. We did a study to assess feasibility of state-of-the-art, electroencephalogram-based seizure-prediction techniques in patients with uncontrollable multifocal seizures. We obtained significant predictive information about upcoming seizures in more than two thirds of patients. Unexpectedly, the emergence of seizure precursors was confined to non-affected brain areas. Our findings clearly indicate that epileptic networks, spanning lobes and hemispheres, underlie generation of seizures. Our proof-of-concept study is an important milestone towards new therapeutic strategies based on seizure-prediction techniques for clinical practice.

  10. Carnosine inhibits carbonic anhydrase IX-mediated extracellular acidosis and suppresses growth of HeLa tumor xenografts

    International Nuclear Information System (INIS)

    Ditte, Zuzana; Ditte, Peter; Labudova, Martina; Simko, Veronika; Iuliano, Filippo; Zatovicova, Miriam; Csaderova, Lucia; Pastorekova, Silvia; Pastorek, Jaromir

    2014-01-01

    Carbonic anhydrase IX (CA IX) is a transmembrane enzyme that is present in many types of solid tumors. Expression of CA IX is driven predominantly by the hypoxia-inducible factor (HIF) pathway and helps to maintain intracellular pH homeostasis under hypoxic conditions, resulting in acidification of the tumor microenvironment. Carnosine (β-alanyl-L-histidine) is an anti-tumorigenic agent that inhibits the proliferation of cancer cells. In this study, we investigated the role of CA IX in carnosine-mediated antitumor activity and whether the underlying mechanism involves transcriptional and translational modulation of HIF-1α and CA IX and/or altered CA IX function. The effect of carnosine was studied using two-dimensional cell monolayers of several cell lines with endogenous CA IX expression as well as Madin Darby canine kidney transfectants, three-dimensional HeLa spheroids, and an in vivo model of HeLa xenografts in nude mice. mRNA and protein expression and protein localization were analyzed by real-time PCR, western blot analysis, and immunofluorescence staining, respectively. Cell viability was measured by a flow cytometric assay. Expression of HIF-1α and CA IX in tumors was assessed by immunohistochemical staining. Real-time measurement of pH was performed using a sensor dish reader. Binding of CA IX to specific antibodies and metabolon partners was investigated by competitive ELISA and proximity ligation assays, respectively. Carnosine increased the expression levels of HIF-1α and HIF targets and increased the extracellular pH, suggesting an inhibitory effect on CA IX-mediated acidosis. Moreover, carnosine significantly inhibited the growth of three-dimensional spheroids and tumor xenografts compared with untreated controls. Competitive ELISA showed that carnosine disrupted binding between CA IX and antibodies specific for its catalytic domain. This finding was supported by reduced formation of the functional metabolon of CA IX and anion exchanger 2 in the

  11. Fish oil suppresses cell growth and metastatic potential by regulating PTEN and NF-κB signaling in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Shevali Kansal

    Full Text Available Homeostasis in eukaryotic tissues is tightly regulated by an intricate balance of the prosurvival and antisurvival signals. The tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10, a dual-specificity phosphatase, plays a functional role in cell cycle arrest and apoptosis. NF-κB and its downstream regulators (such as VEGF play a central role in prevention of apoptosis, promotion of inflammation and tumor growth. Therefore, we thought to estimate the expression of PTEN, Poly-ADP-ribose polymerase (PARP, NF-κBp50, NF-κBp65 and VEGF to evaluate the effect of supplementation of fish oil on apoptotic and inflammatory signaling in colon carcinoma. Male wistar rats in Group I received purified diet while Group II and III received modified diet supplemented with FO∶CO(1∶1&FO∶CO(2.5∶1 respectively. These were further subdivided into controls receiving ethylenediamine-tetra acetic-acid and treated groups received dimethylhydrazine-dihydrochloride (DMH/week for 4 weeks. Animals sacrificed 48 hours after last injection constituted initiation phase and that sacrificed after 16 weeks constituted post-initiation phase. We have analysed expression of PTEN, NF-κBp50, NF-κBp65 by flowcytometer and nuclear localization of NF-κB by immunofluorescence. PARP and VEGF were assessed by immunohistochemistry. In the initiation phase, animals receiving DMH have shown increased % of apoptotic cells, PTEN, PARP, NF-κBp50, NF-κBp65 and VEGF however in post-initiation phase no significant alteration in apoptosis with decreased PTEN and increased PARP, NF-κBp50, NF-κBp65 and VEGF were observed as compared to control animals. On treatment with both ratios of fish oil in both the phases, augmentation in % of apoptotic cells, decreased PTEN, PARP, NF-κBp50, NF-κBp65 and VEGF were documented with respect to DMH treated animals with effect being more exerted with higher ration in post-initiation phase. Hence, fish oil activates

  12. Chitosan nanoparticle-based delivery of fused NKG2D–IL-21 gene suppresses colon cancer growth in mice

    Directory of Open Access Journals (Sweden)

    Tan L

    2017-04-01

    Full Text Available Lunmei Tan,1 Sen Han,2 Shizhen Ding,2 Weiming Xiao,3,4 Yanbing Ding,3 Li Qian,2,4 Chenming Wang,1,5 Weijuan Gong1–5 1Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, 2Department of Immunology, School of Medicine, 3Department of Gastroenterology, The Second Clinical Medical College, 4Department of Integrated Chinese and Western Medicine, School of Medicine, 5Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, People’s Republic of China Abstract: Nanoparticles can be loaded with exogenous DNA for the potential expression of cytokines with immune-stimulatory function. NKG2D identifies major histocompatibility complex class I chain-related protein in human and retinoic acid early induced transcript-1 in mouse, which acts as tumor-associated antigens. Biologic agents based on interleukin 21 (IL-21 have displayed antitumor activities through lymphocyte activation. The NKG2D–IL-21 fusion protein theoretically identifies tumor cells through NKG2D moiety and activates T cells through IL-21 moiety. In this study, double-gene fragments that encode the extracellular domains of NKG2D and IL-21 genes were connected and then inserted into the pcDNA3.1(– plasmid. PcDNA3.1–dsNKG2D–IL-21 plasmid nanoparticles based on chitosan were generated. Tumor cells pretransfected with dsNKG2D–IL-21 gene nanoparticles can activate natural killer (NK and CD8+ T cells in vitro. Serum IL-21 levels were enhanced in mice intramuscularly injected with the gene nanoparticles. DsNKG2D–IL-21 gene nanoparticles accumulated in tumor tissues after being intravenously injected for ~4–24 h. Treatment of dsNKG2D–IL-21 gene nanoparticles also retarded tumor growth and elongated the life span of tumor-bearing mice by activating NK and T cells in vivo. Thus, the dsNKG2D–IL-21 gene nanoparticles exerted efficient antitumor activities and would be potentially used for tumor therapy. Keywords: NKG2

  13. Can exercise suppress tumour growth in advanced prostate cancer patients with sclerotic bone metastases? A randomised, controlled study protocol examining feasibility, safety and efficacy.

    Science.gov (United States)

    Hart, Nicolas H; Newton, Robert U; Spry, Nigel A; Taaffe, Dennis R; Chambers, Suzanne K; Feeney, Kynan T; Joseph, David J; Redfern, Andrew D; Ferguson, Tom; Galvão, Daniel A

    2017-05-30

    Exercise may positively alter tumour biology through numerous modulatory and regulatory mechanisms in response to a variety of modes and dosages, evidenced in preclinical models to date. Specifically, localised and systemic biochemical alterations produced during and following exercise may suppress tumour formation, growth and distribution by virtue of altered epigenetics and endocrine-paracrine activity. Given the impressive ability of targeted mechanical loading to interfere with metastasis-driven tumour formation in human osteolytic tumour cells, it is of equal interest to determine whether a similar effect is observed in sclerotic tumour cells. The study aims to (1) establish the feasibility and safety of a combined modular multimodal exercise programme with spinal isometric training in advanced prostate cancer patients with sclerotic bone metastases and (2) examine whether targeted and supervised exercise can suppress sclerotic tumour growth and activity in spinal metastases in humans. A single-blinded, two-armed, randomised, controlled and explorative phase I clinical trial combining spinal isometric training with a modular multimodal exercise programme in 40 men with advanced prostate cancer and stable sclerotic spinal metastases. Participants will be randomly assigned to (1) the exercise intervention or (2) usual medical care. The intervention arm will receive a 3-month, supervised and individually tailored modular multimodal exercise programme with spinal isometric training. Primary endpoints (feasibility and safety) and secondary endpoints (tumour morphology; biomarker activity; anthropometry; musculoskeletal health; adiposity; physical function; quality of life; anxiety; distress; fatigue; insomnia; physical activity levels) will be measured at baseline and following the intervention. Statistical analyses will include descriptive characteristics, t-tests, effect sizes and two-way (group × time) repeated-measures analysis of variance (or analysis of

  14. Suppressed Belief

    Directory of Open Access Journals (Sweden)

    Komarine Romdenh-Romluc

    2009-12-01

    Full Text Available Moran’s revised conception of conscious belief requires us to reconceptualise suppressed belief. The work of Merleau-Ponty offers a way to do this. His account of motor-skills allows us to understand suppressed beliefs as pre-reflective ways of dealing with the world.

  15. Embelin suppresses growth of human pancreatic cancer xenografts, and pancreatic cancer cells isolated from KrasG12D mice by inhibiting Akt and Sonic hedgehog pathways.

    Directory of Open Access Journals (Sweden)

    Minzhao Huang

    Full Text Available Pancreatic cancer is a deadly disease, and therefore effective treatment and/or prevention strategies are urgently needed. The objectives of this study were to examine the molecular mechanisms by which embelin inhibited human pancreatic cancer cell growth in vitro, and xenografts in Balb C nude mice, and pancreatic cancer cell growth isolated from KrasG12D transgenic mice. XTT assays were performed to measure cell viability. AsPC-1 cells were injected subcutaneously into Balb c nude mice and treated with embelin. Cell proliferation and apoptosis were measured by Ki67 and TUNEL staining, respectively. The expression of Akt, and Sonic Hedgehog (Shh and their target gene products were measured by the immunohistochemistry, and Western blot analysis. The effects of embelin on pancreatic cancer cells isolated from 10-months old KrasG12D mice were also examined. Embelin inhibited cell viability in pancreatic cancer AsPC-1, PANC-1, MIA PaCa-2 and Hs 766T cell lines, and these inhibitory effects were blocked either by constitutively active Akt or Shh protein. Embelin-treated mice showed significant inhibition in tumor growth which was associated with reduced expression of markers of cell proliferation (Ki67, PCNA and Bcl-2 and cell cycle (cyclin D1, CDK2, and CDK6, and induction of apoptosis (activation of caspase-3 and cleavage of PARP, and increased expression of Bax. In addition, embelin inhibited the expression of markers of angiogenesis (COX-2, VEGF, VEGFR, and IL-8, and metastasis (MMP-2 and MMP-9 in tumor tissues. Antitumor activity of embelin was associated with inhibition of Akt and Shh pathways in xenografts, and pancreatic cancer cells isolated from KrasG12D mice. Furthermore, embelin also inhibited epithelial-to-mesenchymal transition (EMT by up-regulating E-cadherin and inhibiting the expression of Snail, Slug, and ZEB1. These data suggest that embelin can inhibit pancreatic cancer growth, angiogenesis and metastasis by suppressing Akt and

  16. Norcantharidin inhibits tumor growth and vasculogenic mimicry of human gallbladder carcinomas by suppression of the PI3-K/MMPs/Ln-5γ2 signaling pathway

    International Nuclear Information System (INIS)

    Zhang, Jing-Tao; Sun, Wei; Zhang, Wen-Zhong; Ge, Chun-Yan; Liu, Zhong-Yan; Zhao, Ze-Ming; Lu, Xing-Sui; Fan, Yue-Zu

    2014-01-01

    < 0.01, vs. control group); NCTD down-regulated expression of these VM signaling-related markers in vitro and in vivo. NCTD inhibited tumor growth and VM of human GBCs in vitro and in vivo by suppression of the PI3-K/MMPs/Ln-5γ2 signaling pathway. It is firstly concluded that NCTD may be a potential anti-VM agent for human GBCs

  17. Corticóide inalatório: efeitos no crescimento e na supressão adrenal Inhaled corticosteroids: effects on growth and adrenal suppression

    Directory of Open Access Journals (Sweden)

    Elisete E. Arend

    2005-08-01

    Full Text Available Este artigo é uma revisão da literatura médica sobre os corticosteróides inalatórios e seus efeitos no crescimento e na supressão adrenal em crianças e adolescentes. Utilizaram-se o Medline e artigos publicados em jornais científicos nacionais e internacionais, principalmente nos últimos cinco anos, para a revisão da literatura. Há controvérsias acerca dos efeitos colaterais dos corticóides inalatórios. Nos 21 estudos sobre crescimento e uso de corticóides inalatórios, notou-se que houve diferença significativa no primeiro ano (retardo de 1 a 1,5 cm quando se utilizou principalmente beclometasona e budesonida inalatórias, mas não se verificou diferença na altura final adulta quando estudos de mais longa duração foram conduzidos, fazendo-se relação com a altura dos pais. Entretanto, em dez artigos sobre uso de corticóide inalatório e supressão adrenal, foram relatadas hipoglicemia, parada de ganho de peso e altura, e alterações nos exames de cortisol sérico matinal e urinário de 24 h, principalmente com uso de doses altas de corticóide inalatório. Corticóides inalatórios podem diminuir o crescimento no primeiro ano de uso, mas não a altura final adulta. São necessárias mais pesquisas com longo tempo de acompanhamento de crianças em uso de corticóide inalatório para se avaliar o impacto sobre o crescimento final. Monitorar a altura é uma medida para se avaliar eficácia e segurança no uso de corticóide inalatório em crianças. Exames que avaliam o eixo hipotalâmico pituitário adrenal e a insuficiência adrenal devem ser correlacionados com sintomas clínicos ou efeitos colaterais.This is a review of the medical literature regarding inhaled corticosteroids and their effects on growth and adrenal suppression in children and adolescents. A review of the literature, principally that published over the last five years, was conducted using Medline and searching indexes of articles published in national and

  18. Yongdamsagan-tang, a traditional herbal formula, inhibits cell growth through the suppression of proliferation and inflammation in benign prostatic hyperplasia epithelial-1 cells.

    Science.gov (United States)

    Park, Eunsook; Lee, Mee-Young; Seo, Chang-Seob; Jeon, Woo-Young; Shin, Hyeun-Kyoo

    2017-09-14

    Benign prostatic hyperplasia (BPH), also called benign enlargement of the prostate, is a progressive disease that is observed in most elderly men. Yongdamsagan-tang, a traditional herbal formula, is used commonly for the treatment of inflammation-related diseases. Although the therapeutic efficacy of Yongdamsagan-tang against BPH in vivo was reported previously, its underlying mechanisms are not clearly understood. In this study, we investigated the effect of Yongdamsagan-tang water extract (YSTE) and its mechanism on the growth of human BPH epithelial BPH-1 cells. YSTE was extracted from 11 herbaceous plants and its chemical composition was analyzed by High-performance liquid chromatography (HPLC). YSTE was treated in the epithelial BPH-1 cell line and then cell lysates or supernant were used to evaluate cell viability, cell cycle, proliferation and cytokine production. HPLC revealed that Baicalin and gentiopicroside were involved as the major compounds of YSTE. YSTE treatment in BPH-1 cells repressed cell viability in a dose-dependent manner. Regarding the inhibitory mechanisms of YSTE on cell growth, YSTE inhibited cell proliferation via a decrease in endogenous cyclin D1 protein levels and arrest at the S phase during cell-cycle progression. Furthermore, YSTE treatment in BPH-1 cells suppressed prostaglandin E 2 production and cyclooxygenase-2 (COX-2) protein levels. The secretion of the proinflammatory cytokines, interleukin-8 and interleukin-6, was also reduced by YSTE treatment. YSTE in BPH-1 cells showed antiproliferative and anti-inflammatory activities via cell-cycle arrest and downregulation of COX-2 expression, respectively. Taken together, the results of the present study will enhance our understanding of the mechanisms underlying the effect of YSTE in BPH. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  19. Silibinin and its 2,3-dehydro-derivative inhibit basal cell carcinoma growth via suppression of mitogenic signaling and transcription factors activation.

    Science.gov (United States)

    Tilley, Cynthia; Deep, Gagan; Agarwal, Chapla; Wempe, Michael F; Biedermann, David; Valentová, Kateřina; Kren, Vladimir; Agarwal, Rajesh

    2016-01-01

    Basal cell carcinoma (BCC) is the most common cancer worldwide, and its current treatment options are insufficient and toxic. Surprisingly, unlike several other malignancies, chemopreventive efforts against BCC are almost lacking. Silibinin, a natural agent from milk thistle seeds, has shown strong efficacy against several cancers including ultraviolet radiation-induced skin (squamous) cancer; however, its potential activity against BCC is not yet examined. Herein, for the first time, we report the efficacy of silibinin and its oxidation product 2,3-dehydrosilibinin (DHS) against BCC both in vitro and in vivo using ASZ (p53 mutated) and BSZ (p53 deleted) cell lines derived from murine BCC tumors. Both silibinin and DHS significantly inhibited cell growth and clonogenicity while inducing apoptosis in a dose- and time-dependent manner, with DHS showing higher activity at lower concentrations. Both agents also inhibited the mitogenic signaling by reducing EGFR, ERK1/2, Akt, and STAT3 phosphorylation and suppressed the activation of transcription factors NF-κB and AP-1. More importantly, in an ectopic allograft model, oral administration of silibinin and DHS (200 mg/kg body weight) strongly inhibited the ASZ tumor growth by 44% and 71% (P < 0.05), respectively, and decreased the expression of proliferation biomarkers (PCNA and cyclin D1) as well as NF-κB p50 and c-Fos in the tumor tissues. Taken together, these results provide the first evidence for the efficacy and usefulness of silibinin and its derivative DHS against BCC, and suggest the need for additional studies with these agents in pre-clinical and clinical BCC chemoprevention and therapy models. © 2014 Wiley Periodicals, Inc.

  20. Blockade of A2b Adenosine Receptor Reduces Tumor Growth and Immune Suppression Mediated by Myeloid-Derived Suppressor Cells in a Mouse Model of Melanoma

    Directory of Open Access Journals (Sweden)

    Raffaella Iannone

    2013-12-01

    Full Text Available The A2b receptor (A2bR belongs to the adenosine receptor family. Emerging evidence suggest that A2bR is implicated in tumor progression in some murine tumor models, but the therapeutic potential of targeting A2bR in melanoma has not been examined. This study first shows that melanoma-bearing mice treated with Bay 60-6583, a selective A2bR agonist, had increased melanoma growth. This effect was associated with higher levels of immune regulatory mediators interleukin-10 (IL-10 and monocyte chemoattractant protein 1 (MCP-1 and accumulation of tumor-associated CD11b positive Gr1 positive cells (CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs. Depletion of CD11b+Gr1+ cells completely reversed the protumor activity of Bay 60-6583. Conversely, pharmacological blockade of A2bR with PSB1115 reversed immune suppression in the tumor microenvironment, leading to a significant melanoma growth delay. PSB1115 treatment reduced both levels of IL-10 and MCP-1 and CD11b+Gr1+ cell number in melanoma lesions. These effects were associated with higher frequency of tumor-infiltrating CD8 positive (CD8+ T cells and natural killer T (NKT cells and increased levels of T helper 1 (Th1-like cytokines. Adoptive transfer of CD11b+Gr1+ cells abrogated the antitumor activity of PSB1115. These data suggest that the antitumor activity of PSB1115 relies on its ability to lower accumulation of tumor-infiltrating MDSCs and restore an efficient antitumor T cell response. The antitumor effect of PSB1115 was not observed in melanoma-bearing nude mice. Furthermore, PSB1115 enhanced the antitumor efficacy of dacarbazine. These data indicate that A2bR antagonists such as PSB1115 should be investigated as adjuvants in the treatment of melanoma.

  1. Development of novel FePt/nanodiamond hybrid nanostructures: L1{sub 0} phase size-growth suppression and magnetic properties

    Energy Technology Data Exchange (ETDEWEB)

    Douvalis, A. P., E-mail: adouval@uoi.gr; Bourlinos, A. B. [University of Ioannina, Physics Department (Greece); Tucek, J.; Čépe, K. [Palacký University Olomouc, Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (Czech Republic); Bakas, T. [University of Ioannina, Physics Department (Greece); Zboril, R. [Palacký University Olomouc, Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (Czech Republic)

    2016-05-15

    A new type of hybrid nanomaterial composed of magnetic FePt nanoparticles grown on the surface of nanodiamond nanotemplate assemblies is described for the first time. Post annealing in vacuum of the as-made nanomaterial bearing cubic A1 soft magnetic FePt nanoparticles leads to the development of FePt nanoparticles with tetragonal L1{sub 0} hard, magnetic-phase characteristics, leaving untouched the nanodiamond nanotemplate assemblies. X-ray diffraction, high-resolution transmission electron microscopy including chemical mapping (HRTEM/HAADF), magnetization measurements, and {sup 57}Fe Mössbauer spectroscopy data show that the magnetic FePt nanoparticles, with average sizes of 3 and 8 nm in the as-made and annealed hybrids, respectively, are homogenously distributed within the nanodiamond template in both nanomaterials. As a consequence, their structural, morphological, and magnetic properties differ significantly from the corresponding properties of the nonsupported (free) as-made and annealed FePt nanoparticles with average sizes of 6 and 32 nm, respectively, developed by the same methods. This spatial isolation suppresses the size-growth of the FePt nanoparticles during the post-annealing procedure, triggering superparamagnetic relaxation phenomena, which are exposed as a combination of hard and soft magnetic-phase characteristics.

  2. Unanticipated Mycobacterium tuberculosis complex culture inhibition by immune modulators, immune suppressants, a growth enhancer, and vitamins A and D: clinical implications.

    Science.gov (United States)

    Greenstein, Robert J; Su, Liya; Shahidi, Azra; Brown, William D; Clifford, Anya; Brown, Sheldon T

    2014-09-01

    The development of novel antibiotics to treat multidrug-resistant (MDR) tuberculosis is time-consuming and expensive. Multiple immune modulators, immune suppressants, anti-inflammatories, and growth enhancers, and vitamins A and D, inhibit Mycobacterium avium subspecies paratuberculosis (MAP) in culture. We studied the culture inhibition of Mycobacterium tuberculosis complex by these agents. Biosafety level two M. tuberculosis complex (ATCC 19015 and ATCC 25177) was studied in radiometric Bactec or MGIT culture. Agents evaluated included clofazimine, methotrexate, 6-mercaptopurine, cyclosporine A, rapamycin, tacrolimus, monensin, and vitamins A and D. All the agents mentioned above caused dose-dependent inhibition of the M. tuberculosis complex. There was no inhibition by the anti-inflammatory 5-aminosalicylic acid, which causes bacteriostatic inhibition of MAP. We conclude that, at a minimum, studies with virulent M. tuberculosis are indicated with the agents mentioned above, as well as with the thioamide 5-propothiouricil, which has previously been shown to inhibit the M. tuberculosis complex in culture. Our data additionally emphasize the importance of vitamins A and D in treating mycobacterial diseases. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  3. Facial Recognition in Uncontrolled Conditions for Information Security

    Science.gov (United States)

    Xiao, Qinghan; Yang, Xue-Dong

    2010-12-01

    With the increasing use of computers nowadays, information security is becoming an important issue for private companies and government organizations. Various security technologies have been developed, such as authentication, authorization, and auditing. However, once a user logs on, it is assumed that the system would be controlled by the same person. To address this flaw, we developed a demonstration system that uses facial recognition technology to periodically verify the identity of the user. If the authenticated user's face disappears, the system automatically performs a log-off or screen-lock operation. This paper presents our further efforts in developing image preprocessing algorithms and dealing with angled facial images. The objective is to improve the accuracy of facial recognition under uncontrolled conditions. To compare the results with others, the frontal pose subset of the Face Recognition Technology (FERET) database was used for the test. The experiments showed that the proposed algorithms provided promising results.

  4. Facial Recognition in Uncontrolled Conditions for Information Security

    Directory of Open Access Journals (Sweden)

    Qinghan Xiao

    2010-01-01

    Full Text Available With the increasing use of computers nowadays, information security is becoming an important issue for private companies and government organizations. Various security technologies have been developed, such as authentication, authorization, and auditing. However, once a user logs on, it is assumed that the system would be controlled by the same person. To address this flaw, we developed a demonstration system that uses facial recognition technology to periodically verify the identity of the user. If the authenticated user's face disappears, the system automatically performs a log-off or screen-lock operation. This paper presents our further efforts in developing image preprocessing algorithms and dealing with angled facial images. The objective is to improve the accuracy of facial recognition under uncontrolled conditions. To compare the results with others, the frontal pose subset of the Face Recognition Technology (FERET database was used for the test. The experiments showed that the proposed algorithms provided promising results.

  5. Reoxygenation of human coronary smooth muscle cells suppresses HIF-1{alpha} gene expression and augments radiation-induced growth delay and apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Grumann, T.; Arab, A.; Bode, C.; Hehrlein, C. [Dept. of Cardiology, Univ. Clinic of Freiburg (Germany); Guttenberger, R. [Dept. of Radiotherapy, Univ. Clinic of Freiburg (Germany)

    2006-01-01

    Background and Purpose: Catheter-based coronary brachytherapy with {beta}- and {gamma}-radiation is an evidence-based method to prevent restenosis after percutaneous transluminal coronary angioplasty (PTCA) and stent implantation, but the outcome may be PTCA are hypoxic. A lack of oxygen decreases the effect of low LET (linear energy transfer) irradiation. The authors assumed that reoxygenation of hypoxic human coronary smooth muscle cells (HCSMCs) improves the results of coronary brachytherapy. The expression of hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) gene, and the rates of growth and apoptosis of hypoxic and reoxygenated HCSMCs after {gamma}-iradiation were therefore analyzed. Material and Methods: An in vitro model of megacolonies of HCSMCs was developed. After exposure to chronic hypoxia the HCSMCs were irradiated with graded doses of 2, 4, 8, and 16 Gy using a {sup 60}Co source either under hypoxia (pO{sub 2}<3 mmHg) or after reoxygenation (pO{sub 2}{approx}150 mmHg). RT-PCR (reverse transcription-polymerase chain reaction) analysis was used to quantify HIF-1{alpha} gene expression and the growth of HCSMC megacolonies was measured serially. The oxygen enhancement ratio (OER) was calculate from the specific growth delay. Apoptosis of HCSMCs was quantified by counting cells with specific DNA strand breaks using the TUNEL assy. Results: HIF-1{alpha} gene expression was markedly suppressed in reoxygenated cells versus hypoxic cells 30 min after {gamma}-irradiation at all radiation doses (158{+-}46% vs. 1,675{+-}1,211%; p<0.01). Apoptosis was markedly increased in reoxygenated HCSMCs. The OER was 1.8(95% CI[confidence interval]1.3-2.4). Therefore, reoxygenated HCSMCs require 44% less radiation dose to achieve the equivalent biological radiation effect compared to hypoxic HCSMCs. Conclusion: Reoxygenation of coronary smooth muscle cells should be considered an option to increase efficacy of coronary brachytherapy. This could be used to reduce radiation dose

  6. Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage infiltration and M2 polarization

    International Nuclear Information System (INIS)

    Jang, Ji-Young; Lee, Jong-Kuen; Jeon, Yoon-Kyung; Kim, Chul-Woo

    2013-01-01

    Tumor-associated macrophages (TAM) play an important role in tumor microenvironment. Particularly, M2 macrophages contribute to tumor progression, depending on the expression of NF-κB. Tumor-derived exosomes can modulate tumor microenvironment by transferring miRNAs to immune cells. Epigallocatechin gallate (EGCG) has well known anti-tumor effects; however, no data are available on the influence of EGCG on communication with cancer cells and TAM. Murine breast cancer cell lines, 4T1, was used for in vivo and ex vivo studies. Exosome was extracted from EGCG-treated 4T1 cells, and the change of miRNAs was screened using microarray. Tumor cells or TAM isolated from murine tumor graft were incubated with exosomes derived from EGCG-treated and/or miR-16 inhibitor-transfected 4T1 cells. Chemokines for monocytes (CSF-1 and CCL-2), cytokines both with high (IL-6 and TGF-β) and low (TNF-α) expression in M2 macrophages, and molecules in NF-κB pathway (IKKα and Iκ-B) were evaluated by RT-qPCR or western blot. EGCG suppressed tumor growth in murine breast cancer model, which was associated with decreased TAM and M2 macrophage infiltration. Expression of chemokine for monocytes (CSF-1 and CCL-2) were low in tumor cells from EGCG-treated mice, and cytokines of TAM was skewed from M2- into M1-like phenotype by EGCG as evidenced by decreased IL-6 and TGF-β and increased TNF-α. Ex vivo incubation of isolated tumor cells with EGCG inhibited the CSF-1 and CCL-2 expression. Ex vivo incubation of TAM with exosomes from EGCG-treated 4T1 cells led to IKKα suppression and concomitant I-κB accumulation; increase of IL-6 and TGF-β; and, decrease of TNF-α. EGCG up-regulated miR-16 in 4T1 cells and in the exosomes. Treatment of tumor cells or TAM with exosomes derived from EGCG-treated and miR-16-knock-downed 4T1 cells restored the above effects on chemokines, cytokines, and NF-κB pathway elicited by EGCG-treated exosomes. Our data demonstrate that EGCG up-regulates miR-16 in

  7. Anticancer effect of genistein on BG-1 ovarian cancer growth induced by 17 β-estradiol or bisphenol A via the suppression of the crosstalk between estrogen receptor alpha and insulin-like growth factor-1 receptor signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, Kyung-A; Park, Min-Ah; Kang, Nam-Hee; Yi, Bo-Rim; Hyun, Sang-Hwan; Jeung, Eui-Bae; Choi, Kyung-Chul, E-mail: kchoi@cbu.ac.kr

    2013-11-01

    The interaction between estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling pathway plays an important role in proliferation of and resistance to endocrine therapy to estrogen dependent cancers. Estrogen (E2) upregulates the expression of components of IGF-1 system and induces the downstream of mitogenic signaling cascades via phosphorylation of insulin receptor substrate-1 (IRS-1). In the present study, we evaluated the xenoestrogenic effect of bisphenol A (BPA) and antiproliferative activity of genistein (GEN) in accordance with the influence on this crosstalk. BPA was determined to affect this crosstalk by upregulating mRNA expressions of ERα and IGF-1R and inducing phosphorylation of IRS-1 and Akt in protein level in BG-1 ovarian cancer cells as E2 did. In the mouse model xenografted with BG-1 cells, BPA significantly increased a tumor burden of mice and expressions of ERα, pIRS-1, and cyclin D1 in tumor mass compared to vehicle, indicating that BPA induces ovarian cancer growth by promoting the crosstalk between ER and IGF-1R signals. On the other hand, GEN effectively reversed estrogenicity of BPA by reversing mRNA and protein expressions of ERα, IGF-1R, pIRS-1, and pAkt induced by BPA in cellular model and also significantly decreased tumor growth and in vivo expressions of ERα, pIRS-1, and pAkt in xenografted mouse model. Also, GEN was confirmed to have an antiproliferative effect by inducing apoptotic signaling cascades. Taken together, these results suggest that GEN effectively reversed the increased proliferation of BG-1 ovarian cancer by suppressing the crosstalk between ERα and IGF-1R signaling pathways upregulated by BPA or E2.

  8. Anticancer effect of genistein on BG-1 ovarian cancer growth induced by 17 β-estradiol or bisphenol A via the suppression of the crosstalk between estrogen receptor alpha and insulin-like growth factor-1 receptor signaling pathways

    International Nuclear Information System (INIS)

    Hwang, Kyung-A; Park, Min-Ah; Kang, Nam-Hee; Yi, Bo-Rim; Hyun, Sang-Hwan; Jeung, Eui-Bae; Choi, Kyung-Chul

    2013-01-01

    The interaction between estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling pathway plays an important role in proliferation of and resistance to endocrine therapy to estrogen dependent cancers. Estrogen (E2) upregulates the expression of components of IGF-1 system and induces the downstream of mitogenic signaling cascades via phosphorylation of insulin receptor substrate-1 (IRS-1). In the present study, we evaluated the xenoestrogenic effect of bisphenol A (BPA) and antiproliferative activity of genistein (GEN) in accordance with the influence on this crosstalk. BPA was determined to affect this crosstalk by upregulating mRNA expressions of ERα and IGF-1R and inducing phosphorylation of IRS-1 and Akt in protein level in BG-1 ovarian cancer cells as E2 did. In the mouse model xenografted with BG-1 cells, BPA significantly increased a tumor burden of mice and expressions of ERα, pIRS-1, and cyclin D1 in tumor mass compared to vehicle, indicating that BPA induces ovarian cancer growth by promoting the crosstalk between ER and IGF-1R signals. On the other hand, GEN effectively reversed estrogenicity of BPA by reversing mRNA and protein expressions of ERα, IGF-1R, pIRS-1, and pAkt induced by BPA in cellular model and also significantly decreased tumor growth and in vivo expressions of ERα, pIRS-1, and pAkt in xenografted mouse model. Also, GEN was confirmed to have an antiproliferative effect by inducing apoptotic signaling cascades. Taken together, these results suggest that GEN effectively reversed the increased proliferation of BG-1 ovarian cancer by suppressing the crosstalk between ERα and IGF-1R signaling pathways upregulated by BPA or E2

  9. Evaluation of the contamination risk by 241AM from lightning rods disposed at uncontrolled garbage dump

    International Nuclear Information System (INIS)

    Marumo, Julio Takehiro

    2006-01-01

    Radioactive lightning rods were manufactured in Brazil until 1989, when the licenses for using radioactive sources in these products were lifted by the national nuclear authority. Since then, radioactive devices have been replaced by Franklin type one and collected as radioactive waste. However, only 23 percent of the estimated total number of installed rods was delivered to Brazilian Nuclear Commission (Comissao Nacional de Energia Nuclear - CNEN). This situation is of concern as there is a possibility of the rods being discarded as domestic waste, considering that in Brazil, 63.6 percent of the municipal solid waste is disposed at uncontrolled garbage dump, according to Instituto Brasileiro de Geografia e Estatistica (IBGE) in 2000. In addition, americium, the most common employed radionuclide, is classified as a high toxicity element, when ingested or inhaled. In the present study, it was performed migration experiments of Am-241 by lysimeter system in order to evaluate the risk of contamination caused by radioactive lightning rods disposed as a common solid waste. Sources removed from lightning rods were placed inside lysimeters filled with organic waste, collected at the restaurant of Instituto de Pesquisas Energeticas e Nucleares, IPEN-CNEN/SP, and the generated leachate was periodically analyzed to determine its characteristics such as pH, redox potential, solid content and concentration of the radioactive material. Microbial growth was also evaluated by counting the number of colony forming units. The equivalent dose to members of the public has been calculated considering the ingestion of drinking water, the most probable mode of exposure. The final result was about 145 times below the effective dose limit of 1 mSv.year-1 for members of the public, established by the International Commission on Radiological Protection (ICRP), demonstrating that the risk caused by lightning rods disposed at uncontrolled garbage dump is low. (author)

  10. 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...

  11. Growth differentiation factor 9 reverses activin A suppression of steroidogenic acute regulatory protein expression and progesterone production in human granulosa-lutein cells.

    Science.gov (United States)

    Shi, Feng-Tao; Cheung, Anthony P; Klausen, Christian; Huang, He-Feng; Leung, Peter C K

    2010-10-01

    We have reported that growth differentiation factor 9 (GDF9) can enhance activin A (β(A)β(A))-induced inhibin B (αβ(B)) secretion in human granulosa-lutein (hGL) cells, but its effects on steroidogenic acute regulatory protein (StAR), ovarian steroidogenic enzymes, and progesterone production are unknown. We undertook this study to further evaluate GDF9 in this regard. hGL cells from women undergoing in vitro fertilization treatment were cultured with and without small interfering RNA (siRNA) transfection targeted at inhibin α-subunit or GDF9 before treatment with GDF9, activin A, FSH, or combinations. We compared StAR, P450 side-chain cleavage enzyme, and 3β-hydroxysteroid dehydrogenase expression in hGL cells and progesterone levels in culture media after these treatments. mRNA, protein, and hormone levels were assessed with real-time RT-PCR, immunoblotting, and ELISA, respectively. Data were analyzed by ANOVA followed by Tukey's test. Activin A alone reduced basal and FSH-induced progesterone production by decreasing the expression of StAR protein, which regulates the rate-limiting step in steroidogenesis but not P450 side-chain cleavage enzyme and 3β-hydroxysteroid dehydrogenase. GDF9 attenuated these activin A effects on StAR and progesterone. After transfection of α-subunit siRNA, activin A level increased (P progesterone production were attenuated (P progesterone secretion than those observed with activin A treatment alone. GDF9 attenuates the suppressive effects of activin A on StAR expression and progesterone production by increasing the expression of inhibin B, which acts as an activin A competitor.

  12. Anti-Vascular Endothelial Growth Factor Antibody Suppresses ERK and NF-κB Activation in Ischemia-Reperfusion Lung Injury.

    Directory of Open Access Journals (Sweden)

    Chou-Chin Lan

    Full Text Available Ischemia-reperfusion (IR-induced acute lung injury (ALI is implicated in several clinical conditions like lung transplantation, acute pulmonary embolism after thrombolytic therapy, re-expansion of collapsed lung from pneumothorax or pleural effusion, cardiopulmonary bypass and etc. Because mortality remains high despite advanced medical care, prevention and treatment are important clinical issues for IR-induced ALI. Vascular endothelial growth factor (VEGF has a controversial role in ALI. We therefore conducted this study to determine the effects of anti-VEGF antibody in IR-induced ALI. In the current study, the IR-induced ALI was conducted in a rat model of isolated-perfused lung in situ in the chest. The animals were divided into the control, control + preconditioning anti-VEGF antibody (bevacizumab, 5mg/kg, IR, IR + preconditioning anti-VEGF antibody (1mg/kg, IR+ preconditioning anti-VEGF antibody (5mg/kg and IR+ post-IR anti-VEGF antibody (5mg/kg group. There were eight adult male Sprague-Dawley rats in each group. The IR caused significant pulmonary micro-vascular hyper-permeability, pulmonary edema, neutrophilic infiltration in lung tissues, increased tumor necrosis factor-α, and total protein concentrations in bronchoalveolar lavage fluid. VEGF and extracellular signal-regulated kinase (ERK were increased in IR-induced ALI. Administration of preconditioning anti-VEGF antibody significantly suppressed the VEGF and ERK expressions and attenuated the IR-induced lung injury. This study demonstrates the important role of VEGF in early IR-induced ALI. The beneficial effects of preconditioning anti-VEGF antibody in IR-induced ALI include the attenuation of lung injury, pro-inflammatory cytokines, and neutrophilic infiltration into the lung tissues.

  13. Fibroblast growth factor 21 protects mouse brain against D-galactose induced aging via suppression of oxidative stress response and advanced glycation end products formation.

    Science.gov (United States)

    Yu, Yinhang; Bai, Fuliang; Wang, Wenfei; Liu, Yaonan; Yuan, Qingyan; Qu, Susu; Zhang, Tong; Tian, Guiyou; Li, Siming; Li, Deshan; Ren, Guiping

    2015-06-01

    Fibroblast growth factor 21 (FGF21) is a hormone secreted predominantly in the liver, pancreas and adipose tissue. Recently, it has been reported that FGF21-Transgenic mice can extend their lifespan compared with wild type counterparts. Thus, we hypothesize that FGF21 may play some roles in aging of organisms. In this study d-galactose (d-gal)-induced aging mice were used to study the mechanism that FGF21 protects mice from aging. The three-month-old Kunming mice were subcutaneously injected with d-gal (180mg·kg(-1)·d(-1)) for 8weeks and administered simultaneously with FGF21 (1, 2 or 5mg·kg(-1)·d(-1)). Our results showed that administration of FGF21 significantly improved behavioral performance of d-gal-treated mice in water maze task and step-down test, reduced brain cell damage in the hippocampus, and attenuated the d-gal-induced production of MDA, ROS and advanced glycation end products (AGEs). At the same time, FGF21 also markedly renewed the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total anti-oxidation capability (T-AOC), and decreased the enhanced total cholinesterase (TChE) activity in the brain of d-gal-treated mice. The expression of aldose reductase (AR), sorbitol dehydrogenase (SDH) and member-anchored receptor for AGEs (RAGE) declined significantly after FGF21 treatment. Furthermore, FGF21 suppressed inflamm-aging by inhibiting IκBα degradation and NF-κB p65 nuclear translocation. The expression levels of pro-inflammatory cytokines, such as TNF-α and IL-6, decreased significantly. In conclusion, these results suggest that FGF21 protects the aging mice brain from d-gal-induced injury by attenuating oxidative stress damage and decreasing AGE formation. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Fisetin inhibits epidermal growth factor-induced migration of ARPE-19 cells by suppression of AKT activation and Sp1-dependent MMP-9 expression.

    Science.gov (United States)

    Lin, Hung-Yu; Chen, Yong-Syuan; Wang, Kai; Chien, Hsiang-Wen; Hsieh, Yi-Hsien; Yang, Shun-Fa

    2017-01-01

    Proliferative vitreoretinopathy (PVR) can result in abnormal migration of RPE cells. Fisetin is a naturally occurring compound that has been reported to have antitumor effects, but its effects on epidermal growth factor (EGF)-induced cell migration and the underlying mechanisms remain unclear. Effects of fisetin on EGF-induced cell viability and migration were examined with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and in vitro migration assays. Reverse transcription-PCR (RT-PCR) and immunoblotting were performed to evaluate matrix metallopeptidase-9 (MMP-9) expression and activation of specificity protein-1 (Sp1) and protein kinase B (AKT) in ARPE-19 cells treated with EGF and with or without fisetin. Luciferase and chromatin immunoprecipitation (ChIP) assays were performed to examine Sp1 transcription activity and MMP-9 binding activity. Fisetin did not affect ARPE-19 cell viability and significantly inhibited the EGF-induced migration capacity of ARPE-19 cells. Furthermore, fisetin exerted an antimigratory effect and suppressed MMP-9 mRNA and protein expression. Treatment with EGF induced phosphorylation of AKT and expression of MMP-9 and Sp1. Fisetin combined with LY294002 (an inhibitor of AKT) prevented the EGF-induced migration involved in downregulation of Sp1 and MMP-9 expression. Luciferase and ChIP assays suggested that fisetin remarkably decreased the EGF-induced transcription activity of MMP-9 and Sp1 and inhibited EGF-mediated Sp1 from directly binding to the MMP-9 promoter in ARPE-19 cells. Fisetin inhibited EGF-induced cell migration via modulation of AKT/Sp1-dependent MMP-9 transcriptional activity. Therefore, fisetin may be a potential agent in the treatment of migratory PVR diseases.

  15. Fisetin inhibits epidermal growth factor–induced migration of ARPE-19 cells by suppression of AKT activation and Sp1-dependent MMP-9 expression

    Science.gov (United States)

    Lin, Hung-Yu; Chen, Yong-Syuan; Wang, Kai; Chien, Hsiang-Wen

    2017-01-01

    Purpose Proliferative vitreoretinopathy (PVR) can result in abnormal migration of RPE cells. Fisetin is a naturally occurring compound that has been reported to have antitumor effects, but its effects on epidermal growth factor (EGF)–induced cell migration and the underlying mechanisms remain unclear. Methods Effects of fisetin on EGF-induced cell viability and migration were examined with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and in vitro migration assays. Reverse transcription–PCR (RT–PCR) and immunoblotting were performed to evaluate matrix metallopeptidase-9 (MMP-9) expression and activation of specificity protein-1 (Sp1) and protein kinase B (AKT) in ARPE-19 cells treated with EGF and with or without fisetin. Luciferase and chromatin immunoprecipitation (ChIP) assays were performed to examine Sp1 transcription activity and MMP-9 binding activity. Results Fisetin did not affect ARPE-19 cell viability and significantly inhibited the EGF-induced migration capacity of ARPE-19 cells. Furthermore, fisetin exerted an antimigratory effect and suppressed MMP-9 mRNA and protein expression. Treatment with EGF induced phosphorylation of AKT and expression of MMP-9 and Sp1. Fisetin combined with LY294002 (an inhibitor of AKT) prevented the EGF-induced migration involved in downregulation of Sp1 and MMP-9 expression. Luciferase and ChIP assays suggested that fisetin remarkably decreased the EGF-induced transcription activity of MMP-9 and Sp1 and inhibited EGF-mediated Sp1 from directly binding to the MMP-9 promoter in ARPE-19 cells. Conclusions Fisetin inhibited EGF-induced cell migration via modulation of AKT/Sp1–dependent MMP-9 transcriptional activity. Therefore, fisetin may be a potential agent in the treatment of migratory PVR diseases. PMID:29296070

  16. Uncontrolled withdrawal of a control rod without scram

    International Nuclear Information System (INIS)

    Abou-EL-Maaty, Talal

    2008-01-01

    In the present work the thermal-hydraulics of reactivity-induced transients in low enriched uranium (LEU) core of a typical material test research reactor (MTR) are analyzed using the previous program developed by Khater et al. The analysis was done for uncontrolled withdrawal of a control rod with scram-disabled conditions. Initiating reactivity events with and without the influence of reactivity efficiency curve ('S' curve) were considered. The results of the proposed transients are analyzed and compared with each other. In transient without the 'S' curve influence, a high primary peak power of 406.18 MW is attained and a clad melt down takes place after 1.85 s. In the transient with the 'S' curve influence, a high super prompt-critical situation is produced (1.762$ at 0.895 s) with a very high primary peak power of 801.05 MW at 0.912 s. Also, a fast clad melt down is resulted in the hot channel at 1.088 s and a stable film boiling is established. This study indicates that, compared to the application of linear reactivity curve, the application of the reactivity efficiency curve results in the prediction of higher peaks in power and temperatures (fuel, clad and coolant) with a fast clad melt down

  17. Uncontrolled withdrawal of a control rod without SCRAM

    International Nuclear Information System (INIS)

    Abou-El-Maaty, T.

    2007-01-01

    In the present work, the thermal-hydraulic analysis of reactivity-induced transients in a Low Enriched Uranium (LEU) core of a typical material test research reactor is conducted using the previous program developed Khater et al. The analysis was done for the uncontrolled withdrawal of a control rod under scram-disabled conditions. The initiating event reactivity was considered with and without influence of the reactivity efficiency curve (''S'' curve). The results of the transient calculations are analyzed and compared with each other. In the transient without the ''S'' curve influence, a high primary peak power of 406.18 MW is attained and a clad melt down is occurring after 1.85 s. In the transient with the ''S'' curve influence, a super prompt highly critical situation is produced (1.762 $ at 0.895 s) with a very high primary peak power of 801.05 MW at 0.912 s. A fast clad melt down is resulting in the hot channel at 1.088 s and a stable film boiling is occurring. This study shows that the influence of the reactivity efficiency curve results in higher peaks in power and temperatures (fuel, clad and coolant) with a fast clad melt down than that of a linear assumption. (orig.)

  18. Flies cope with uncontrollable stress by learned helplessness.

    Science.gov (United States)

    Yang, Zhenghong; Bertolucci, Franco; Wolf, Reinhard; Heisenberg, Martin

    2013-05-06

    In a wide range of animals, uncontrollable stressful events can induce a condition called "learned helplessness." In mammals it is associated with low general activity, poor learning, disorders of sleep and feeding, ulcers, and reduced immune status, as well as with increased serotonin in parts of the brain. It is considered an animal model of depression in humans. Here we investigate learned helplessness in Drosophila, showing that this behavioral state consists of a cognitive and a modulatory, possibly mood-like, component. A fly, getting heated as soon as it stops walking, reliably resumes walking to escape the heat. If, in contrast, the fly is not in control of the heat, it learns that its behavior has no effect and quits responding. In this state, the fly walks slowly and takes longer and more frequent rests, as if it were "depressed." This downregulation of walking behavior is more pronounced in females than in males. Learned helplessness in Drosophila is an example of how, in a certain situation, behavior is organized according to its expected consequences. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. An algorithmic approach for the treatment of severe uncontrolled asthma

    Science.gov (United States)

    Zervas, Eleftherios; Samitas, Konstantinos; Papaioannou, Andriana I.; Bakakos, Petros; Loukides, Stelios; Gaga, Mina

    2018-01-01

    A small subgroup of patients with asthma suffers from severe disease that is either partially controlled or uncontrolled despite intensive, guideline-based treatment. These patients have significantly impaired quality of life and although they constitute asthma patients, they are responsible for more than half of asthma-related healthcare costs. Here, we review a definition for severe asthma and present all therapeutic options currently available for these severe asthma patients. Moreover, we suggest a specific algorithmic treatment approach for the management of severe, difficult-to-treat asthma based on specific phenotype characteristics and biomarkers. The diagnosis and management of severe asthma requires specialised experience, time and effort to comprehend the needs and expectations of each individual patient and incorporate those as well as his/her specific phenotype characteristics into the management planning. Although some new treatment options are currently available for these patients, there is still a need for further research into severe asthma and yet more treatment options. PMID:29531957

  20. Interocular suppression

    Science.gov (United States)

    Tuna, Ana Rita; Almeida Neves Carrega, Filipa; Nunes, Amélia Fernandes

    2017-08-01

    The objective of this work is to quantify the suppressive imbalance, based on the manipulation of ocular luminance, between a group of subjects with normal binocular vision and a group of subjects with amblyopia. The result reveals that there are statistically significant differences in interocular dominance between two groups, evidencing a greater suppressive imbalance in amblyopic subjects. The technique used, proved to be a simple, easy to apply and economic method, for quantified ocular dominance. It is presented as a technique with the potential to accompany subjects with a marked dominance in one of the eyes that makes fusion difficult.

  1. Long-term treatment outcomes of acromegaly patients presenting biochemically-uncontrolled at a tertiary pituitary center.

    Science.gov (United States)

    Carmichael, John D; Broder, Michael S; Cherepanov, Dasha; Chang, Eunice; Mamelak, Adam; Said, Qayyim; Neary, Maureen P; Bonert, Vivien

    2017-08-04

    Acromegaly is a rare, slowly progressive disorder resulting from excessive growth hormone (GH) production by a pituitary somatotroph tumor. The objective of this study was to examine acromegaly treatment outcomes during long-term care at a specialized pituitary center in patients presenting with lack of biochemical control. Data came from an acromegaly registry at the Cedars-Sinai Medical Center Pituitary Center (center). Acromegaly patients included in this study were those who presented biochemically-uncontrolled for care at the center. Biochemical control status, based on serum insulin-like growth factor-1 values, was determined at presentation and at study end. Patient characteristics and acromegaly treatments were reported before and after presentation by presenting treatment status and final biochemical control status. Data on long-term follow-up were recorded from 1985 through June 2013. Seventy-four patients presented uncontrolled: 40 untreated (54.1%) and 34 (45.9%) previously-treated. Mean (SD) age at diagnosis was 43.2 (14.7); 32 (43.2%) were female patients. Of 65 patients with tumor size information, 59 (90.8%) had macroadenomas. Prior treatments among the 34 previously-treated patients were pituitary surgery alone (47.1%), surgery and medication (41.2%), and medication alone (11.8%). Of the 40 patients without prior treatment, 82.5% achieved control by study end. Of the 34 with prior treatment, 50% achieved control by study end. This observational study shows that treatment outcomes of biochemically-uncontrolled acromegaly patients improve with directed care, particularly for those that initially present untreated. Patients often require multiple modalities of treatment, many of which are offered with the highest quality at specialized pituitary centers. Despite specialized care, some patients were not able to achieve biochemical control with methods of treatment that were available at the time of their treatment, showing the need for additional

  2. Model-Based Illumination Correction for Face Images in Uncontrolled Scenarios

    NARCIS (Netherlands)

    Boom, B.J.; Spreeuwers, Lieuwe Jan; Veldhuis, Raymond N.J.

    2009-01-01

    Face Recognition under uncontrolled illumination conditions is partly an unsolved problem. Several illumination correction methods have been proposed, but these are usually tested on illumination conditions created in a laboratory. Our focus is more on uncontrolled conditions. We use the Phong model

  3. CONTROL ALGORITMS OF BOF MELTING WITH CONSIDERING THE INFLUENCE OF UNCONTROLLED DISTURBANCE

    Directory of Open Access Journals (Sweden)

    V. S. Bogushevsky

    2016-01-01

    Full Text Available The article describes influence of uncontrollable disturbances for output parameters of converting smelting. You also find numerical values of impact impurity of scrap, falling mixer slag with cast iron, limestone instead of lime and water from cooled elements on decarbonization, bathtub temperature and slag basicity. Created a control algorithm with the influence of uncontrolled disturbance.

  4. Getting the basics right resolves most cases of uncontrolled and problematic asthma

    NARCIS (Netherlands)

    de Groot, Eric P.; Kreggemeijer, Wendy J.; Brand, Paul L. P.

    AimThe prevalence of true therapy-resistant asthma among children whose asthma remains uncontrolled, despite daily controller therapy, is unknown. The aim of this study was to investigate the underlying causes in children with uncontrolled asthma. MethodsThis was a retrospective chart review of 142

  5. EGCG, a major green tea catechin suppresses breast tumor angiogenesis and growth via inhibiting the activation of HIF-1α and NFκB, and VEGF expression.

    Science.gov (United States)

    Gu, Jian-Wei; Makey, Kristina L; Tucker, Kevan B; Chinchar, Edmund; Mao, Xiaowen; Pei, Ivy; Thomas, Emily Y; Miele, Lucio

    2013-05-02

    The role of EGCG, a major green tea catechin in breast cancer therapy is poorly understood. The present study tests the hypothesis that EGCG can inhibit the activation of HIF-1α and NFκB, and VEGF expression, thereby suppressing tumor angiogenesis and breast cancer progression. Sixteen eight-wk-old female mice (C57BL/6 J) were inoculated with 10^6 E0771 (mouse breast cancer) cells in the left fourth mammary gland fat pad. Eight mice received EGCG at 50-100 mg/kg/d in drinking water for 4 weeks. 8 control mice received drinking water only. Tumor size was monitored using dial calipers. At the end of the experiment, blood samples, tumors, heart and limb muscles were collected for measuring VEGF expression using ELISA and capillary density (CD) using CD31 immunohistochemistry. EGCG treatment significantly reduced tumor weight over the control (0.37 ± 0.15 vs. 1.16 ± 0.30 g; P < 0.01), tumor CD (109 ± 20 vs. 156 ± 12 capillary #/mm^2; P < 0.01), tumor VEGF expression (45.72 ± 1.4 vs. 59.03 ± 3.8 pg/mg; P < 0.01), respectively. But, it has no effects on the body weight, heart weight, angiogenesis and VEGF expression in the heart and skeletal muscle of mice. EGCG at 50 μg/ml significantly inhibited the activation of HIF-1α and NFκB as well as VEGF expression in cultured E0771 cells, compared to the control, respectively. These findings support the hypothesis that EGCG, a major green tea catechin, directly targets both tumor cells and tumor vasculature, thereby inhibiting tumor growth, proliferation, migration, and angiogenesis of breast cancer, which is mediated by the inhibition of HIF-1α and NFκB activation as well as VEGF expression.

  6. Albuminuria and masked uncontrolled hypertension in chronic kidney disease.

    Science.gov (United States)

    Agarwal, Rajiv

    2017-12-01

    Masked uncontrolled hypertension (MUCH) is associated with greater target organ damage such as left ventricular hypertrophy, increased arterial stiffness and albuminuria. Whether MUCH independently associates with greater cardiovascular end-organ damage or kidney damage is unclear. The objective of this study was to assess the strength of the relationship of MUCH (awake ambulatory blood pressure ≥135/85 mmHg and clinic blood pressure <140/90 mmHg) with target organ damage. In a cross-sectional study at a veterans' administration medical center, clinically normotensive veterans without chronic kidney disease (CKD) (n = 29) and 287 patients with CKD and controlled hypertension (CH, n = 193), MUCH (n = 67) and uncontrolled hypertension (UCH, n = 27) had evaluation of target organ damage. Target organ damage was measured by echocardiography [left ventricular mass index (LVMI)], arterial ultrasonography [aortic pulse wave velocity (PWV)] and 24-h urine collection [albuminuria (urine albumin to creatinine ratio)] in all participants. Compared to that of controls, LVMI was higher by 21.8 g/m2 (CI, 4.0-39.7 g/m2) in CH, 27.9 (CI, 8-47.8) in MUCH and 39.5 (CI, 15.7-63.2) in UCH (P < 0.01 for group differences, P < 0.01 for linear trend). Although differences persisted after adjustment for age, sex and race, they lost significance after adjustments for cardiovascular risk factors and their treatment. Compared to that of controls, PWV was different among CH, MUCH and UCH (P = 0.04 for group differences, P = 0.02 for linear trend). However, differences lost significance after adjustments for age, sex and race. Compared to that of controls, log2 UACR was higher by 2.40 mg/mg (CI, 1.28-3.52) in CH, 4.94 (CI, 3.70-6.18) in MUCH and 6.01 (CI, 4.49-7.53) in UCH (P < 0.0001 for group difference, P < 0.0001 for linear trend). Differences persisted after adjustment for age, sex and race, cardiovascular risk factors and their treatment and cardiovascular disease (P < 0.0001 for group

  7. METHOD OF SUPPRESSING GASTROINTESTINAL UREASE ACTIVITY

    Science.gov (United States)

    Visek, W.J.

    1963-04-23

    This patent shows a method of increasing the growth rate of chicks. Certain diacyl substituted ureas such as alloxan, murexide, and barbituric acid are added to their feed, thereby suppressing gastrointestinal urease activity and thus promoting growth. (AEC)

  8. Dioscin and methylprotodioscin isolated from the root of Asparagus cochinchinensis suppressed the gene expression and production of airway MUC5AC mucin induced by phorbol ester and growth factor.

    Science.gov (United States)

    Lee, Hyun Jae; Park, Jin Sung; Yoon, Yong Pill; Shin, Ye Jin; Lee, Sang Kook; Kim, Yeong Shik; Hong, Jang-Hee; Son, Kun Ho; Lee, Choong Jae

    2015-05-15

    The root of Asparagus cochinchinensis (Lour.) Merr. has been utilized as mucoregulators and expectorants for controlling the airway inflammatory diseases in folk medicine. We investigated whether dioscin and methylprotodioscin isolated from the root of Asparagus cochinchinensis (Lour.) Merr. suppress the gene expression and production of airway MUC5AC mucin induced by phorbol ester and growth factor. Confluent NCI-H292 cells were pretreated with dioscin or methylprotodioscin for 30 min and then stimulated with EGF or PMA for 24 h. The MUC5AC mucin gene expression was measured by RT-PCR. Production of MUC5AC mucin protein was measured by ELISA. (1) Dioscin and methylprotodioscin suppressed the expression of MUC5AC mucin gene induced by EGF or PMA; (2) dioscin suppressed the production of MUC5AC mucin induced by either EGF at 10(-5) M (p Asparagus cochinchinensis suppress the gene expression and production of MUC5AC mucin, by directly acting on airway epithelial cells, and the results are consistent with the traditional use of Asparagus cochinchinensis as remedy for diverse inflammatory pulmonary diseases. Copyright © 2015 Elsevier GmbH. All rights reserved.

  9. Insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-5 mediate TGF-β- and myostatin-induced suppression of proliferation in porcine embryonic myogenic cell cultures

    International Nuclear Information System (INIS)

    Kamanga-Sollo, E.; Pampusch, M.S.; White, M.E.; Hathaway, M.R.; Dayton, W.R.

    2005-01-01

    We have previously shown that cultured porcine embryonic myogenic cells (PEMC) produce both insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-5 and secrete these proteins into their media. Exogenously added recombinant porcine (rp) IGFBP-3 and rpIGFBP-5 act via IGF-dependent and IGF-independent mechanisms to suppress proliferation of PEMC cultures. Furthermore, immunoneutralization of endogenous IGFBP-3 and IGFBP-5 in the PEMC culture medium results in increased DNA synthesis rate suggesting that endogenous IGFBP-3 and IGFBP-5 suppress PEMC proliferation. TGF-β superfamily members myostatin and TGF-β 1 have also been shown to suppress proliferation of myogenic cells, and treatment of cultured PEMC with either TGF-β 1 or myostatin significantly (P 1 and myostatin. Here, we show that immunoneutralization of IGFBP-5 also significantly (P 1 or myostatin-treated PEMC cultures restores Long-R3-IGF-I-stimulated DNA synthesis rates to 90% of the levels observed in control cultures receiving no TGF-β 1 or myostatin treatment (P 1 or myostatin-treated PEMC cultures, phosphosmad2 levels in these cultures were not affected. These findings strongly suggest that IGFBP-3 and IGFBP-5 affect processes downstream from receptor-mediated Smad phosphorylation that facilitate the ability of TGF-β and myostatin to suppress proliferation of PEMC

  10. Dynamic Determinants of the Uncontrolled Manifold during Human Quiet Stance.

    Science.gov (United States)

    Suzuki, Yasuyuki; Morimoto, Hiroki; Kiyono, Ken; Morasso, Pietro G; Nomura, Taishin

    2016-01-01

    Human postural sway during stance arises from coordinated multi-joint movements. Thus, a sway trajectory represented by a time-varying postural vector in the multiple-joint-angle-space tends to be constrained to a low-dimensional subspace. It has been proposed that the subspace corresponds to a manifold defined by a kinematic constraint, such that the position of the center of mass (CoM) of the whole body is constant in time, referred to as the kinematic uncontrolled manifold ( kinematic-UCM ). A control strategy related to this hypothesis ( CoM-control-strategy ) claims that the central nervous system (CNS) aims to keep the posture close to the kinematic-UCM using a continuous feedback controller, leading to sway patterns that mostly occur within the kinematic-UCM, where no corrective control is exerted. An alternative strategy proposed by the authors ( intermittent control-strategy ) claims that the CNS stabilizes posture by intermittently suspending the active feedback controller, in such a way to allow the CNS to exploit a stable manifold of the saddle-type upright equilibrium in the state-space of the system, referred to as the dynamic-UCM , when the state point is on or near the manifold. Although the mathematical definitions of the kinematic- and dynamic-UCM are completely different, both UCMs play similar roles in the stabilization of multi-joint upright posture. The purpose of this study was to compare the dynamic performance of the two control strategies. In particular, we considered a double-inverted-pendulum-model of postural control, and analyzed the two UCMs defined above. We first showed that the geometric configurations of the two UCMs are almost identical. We then investigated whether the UCM-component of experimental sway could be considered as passive dynamics with no active control, and showed that such UCM-component mainly consists of high frequency oscillations above 1 Hz, corresponding to anti-phase coordination between the ankle and hip. We

  11. Dynamic determinants of the uncontrolled manifold during human quiet stance

    Directory of Open Access Journals (Sweden)

    Yasuyuki Suzuki

    2016-12-01

    Full Text Available Human postural sway during stance arises from coordinated multi-joint movements. Thus, a sway trajectory represented by a time-varying postural vector in the multiple-joint-angle-space tends to be constrained to a low-dimensional subspace. It has been proposed that the subspace corresponds to a manifold defined by a kinematic constraint, such that the position of the center of mass (CoM of the whole body is constant in time, referred to as the kinematic uncontrolled manifold (kinematic-UCM. A control strategy related to this hypothesis (CoM-control-strategy claims that the central nervous system (CNS aims to keep the posture close to the kinematic-UCM using a continuous feedback controller, leading to sway patterns that mostly occur within the kinematic-UCM, where no corrective control is exerted. An alternative strategy proposed by the authors (intermittent control-strategy claims that the CNS stabilizes posture by intermittently suspending the active feedback controller, in such a way to allow the CNS to exploit a stable manifold of the saddle-type upright equilibrium in the state-space of the system, referred to as the dynamic-UCM, when the state point is on or near the manifold. Although the mathematical definitions of the kinematic- and dynamic-UCM are completely different, both UCMs play similar roles in the stabilization of multi-joint upright posture. The purpose of this study was to compare the dynamic performance of the two control strategies. In particular, we considered a double-inverted-pendulum-model of postural control, and analyzed the two UCMs defined above. We first showed that the geometric configurations of the two UCMs are almost identical. We then investigated whether the UCM-component of experimental sway could be considered as passive dynamics with no active control, and showed that such UCM-component mainly consists of high frequency oscillations above 1 Hz, corresponding to anti-phase coordination between the ankle and

  12. RItA: The Italian severe/uncontrolled asthma registry.

    Science.gov (United States)

    Maio, S; Baldacci, S; Bresciani, M; Simoni, M; Latorre, M; Murgia, N; Spinozzi, F; Braschi, M; Antonicelli, L; Brunetto, B; Iacovacci, P; Roazzi, P; Pini, C; Pata, M; La Grasta, L; Paggiaro, P; Viegi, G

    2018-03-01

    The Italian severe/uncontrolled asthma (SUA) web-based registry encompasses demographic, clinical, functional, and inflammatory data; it aims to raise SUA awareness, identifying specific phenotypes and promoting optimal care. Four hundred and ninety three adult patients from 27 Italian centers (recruited in 2011-2014) were analyzed. Mean age was 53.8 years. SUA patients were more frequently female (60.6%), with allergic asthma (83.1%). About 30% showed late onset of asthma diagnosis/symptoms (>40 years); the mean age for asthma symptoms onset was 30.2 years and for asthma diagnosis 34.4 years. 97.1% used ICS (dose 2000 BDP), 93.6% LABA in association with ICS, 53.3% LTRAs, 64.1% anti-IgE, 10.7% theophylline, and 16.0% oral corticosteroids. Mean FEV 1 % pred of 75.1%, median values of 300/mm 3 of blood eosinophil count, 323 kU/L of serum total IgE, and 24 ppb of FENO were shown. Most common comorbidities were allergic rhinitis (62.4%), gastroesophageal reflux (42.1%), sinusitis (37.9%), nasal polyposis (30.2%), and allergic conjunctivitis (30.2%). 55.7% of SUA patients had exacerbations in the last 12 months, 9.7% emergency department visits, and 7.3% hospitalizations. Factors associated with exacerbation risk were obesity (OR, 95% CI 2.46, 1.11-5.41), psychic disorders (2.87, 0.89-9.30-borderline), nasal polyps (1.86, 0.88-3.89-borderline), partial/poor asthma treatment adherence (2.54, 0.97-6.67-borderline), and anti-IgE use in a protective way (0.26, 0.12-0.53). Comparisons to severe asthma multicenter studies and available registries showed data consistency across European and American populations. An international effort in the implementation of SUA patients' registries could help to better understand the clinical features and to manage severe asthma, representing a non-negligible socioeconomic burden for health services. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

  13. Uncontrolled hypertension is associated with coronary artery calcification and electrocardiographic left ventricular hypertrophy

    DEFF Research Database (Denmark)

    Nielsen, Mette Lundgren; Pareek, Manan; Gerke, O

    2015-01-01

    We conducted a 1:2 matched case-control study in order to evaluate whether the prevalence of coronary artery calcium (CAC) and electrocardiographic left ventricular hypertrophy (LVH) or strain was higher in patients with uncontrolled hypertension than in subjects from the general population......, and evaluate the association between CAC and LVH in patients with uncontrolled hypertension. Cases were patients with uncontrolled hypertension, whereas the controls were random individuals from the general population without cardiovascular disease. CAC score was assessed using a non-contrast computed...

  14. 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...

  15. Analysis of means of improving the uncontrolled lateral motions of personal airplanes

    Science.gov (United States)

    Mckinney, Marion O , Jr

    1951-01-01

    A theoretical analysis has been made of means of improving the uncontrolled motions of personal airplanes. The purpose of this investigation was to determine whether such airplanes could be made to fly uncontrolled for an indefinite period of time without getting into dangerous attitudes and for a reasonable period of time (1 to 3 min) without deviating excessively from their original course. The results of this analysis indicated that the uncontrolled motions of a personal airplane could be made safe as regards spiral tendencies and could be greatly improved as regards maintenance of course without resort to an autopilot. The only way to make the uncontrolled motions completely satisfactory as regards continuous maintenance of course, however, is to use a conventional type of autopilot.

  16. Sudden death in young persons with uncontrolled asthma--a nationwide cohort study in Denmark

    DEFF Research Database (Denmark)

    Gullach, Anders Juul; Risgaard, Bjarke; Lynge, Thomas Hadberg

    2015-01-01

    BACKGROUND: Asthma is a common chronic disease among young adults, and several studies have reported increased mortality rates in patients with asthma. However, no study has described sudden unexpected death in a nationwide setting in patients with uncontrolled asthma. We defined uncontrolled...... in preventing sudden unexpected deaths. We therefore aimed to describe clinical characteristics, symptoms, causes of death, and contact with the healthcare system prior to sudden unexpected death in young persons with uncontrolled asthma. METHODS: Through the review of death certificates, we found 625 sudden...... individuals who suffered from uncontrolled asthma. This corresponds to an incidence rate of 0.32 per 100,000 person-years. The cause of death in 31 cases (63%) was sudden cardiac death, and in 13 cases (27%), it was a fatal asthma attack. Symptoms (chest pain, dyspnea, seizures, general malaise, syncope...

  17. The retinamide VNLG-152 inhibits f-AR/AR-V7 and MNK-eIF4E signaling pathways to suppress EMT and castration-resistant prostate cancer xenograft growth.

    Science.gov (United States)

    Ramamurthy, Vidya P; Ramalingam, Senthilmurugan; Gediya, Lalji K; Njar, Vincent C O

    2018-03-01

    VNLG-152 is a novel retinamide (NR) shown to suppress growth and progression of genetically diverse prostate cancer cells via inhibition of androgen receptor signaling and eukaryotic initiation factor 4E (eIF4E) translational machinery. Herein, we report therapeutic effects of VNLG-152 on castration-resistant prostate cancer (CRPC) growth and metastatic phenotype in a CRPC tumor xenograft model. Administration of VNLG-152 significantly and dose-dependently suppressed the growth of aggressive CWR22Rv1 tumors by 63.4% and 76.3% at 10 and 20 mg·kg -1 bw, respectively (P AR)/androgen receptor splice variant-7 (AR-V7), mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1/2), phosphorylated eIF4E and their associated target proteins, including prostate-specific antigen, cyclin D1 and Bcl-2, were strongly decreased in VNLG-152-treated tumors signifying inhibition of f-AR/AR-V7 and MNK-eIF4E signaling in VNLG-152-treated CWR22Rv1 tumors as observed in vitro. VNLG-152 also suppressed the epithelial to mesenchymal transition in CWR22Rv1 tumors as evidenced by repression of N-cadherin, β-catenin, claudin, Slug, Snail, Twist, vimentin and matrix metalloproteinases (MMP-2 and MMP-9) with upsurge in E-cadherin. These results highlight the promising use of VNLG-152 in CRPC therapy and justify its further development towards clinical trials. © 2018 Federation of European Biochemical Societies.

  18. Direct costs of asthma in Brazil: a comparison between controlled and uncontrolled asthmatic patients

    Directory of Open Access Journals (Sweden)

    L.A. Santos

    2007-07-01

    Full Text Available Asthma is a common chronic illness that imposes a heavy burden on all aspects of the patient's life, including personal and health care cost expenditures. To analyze the direct cost associated to uncontrolled asthma patients, a cross-sectional study was conducted to determine costs related to patients with uncontrolled and controlled asthma. Uncontrolled patient was defined by daytime symptoms more than twice a week or nocturnal symptoms during two consecutive nights or any limitations of activities, or need for relief rescue medication more than twice a week, and an ACQ score less than 2 points. A questionnaire about direct cost stratification in health services, including emergency room visits, hospitalization, ambulatory visits, and asthma medications prescribed, was applied. Ninety asthma patients were enrolled (45 uncontrolled/45 controlled. Uncontrolled asthmatics accounted for higher health care expenditures than controlled patients, US$125.45 and US$15.58, respectively [emergency room visits (US$39.15 vs US$2.70 and hospitalization (US$86.30 vs US$12.88], per patient over 6 months. The costs with medications in the last month for patients with mild, moderate and severe asthma were US$1.60, 9.60, and 25.00 in the uncontrolled patients, respectively, and US$6.50, 19.00 and 49.00 in the controlled patients. In view of the small proportion of uncontrolled subjects receiving regular maintenance medication (22.2% and their lack of resources, providing free medication for uncontrolled patients might be a cost-effective strategy for the public health system.

  19. 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.

  20. Characterization of a novel androgen receptor (AR) coregulator RIPK1 and related chemicals that suppress AR-mediated prostate cancer growth via peptide and chemical screening.

    Science.gov (United States)

    Hsu, Cheng-Lung; Liu, Jai-Shin; Lin, Ting-Wei; Chang, Ying-Hsu; Kuo, Yung-Chia; Lin, An-Chi; Ting, Huei-Ju; Pang, See-Tong; Lee, Li-Yu; Ma, Wen-Lung; Lin, Chun-Cheng; Wu, Wen-Guey

    2017-09-19

    Using bicalutamide-androgen receptor (AR) DNA binding domain-ligand binding domain as bait, we observed enrichment of FxxFY motif-containing peptides. Protein database searches revealed the presence of receptor-interacting protein kinase 1 (RIPK1) harboring one FxxFY motif. RIPK1 interacted directly with AR and suppressed AR transactivation in a dose-dependent manner. Domain mapping experiments showed that the FxxFY motif in RIPK1 is critical for interactions with AR and the death domain of RIPK1 plays a crucial role in its inhibitory effect on transactivation. In terms of tissue expression, RIPK1 levels were markedly higher in benign prostate hyperplasia and non-cancerous tissue regions relative to the tumor area. With the aid of computer modeling for screening of chemicals targeting activation function 2 (AF-2) of AR, we identified oxadiazole derivatives as good candidates and subsequently generated a small library of these compounds. A number of candidates could effectively suppress AR transactivation and AR-related functions in vitro and in vivo with tolerable toxicity via inhibiting AR-peptide, AR-coregulator and AR N-C interactions. Combination of these chemicals with antiandrogen had an additive suppressive effect on AR transcriptional activity. Our collective findings may pave the way in creating new strategies for the development and design of anti-AR drugs.

  1. Identification of a new androgen receptor (AR) co-regulator BUD31 and related peptides to suppress wild-type and mutated AR-mediated prostate cancer growth via peptide screening and X-ray structure analysis.

    Science.gov (United States)

    Hsu, Cheng-Lung; Liu, Jai-Shin; Wu, Po-Long; Guan, Hong-Hsiang; Chen, Yuh-Ling; Lin, An-Chi; Ting, Huei-Ju; Pang, See-Tong; Yeh, Shauh-Der; Ma, Wen-Lung; Chen, Chung-Jung; Wu, Wen-Guey; Chang, Chawnshang

    2014-12-01

    Treatment with individual anti-androgens is associated with the development of hot-spot mutations in the androgen receptor (AR). Here, we found that anti-androgens-mt-ARs have similar binary structure to the 5α-dihydrotestosterone-wt-AR. Phage display revealed that these ARs bound to similar peptides, including BUD31, containing an Fxx(F/H/L/W/Y)Y motif cluster with Tyr in the +5 position. Structural analyses of the AR-LBD-BUD31 complex revealed formation of an extra hydrogen bond between the Tyr+5 residue of the peptide and the AR. Functional studies showed that BUD31-related peptides suppressed AR transactivation, interrupted AR N-C interaction, and suppressed AR-mediated cell growth. Combination of peptide screening and X-ray structure analysis may serve as a new strategy for developing anti-ARs that simultaneously suppress both wt and mutated AR function. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  2. Time-resolved x-ray diffraction measurements of high-density InAs quantum dots on Sb/GaAs layers and the suppression of coalescence by Sb-irradiated growth interruption

    International Nuclear Information System (INIS)

    Kakuda, Naoki; Yamaguchi, Koichi; Kaizu, Toshiyuki; Takahasi, Masamitu; Fujikawa, Seiji

    2010-01-01

    Self-assembly of high-density InAs quantum dots (QDs) on Sb-irradiated GaAs buffer layers was observed in-situ by a time-resolved X-ray diffraction (XRD) technique using a combination of XRD and molecular beam epitaxy. Evolution of dot height and lattice constant was analyzed during InAs QD growth and subsequent growth interruption (GI), and as a result, dislocated giant dots due to coalescence and coherent dots were separately evaluated. An Sb-irradiated GI (Sb-GI) method to be applied after InAs growth was attempted for the suppression of coalescence. Using this method, the XRD intensity of giant dots decreased, and the photoluminescence intensity of InAs QDs was enhanced. High-density InAs QDs without giant dots were produced by using the combination of the QD growth on the Sb-irradiated GaAs buffer layers and the Sb-GI. (author)

  3. Poppers: more evidence of suppressed immunity.

    Science.gov (United States)

    James, J S

    1999-08-20

    Evidence from studies in mice shows that exposure to isobutyl nitrite suppresses the immune system. This immune suppression allows for bacterial growth in the lungs and livers of infected mice and can inhibit the ability of mediastinal lymph nodes to respond to antigen-specific stimulation. The mechanism for immune suppression may be a reduction in CD4+ and CD8+ T cell populations in the mediastinal lymph nodes following pulmonary infection with Listeria monocytogenes.

  4. IAA-producing Penicillium sp. NICS01 triggers plant growth and suppresses Fusarium sp.-induced oxidative stress in sesame (Sesamum indicum L.).

    Science.gov (United States)

    Radhakrishnan, Ramalingam; Shim, Kang-Bo; Lee, Byeong-Won; Hwang, Chung-Dong; Pae, Suk-Bok; Park, Chang-Hwan; Kim, Sung-Up; Lee, Choon-Ki; Baek, In-Youl

    2013-06-28

    Application of rhizospheric fungi is an effective and environmentally friendly method of improving plant growth and controlling many plant diseases. The current study was aimed to identify phytohormone-producing fungi from soil, to understand their roles in sesame plant growth, and to control Fusarium disease. Three predominant fungi (PNF1, PNF2, and PNF3) isolated from the rhizospheric soil of peanut plants were screened for their growth-promoting efficiency on sesame seedlings. Among these isolates, PNF2 significantly increased the shoot length and fresh weight of seedlings compared with controls. Analysis of the fungal culture filtrate showed a higher concentration of indole acetic acid in PNF2 than in the other isolates. PNF2 was identified as Penicillium sp. on the basis of phylogenetic analysis of ITS sequence similarity. The in vitro biocontrol activity of Penicillium sp. against Fusarium sp. was exhibited by a 49% inhibition of mycelial growth in a dual culture bioassay and by hyphal injuries as observed by scanning electron microscopy. In addition, greenhouse experiments revealed that Fusarium inhibited growth in sesame plants by damaging lipid membranes and reducing protein content. Co-cultivation with Penicillium sp. mitigated Fusarium-induced oxidative stress in sesame plants by limiting membrane lipid peroxidation, and by increasing the protein concentration, levels of antioxidants such as total polyphenols, and peroxidase and polyphenoloxidase activities. Thus, our findings suggest that Penicillium sp. is a potent plant growthpromoting fungus that has the ability to ameliorate damage caused by Fusarium infection in sesame cultivation.

  5. PENAMBAHAN BAKTERI ASAM LAKTAT TERENKAPSULASI UNTUK MENEKAN PERTUMBUHAN BAKTERI PATOGEN PADA PROSES PRODUKSI TAPIOKA [Addition of Encapsulated Lactic Acid Bacteria to Suppress the Growth of Pathogenic Bacteria during Tapioca Production

    Directory of Open Access Journals (Sweden)

    Glisina Dwinoor Rembulan

    2015-07-01

    Full Text Available Lactic acid bacteria (LAB produce organic acids and active compounds which can inhibit the growth of pathogenic bacteria. Lactic acid bacteria potentially can be introduced to inhibit pathogenic bacteria in the tapioca production at the extraction stage, especially during the settling process since there is possibility of starch slurry to be contaminated by pathogenic bacteria from water. The objectives of this research were to design a solid starter of LAB through encapsulation by using modified starch includes sour cassava starch, lintnerized cassava starch and nanocrystalline starch, utilize the starter for suppressing the growth of pathogenic bacteria in the production process of tapioca and characterize the functional properties of tapioca. The encapsulation of lactic acid bacteria was conducted by freeze drying at a temperature of -50°C for 48 hours. The viability of LAB after freeze drying with sour cassava starch matrix was 92% of the liquid starter, with lintnerized cassava starch matrix was 93%, while that with nanocrystalline matrix was 96%. After application of the LAB culture during settling process for tapioca extraction and the tapioca was stored at room temperature for 6 months, it was shown that E. coli, Salmonella and Shigella were  detected in the native tapioca starch (without treatment while the starch added with lactic acid bacteria starter was not absent for the pathogenic bacteria. The addition of lactic acid bacteria in extraction process can suppress the growth of pathogenic bacteria in tapioca. The results showed that lintnerized cassava starch matrix is the best matrix because after 6 months it still contained lactic acid bacteria as compared to liquid starter and that encapsulated with other matrixes.

  6. Concerted suppression of STAT3 and GSK3β is involved in growth inhibition of non-small cell lung cancer by Xanthatin.

    Directory of Open Access Journals (Sweden)

    Li Tao

    Full Text Available Xanthatin, a sesquiterpene lactone purified from Xanthium strumarium L., possesses prominent anticancer activity. We found that disruption of GSK3β activity was essential for xanthatin to exert its anticancer properties in non-small cell lung cancer (NSCLC, concurrent with preferable suppression of constitutive activation of STAT3. Interestingly, inactivation of the two signals are two mutually exclusive events in xanthatin-induced cell death. Moreover, we surprisingly found that exposure of xanthatin failed to trigger the presumable side effect of canonical Wnt/β-Catenin followed by GSK3β inactivation. We further observed that the downregulation of STAT3 was required for xanthatin to fine-tune the risk. Thus, the discovery of xanthatin, which has ability to simultaneously orchestrate two independent signaling cascades, may have important implications for screening promising drugs in cancer therapies.

  7. Concerted suppression of STAT3 and GSK3β is involved in growth inhibition of non-small cell lung cancer by Xanthatin.

    Science.gov (United States)

    Tao, Li; Fan, Fangtian; Liu, Yuping; Li, Weidong; Zhang, Lei; Ruan, Junshan; Shen, Cunsi; Sheng, Xiaobo; Zhu, Zhijie; Wang, Aiyun; Chen, Wenxing; Huang, Shile; Lu, Yin

    2013-01-01

    Xanthatin, a sesquiterpene lactone purified from Xanthium strumarium L., possesses prominent anticancer activity. We found that disruption of GSK3β activity was essential for xanthatin to exert its anticancer properties in non-small cell lung cancer (NSCLC), concurrent with preferable suppression of constitutive activation of STAT3. Interestingly, inactivation of the two signals are two mutually exclusive events in xanthatin-induced cell death. Moreover, we surprisingly found that exposure of xanthatin failed to trigger the presumable side effect of canonical Wnt/β-Catenin followed by GSK3β inactivation. We further observed that the downregulation of STAT3 was required for xanthatin to fine-tune the risk. Thus, the discovery of xanthatin, which has ability to simultaneously orchestrate two independent signaling cascades, may have important implications for screening promising drugs in cancer therapies.

  8. Concerted Suppression of STAT3 and GSK3β Is Involved in Growth Inhibition of Non-Small Cell Lung Cancer by Xanthatin

    Science.gov (United States)

    Tao, Li; Fan, Fangtian; Liu, Yuping; Li, Weidong; Zhang, Lei; Ruan, Junshan; Shen, Cunsi; Sheng, Xiaobo; Zhu, Zhijie; Wang, Aiyun; Chen, Wenxing; Huang, Shile; Lu, Yin

    2013-01-01

    Xanthatin, a sesquiterpene lactone purified from Xanthium strumarium L., possesses prominent anticancer activity. We found that disruption of GSK3β activity was essential for xanthatin to exert its anticancer properties in non-small cell lung cancer (NSCLC), concurrent with preferable suppression of constitutive activation of STAT3. Interestingly, inactivation of the two signals are two mutually exclusive events in xanthatin-induced cell death. Moreover, we surprisingly found that exposure of xanthatin failed to trigger the presumable side effect of canonical Wnt/β-Catenin followed by GSK3β inactivation. We further observed that the downregulation of STAT3 was required for xanthatin to fine-tune the risk. Thus, the discovery of xanthatin, which has ability to simultaneously orchestrate two independent signaling cascades, may have important implications for screening promising drugs in cancer therapies. PMID:24312384

  9. Determinants of Uncontrolled Hypertension in Rural Communities in South Asia - Bangladesh, Pakistan, and Sri Lanka.

    Science.gov (United States)

    Jafar, Tazeen H; Gandhi, Mihir; Jehan, Imtiaz; Naheed, Aliya; de Silva, H Asita; Shahab, Hunaina; Alam, Dewan; Luke, Nathasha; Lim, Ching Wee

    2018-04-26

    Uncontrolled blood pressure (BP) is a leading risk factor for death and disability in South Asia. We aimed to determine the cross-country variation, and the factors associated with uncontrolled BP among adults treated for hypertension in rural South Asia. We enrolled 1718 individuals aged ≥40 years treated for hypertension in a cross-sectional study from rural communities in Bangladesh, Pakistan, and Sri Lanka. Multivariable logistic regression model was used to determine the factors associated with uncontrolled BP (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg). Among hypertensive individuals, 58.0% (95% confidence interval 55.7, 60.4) had uncontrolled BP: 52.8% (49.0, 56.6) in Bangladesh, 70.6% (65.7, 75.1) in Pakistan, and 56.5% (52.7, 60.1) in Sri Lanka. The odds (odds ratio (95% confidence interval)) of uncontrolled BP were significantly higher in individuals with lower wealth index (1.17 (1.02, 1.35)); single vs married (1.46 (1.10, 1.93)); higher log urine albumin-to-creatinine ratio (1.41 (1.24, 1.60)); lower estimated glomerular filtration rate (1.23 (1.01, 1.49)); low vs high adherence to antihypertensive medication (1.50 (1.16, 1.94)); and Pakistan (2.91 (1.60, 5.28)) vs Sri Lanka. However, the odds were lower in those with vs without self-reported kidney disease (0.51 (0.28, 0.91)); and receiving vs not receiving statins (0.62 (0.44, 0.87)). The majority of individuals with treated hypertension have uncontrolled BP in rural Bangladesh, Pakistan, and Sri Lanka with significant disparities among and within countries. Urgent public health efforts are needed to improve access and adherence to antihypertensive medications in disadvantaged populations in rural South Asia.

  10. Suppression of the ATP-binding cassette transporter ABCC4 impairs neuroblastoma tumour growth and sensitises to irinotecan in vivo.

    Science.gov (United States)

    Murray, Jayne; Valli, Emanuele; Yu, Denise M T; Truong, Alan M; Gifford, Andrew J; Eden, Georgina L; Gamble, Laura D; Hanssen, Kimberley M; Flemming, Claudia L; Tan, Alvin; Tivnan, Amanda; Allan, Sophie; Saletta, Federica; Cheung, Leanna; Ruhle, Michelle; Schuetz, John D; Henderson, Michelle J; Byrne, Jennifer A; Norris, Murray D; Haber, Michelle; Fletcher, Jamie I

    2017-09-01

    The ATP-binding cassette transporter ABCC4 (multidrug resistance protein 4, MRP4) mRNA level is a strong predictor of poor clinical outcome in neuroblastoma which may relate to its export of endogenous signalling molecules and chemotherapeutic agents. We sought to determine whether ABCC4 contributes to development, growth and drug response in neuroblastoma in vivo. In neuroblastoma patients, high ABCC4 protein levels were associated with reduced overall survival. Inducible knockdown of ABCC4 strongly inhibited the growth of human neuroblastoma cells in vitro and impaired the growth of neuroblastoma xenografts. Loss of Abcc4 in the Th-MYCN transgenic neuroblastoma mouse model did not impact tumour formation; however, Abcc4-null neuroblastomas were strongly sensitised to the ABCC4 substrate drug irinotecan. Our findings demonstrate a role for ABCC4 in neuroblastoma cell proliferation and chemoresistance and provide rationale for a strategy where inhibition of ABCC4 should both attenuate the growth of neuroblastoma and sensitise tumours to ABCC4 chemotherapeutic substrates. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. MicroRNA-134 regulates lung cancer cell H69 growth and apoptosis by targeting WWOX gene and suppressing the ERK1/2 signaling pathway

    International Nuclear Information System (INIS)

    Chen, Tianjun; Gao, Fei; Feng, Sifang; Yang, Tian; Chen, Mingwei

    2015-01-01

    MicroRNAs have been shown to act as crucial modulators during carcinogenesis. Recent studies have implied that miR-134 expression associated with epithelial-to-mesenchymal transition phenotype and invasive potential of NSCLC cells. Our study investigated the pathogenic implications of miR-134 in small cell lung cancer (SCLC). Overexpression or inhibition MiR-134 expression by miR-134 mimics or miR-134 inhibitors (anti-miR-134) in SCLC cell lines was detected using qRT-PCR. Lactate dehydrogenase (LDH) assay, MTT assays and flow cytometry were performed in order to clarify the growth and apoptosis of SCLC cells which had been transfected with miR-134 mimics or anti-miR-134. WWOX expression in H69 cells was detected by qRT-PCR and western blot, respectively. The results showed that overexpression miR-134 was significantly promoting SCLC cells growth and inhibit its apoptosis. In addition, reduced miR-134 expression was significantly correlated with cell growth inhibition and apoptosis promotion. Furthermore, transfection of miR-134 mimics into the SCLC cells markedly down-regulated the level of WWOX, whereas, anti-miR-134 up-regulated WWOX expression. We also found that overexpression WWOX attenuate miR-134 induced H69 cells growth, and promote cell apoptosis. Moreover, miR-134 promoted cell proliferation and inhibit apoptosis via the activation of ERK1/2 pathway. These findings suggest that miR-134 may be an ideal diagnostic and prognostic marker, and may be attributed to the molecular therapy of SCLC. - Highlights: • MiR-134 play roles in small cell lung cancer cell growth and apoptosis. • MiR-134 negative regulated the level of WWOX in H69 cells. • WWOX overexpression attenuate miR-134 induced H69 cells growth. • MiR-134 promotes cell growth via the activation of ERK1/2 pathway

  12. Racial/ethnic disparity in the associations of smoking status with uncontrolled hypertension subtypes among hypertensive subjects.

    Science.gov (United States)

    Liu, Xuefeng; Zhu, Tinghui; Manojlovich, Milisa; Cohen, Hillel W; Tsilimingras, Dennis

    2017-01-01

    Racial/ethnic differences in the associations of smoking with uncontrolled blood pressure (BP) and its subtypes (isolated uncontrolled systolic BP (SBP), uncontrolled systolic-diastolic BP, and isolated uncontrolled diastolic BP (DBP)) have not been investigated among diagnosed hypertensive subjects. A sample of 7,586 hypertensive patients aged ≥18 years were selected from the National Health and Nutrition Examination Survey 1999-2010. Race/ethnicity was classified into Hispanic, non-Hispanic white, and non-Hispanic black. Smoking was categorized as never smoking, ex-smoking, and current smoking. Uncontrolled BP was determined as SBP≥140 or DBP≥90 mm Hg. Isolated uncontrolled SBP was defined as SBP≥140 and DBPsmokers, current smokers were 29% less likely to have uncontrolled BP in non-Hispanic whites (OR = 0.71, 95% CI = 0.56-0.90), although the likelihood for uncontrolled BP is the same for smokers and never smokers in Hispanics and non-Hispanic blacks. Current smokers were 26% less likely than never smokers to have isolated uncontrolled SBP in non-Hispanic whites (OR = 0.74, 95% CI = 0.58-0.95). However, current smoking is associated with an increased likelihood of uncontrolled systolic-diastolic BP in non-Hispanic blacks, and current smokers in this group were 70% more likely to have uncontrolled systolic-diastolic BP than never smokers (OR = 1.70, 95% CI = 1.10-2.65). The associations between current smoking and uncontrolled BP differed over race/ethnicity. Health practitioners may need to be especially vigilant with non-Hispanic black smokers with diagnosed hypertension.

  13. Inhibition of Epidermal Growth Factor Receptor and PI3K/Akt Signaling Suppresses Cell Proliferation and Survival through Regulation of Stat3 Activation in Human Cutaneous Squamous Cell Carcinoma

    International Nuclear Information System (INIS)

    Bito, T.; Sumita, N.; Ashida, M.; Budiyanto, A.; Ueda, M.; Ichihashi, M.; Nishigori, C.; Tokura, Y.; Bito, T.

    2011-01-01

    Recent studies have emphasized the important role of Stat3 activation in a number of human tumors from the viewpoint of its oncogenic and anti apoptotic activity. In this study, we examined the role and related signaling molecules of Stat3 in the carcinogenesis of human cutaneous squamous cell carcinoma (SCC). In 35 human cutaneous SCC samples, 86% showed overexpression of phosphorylated (p)-Stat3, and most of those simultaneously over expressed p-EGFR or p-Akt. Constitutive activation of EGFR and Stat3 was observed in three SCC cell lines and four of five SCC tissues. AG1478, an inhibitor of the EGFR, down regulated Stat3 activation in HSC-1 human SCC cells. AG1478 inhibited cell proliferation and induced apoptosis of HSC-1 cells but did not inhibit the growth of normal human epidermal keratinocytes that did not show Stat3 activation. Furthermore, a PI3K inhibitor also suppressed Stat3 activation in HSC-1 cells to some degree. Combined treatment with the PI3K inhibitor and AG1478 strongly suppressed Stat3 activity and dramatically induced apoptosis of HSC-1 cells. These data suggest that Stat3 activation through EGFR and/or PI3K/Akt activation plays a critical role in the proliferation and survival of human cutaneous SCC.

  14. Peptides Derived from Type IV Collagen, CXC Chemokines, and Thrombospondin-1 Domain-Containing Proteins Inhibit Neovascularization and Suppress Tumor Growth in MDA-MB-231 Breast Cancer Xenografts

    Directory of Open Access Journals (Sweden)

    Jacob E. Koskimaki

    2009-12-01

    Full Text Available Angiogenesis or neovascularization, the process of new blood vessel formation from preexisting microvasculature, involves interactions among several cell types including parenchymal, endothelial cells, and immune cells. The formation of new vessels is tightly regulated by a balance between endogenous proangiogenic and antiangiogenic factors to maintain homeostasis in tissue; tumor progression and metastasis in breast cancer have been shown to be angiogenesis-dependent. We previously introduced a systematic methodology to identify putative endogenous antiangiogenic peptides and validated these predictions in vitro in human umbilical vein endothelial cell proliferation and migration assays. These peptides are derived from several protein families including type IV collagen, CXC chemokines, and thrombospondin-1 domain-containing proteins. On the basis of the results from the in vitro screening, we have evaluated the ability of one peptide selected from each family named pentastatin-1, chemokinostatin-1, and properdistatin, respectively, to suppress angiogenesis in an MDA-MB-231 human breast cancer orthotopic xenograft model in severe combined immunodeficient mice. Peptides were administered intraperitoneally once per day. We have demonstrated significant suppression of tumor growth in vivo and subsequent reductions in microvascular density, indicating the potential of these peptides as therapeutic agents for breast cancer.

  15. Modeling urban growth in Kigali city Rwanda

    NARCIS (Netherlands)

    Nduwayezu, G.; Sliuzas, R.V.; Kuffer, M.

    2017-01-01

    The uncontrolled urban growth is the key characteristics in most cities in less developed countries. However, having a good understanding of the key drivers of the city's growth dynamism has proven to be a key instrument to manage urban growth. This paper investigates the main determinants of Kigali

  16. Fibroblast growth factor and canonical WNT/beta-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage

    Czech Academy of Sciences Publication Activity Database

    Buchtová, Marcela; Oralová, Veronika; Aklian, A.; Mašek, J.; Veselá, I.; Ouyang, Z.; Obadalová, T.; Konečná, Ž.; Spoustová, T.; Pospíšilová, T.; Matula, P.; Vařecha, M.; Balek, L.; Gudernová, I.; Jelínková, I.; Ďuran, I.; Červenková, I.; Murakami, S.; Kozubík, Alois; Dvořák, P.; Bryja, Vítězslav; Krejčí, P.

    2015-01-01

    Roč. 1852, č. 5 (2015), s. 839-850 ISSN 0925-4439 R&D Projects: GA ČR GCP302/12/J059; GA ČR GBP302/12/G157; GA ČR(CZ) GA14-31540S Institutional support: RVO:67985904 ; RVO:68081707 Keywords : fibroblast growth factor receptor * FGFR3 * WNT Subject RIV: EA - Cell Biology Impact factor: 5.158, year: 2015

  17. Growth and sporulation defects in Bacillus subtilis mutants with a single rrn operon can be suppressed by amplification of the rrn operon.

    Science.gov (United States)

    Yano, Koichi; Masuda, Kenta; Akanuma, Genki; Wada, Tetsuya; Matsumoto, Takashi; Shiwa, Yuh; Ishige, Taichiro; Yoshikawa, Hirofumi; Niki, Hironori; Inaoka, Takashi; Kawamura, Fujio

    2016-01-01

    The genome of Bacillus subtilis strain 168 encodes ten rRNA (rrn) operons. We previously reported that strains with only a single rrn operon had a decreased growth and sporulation frequency. We report here the isolation and characterization of suppressor mutants from seven strains that each have a single rrn operon (rrnO, A, J, I, E, D or B). The suppressor mutants for strain RIK656 with a single rrnO operon had a higher frequency of larger colonies. These suppressor mutants had not only increased growth rates, but also increased sporulation frequencies and ribosome levels compared to the parental mutant strain RIK656. Quantitative PCR analyses showed that all these suppressor mutants had an increased number of copies of the rrnO operon. Suppressor mutants were also isolated from the six other strains with single rrn operons (rrnA, J, I, E, D or B). Next generation and capillary sequencing showed that all of the suppressor mutants had tandem repeats of the chromosomal locus containing the remaining rrn operon (amplicon). These amplicons varied in size from approximately 9 to 179 kb. The amplifications were likely to be initiated by illegitimate recombination between non- or micro-homologous sequences, followed by unequal crossing-over during DNA replication. These results are consistent with our previous report that rrn operon copy number has a major role in cellular processes such as cell growth and sporulation.

  18. Dominant negative insulin-like growth factor-1 receptor inhibits neointimal formation through suppression of vascular smooth muscle cell migration and proliferation, and induction of apoptosis

    International Nuclear Information System (INIS)

    Lim, Hyun-Joung; Park, Hyun-Young; Ko, Young-Guk; Lee, Sea-Hyoung; Cho, Seung-Yeon; Lee, Eun Jig; Jameson, J. Larry; Jang, Yangsoo

    2004-01-01

    Blocking of the IGF-1 signaling pathway targeting the IGF-1 receptor (IGF-1R) provides a potential treatment strategy for restenosis. In this study, we have examined the effects of a dominant negative IGF-1R (IGF-1Rt) on primary rat VSMCs in vitro and on injured rat carotid artery in vivo. Ad/IGF-1Rt infection inhibited VSMC migration and proliferation, and it also induced apoptosis by inhibiting phosphorylation of Akt and phosphorylation of ERK1/2. Consistent with the anti-proliferative and apoptotic effects in vitro, the Ad/IGF-1Rt infection markedly reduced neointimal formation in carotid injury model. Ad/IGF-1Rt treated carotid arteries exhibited a suppressed proliferation index, PCNA expression, and also were stained positive for TUNEL assay. These results indicate that a dominant negative IGF-1R has the potential to reduce neointimal formation of injured rats' carotid arteries. The delivery of dominant negative IGF-1R by adenoviral or other vectors may provide a useful strategy for inhibiting restenosis after angioplasty

  19. Factors associated with lack of awareness and uncontrolled high blood pressure among Canadian adults with hypertension.

    Science.gov (United States)

    Gee, Marianne E; Bienek, Asako; McAlister, Finlay A; Robitaille, Cynthia; Joffres, Michel; Tremblay, Mark S; Johansen, Helen; Campbell, Norm R C

    2012-05-01

    Approximately 17% of Canadians with high blood pressure were unaware of their condition, and of Canadians aware of having the condition, approximately 1 in 5 have uncontrolled high blood pressure despite high rates of pharmacotherapy. The objectives of the current study are to estimate the prevalence of resistant hypertension and examine factors associated with (1) lack of awareness and (2) uncontrolled hypertension despite pharmacotherapy. Using the 2007-2009 Canadian Health Measures Survey (N = 3473, aged 20-79 years) and logistic regression, we quantified relationships between characteristics and (1) presence of hypertension, (2) lack of awareness (among those with hypertension), and (3) uncontrolled high blood pressure (among those treated for hypertension). Older age, lowest income, and less than high school education were associated with presence of hypertension. Men (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.2) and adults high blood pressure (OR, 2.4; 95% CI, 1.1-5.2) despite treatment. Elevated systolic blood pressure was the issue in over 90% of women and 80% of men with uncontrolled hypertension. Depending on the definition employed, 4.4% (95% CI, 2.4-6.4) to 7.8% (95% CI, 6.0-9.6) of the population with hypertension had resistant hypertension. Messaging or interventions encouraging screening may be helpful for all younger Canadian adults and men; programs encouraging blood pressure control may help older women. Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  20. Uncontrolled hypertension in older patients: markers and associated factors to masked and white-coat effect

    Science.gov (United States)

    Lima, Nereida KC; Moriguti, Julio C; Ferriolli, Eduardo

    2016-01-01

    Background Hypertension is the main risk factor for cardiovascular diseases, affecting more than half the elderly population. It is essential to know if they have proper control of hypertension. The aim of this study was to identify the associated factors to masked uncontrolled hypertension and false uncontrolled hypertension in older patients. Methods Two-hundred seventy-three individuals (70.1 ± 6.7 years-old) had blood pressure (BP) measured at the office and by ambulatory BP monitoring (ABPM), with the definition of controlled group (C), individuals with high office BP and adequate ABPM, called white-coat effect group (WCE), uncontrolled (UC), and subjects with appropriate office BP and elevated ABPM denominated masked effect group (ME). Age, body mass index, diabetes, pulse pressure (PP) and BP dipping during sleep were evaluated (Kruskal-Wallis test and logistic regression models). Results Age was higher in UC than in C and ME (P ABPM PP was lower in C (48 ± 7 mmHg) and WCE (51 ± 6 mmHg) than in UC (67 ± 12 mmHg) and ME (59 ± 8 mmHg) (P ABPM favored the identification of a higher PP and a lower BP dipping during sleep in the masked effect and uncontrolled groups. PMID:27781057

  1. Effects of food on cortisol and mood in vulnerable subjects under controllable and uncontrollable stress

    NARCIS (Netherlands)

    Markus, R.; Panhuysen, G.; Tuiten, A.; Koppeschaar, H.

    2000-01-01

    The aim of this study was to investigate whether in stress-prone subjects, carbohydrate-rich, protein-poor food (CR/PP) diminished depressive mood and a cortisol response under controllable as well as uncontrollable laboratory stress. Twenty-two subjects with high stress proneness (HS) and 23

  2. Managing the uncontrollable: Empirical studies of user-generated content online

    NARCIS (Netherlands)

    Lee, H.H.

    2014-01-01

    Addressing "uncontrollability' of online buzz, this thesis examines unstructured user-generated content in response to corporate social responsibility communications in the blogosphere and explores the content of company-administered co-creation communities. Analyzing text-based content online, the

  3. Young-Age Gender Differences in Mathematics Mediated by Independent Control or Uncontrollability

    Science.gov (United States)

    Zirk-Sadowski, Jan; Lamptey, Charlotte; Devine, Amy; Haggard, Mark; Szucs, Dénes

    2014-01-01

    We studied whether the origins of math anxiety can be related to a biologically supported framework of stress induction: (un)controllability perception, here indicated by self-reported independent efforts in mathematics. Math anxiety was tested in 182 children (8- to 11-year-olds). "Latent factor modeling" was used to test hypotheses on…

  4. Environment mapping and localization with an uncontrolled swarm of ultrasound sensor motes

    NARCIS (Netherlands)

    Duisterwinkel, E.; Demi, L.; Dubbelman, G.; Talnishnikh, E.; Wörtche, H.J.; Bergmans, J.W.M.

    2014-01-01

    A method is presented in which a (large) swarm of sensor motes perform simple ultrasonic ranging measurements. The method allows to localize the motes within the swarm, and at the same time, map the environment which the swarm has traversed. The motes float passively uncontrolled through the

  5. Overexpression of the kiwifruit SVP3 gene affects reproductive development and suppresses anthocyanin biosynthesis in petals, but has no effect on vegetative growth, dormancy, or flowering time.

    Science.gov (United States)

    Wu, Rongmei; Wang, Tianchi; McGie, Tony; Voogd, Charlotte; Allan, Andrew C; Hellens, Roger P; Varkonyi-Gasic, Erika

    2014-09-01

    SVP-like MADS domain transcription factors have been shown to regulate flowering time and both inflorescence and flower development in annual plants, while having effects on growth cessation and terminal bud formation in perennial species. Previously, four SVP genes were described in woody perennial vine kiwifruit (Actinidia spp.), with possible distinct roles in bud dormancy and flowering. Kiwifruit SVP3 transcript was confined to vegetative tissues and acted as a repressor of flowering as it was able to rescue the Arabidopsis svp41 mutant. To characterize kiwifruit SVP3 further, ectopic expression in kiwifruit species was performed. Ectopic expression of SVP3 in A. deliciosa did not affect general plant growth or the duration of endodormancy. Ectopic expression of SVP3 in A. eriantha also resulted in plants with normal vegetative growth, bud break, and flowering time. However, significantly prolonged and abnormal flower, fruit, and seed development were observed, arising from SVP3 interactions with kiwifruit floral homeotic MADS-domain proteins. Petal pigmentation was reduced as a result of SVP3-mediated interference with transcription of the kiwifruit flower tissue-specific R2R3 MYB regulator, MYB110a, and the gene encoding the key anthocyanin biosynthetic step, F3GT1. Constitutive expression of SVP3 had a similar impact on reproductive development in transgenic tobacco. The flowering time was not affected in day-neutral and photoperiod-responsive Nicotiana tabacum cultivars, but anthesis and seed germination were significantly delayed. The accumulation of anthocyanin in petals was reduced and the same underlying mechanism of R2R3 MYB NtAN2 transcript reduction was demonstrated. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  6. Endophytic Bacteria Improve Plant Growth, Symbiotic Performance of Chickpea (Cicer arietinum L. and Induce Suppression of Root Rot Caused by Fusarium solani under Salt Stress

    Directory of Open Access Journals (Sweden)

    Dilfuza Egamberdieva

    2017-09-01

    Full Text Available Salinity causes disturbance in symbiotic performance of plants, and increases susceptibility of plants to soil-borne pathogens. Endophytic bacteria are an essential determinant of cross-tolerance to biotic and abiotic stresses in plants. The aim of this study was to isolate non–rhizobial endophytic bacteria from the root nodules of chickpea (Cicer arietinum L., and to assess their ability to improve plant growth and symbiotic performance, and to control root rot in chickpea under saline soil conditions. A total of 40 bacterial isolates from internal root tissues of chickpea grown in salinated soil were isolated. Four bacterial isolates, namely Bacillus cereus NUU1, Achromobacter xylosoxidans NUU2, Bacillus thuringiensis NUU3, and Bacillus subtilis NUU4 colonizing root tissue demonstrated plant beneficial traits and/or antagonistic activity against F. solani and thus were characterized in more detail. The strain B. subtilis NUU4 proved significant plant growth promotion capabilities, improved symbiotic performance of host plant with rhizobia, and promoted yield under saline soil as compared to untreated control plants under field conditions. A combined inoculation of chickpea with M. ciceri IC53 and B. subtilis NUU4 decreased H2O2 concentrations and increased proline contents compared to the un-inoculated plants indicating an alleviation of adverse effects of salt stress. Furthermore, the bacterial isolate was capable to reduce the infection rate of root rot in chickpea caused by F. solani. This is the first report of F. solani causing root rot of chickpea in a salinated soil of Uzbekistan. Our findings demonstrated that the endophytic B. subtilis strain NUU4 provides high potentials as a stimulator for plant growth and as biological control agent of chickpea root rot under saline soil conditions. These multiple relationships could provide promising practical approaches to increase the productivity of legumes under salt stress.

  7. Mutations reducing replication from R-loops suppress the defects of growth, chromosome segregation and DNA supercoiling in cells lacking topoisomerase I and RNase HI activity.

    Science.gov (United States)

    Usongo, Valentine; Martel, Makisha; Balleydier, Aurélien; Drolet, Marc

    2016-04-01

    R-loop formation occurs when the nascent RNA hybridizes with the template DNA strand behind the RNA polymerase. R-loops affect a wide range of cellular processes and their use as origins of replication was the first function attributed to them. In Escherichia coli, R-loop formation is promoted by the ATP-dependent negative supercoiling activity of gyrase (gyrA and gyrB) and is inhibited by topoisomerase (topo) I (topA) relaxing transcription-induced negative supercoiling. RNase HI (rnhA) degrades the RNA moiety of R-loops. The depletion of RNase HI activity in topA null mutants was previously shown to lead to extensive DNA relaxation, due to DNA gyrase inhibition, and to severe growth and chromosome segregation defects that were partially corrected by overproducing topo III (topB). Here, DNA gyrase assays in crude cell extracts showed that the ATP-dependent activity (supercoiling) of gyrase but not its ATP-independent activity (relaxation) was inhibited in topA null cells lacking RNase HI. To characterize the cellular event(s) triggered by the absence of RNase HI, we performed a genetic screen for suppressors of the growth defect of topA rnhA null cells. Suppressors affecting genes in replication (holC2::aph and dnaT18::aph) nucleotide metabolism (dcd49::aph), RNA degradation (rne59::aph) and fimbriae synthesis (fimD22::aph) were found to reduce replication from R-loops and to restore supercoiling, thus pointing to a correlation between R-loop-dependent replication in topA rnhA mutants and the inhibition of gyrase activity and growth. Interestingly, the position of fimD on the E. coli chromosome corresponds to the site of one of the five main putative origins of replication from R-loops in rnhA null cells recently identified by next-generation sequencing, thus suggesting that the fimD22::aph mutation inactivated one of these origins. Furthermore, we show that topo III overproduction is unable to complement the growth defect of topA rnhA null mutants at low

  8. Racial/ethnic disparity in the associations of smoking status with uncontrolled hypertension subtypes among hypertensive subjects.

    Directory of Open Access Journals (Sweden)

    Xuefeng Liu

    Full Text Available Racial/ethnic differences in the associations of smoking with uncontrolled blood pressure (BP and its subtypes (isolated uncontrolled systolic BP (SBP, uncontrolled systolic-diastolic BP, and isolated uncontrolled diastolic BP (DBP have not been investigated among diagnosed hypertensive subjects.A sample of 7,586 hypertensive patients aged ≥18 years were selected from the National Health and Nutrition Examination Survey 1999-2010. Race/ethnicity was classified into Hispanic, non-Hispanic white, and non-Hispanic black. Smoking was categorized as never smoking, ex-smoking, and current smoking. Uncontrolled BP was determined as SBP≥140 or DBP≥90 mm Hg. Isolated uncontrolled SBP was defined as SBP≥140 and DBP<90 mm Hg, uncontrolled SDBP as SBP≥140 and DBP≥90 mm Hg, and isolated uncontrolled DBP as SBP<140 and DBP≥90 mm Hg. Adjusted odds ratios (ORs with 95% confidence intervals (CIs of uncontrolled BP and its subtypes were calculated using weighted logistic regression models.The interaction effect of race and smoking was significant after adjustment for the full potential confounding covariates (Adjusted p = 0.0412. Compared to never smokers, current smokers were 29% less likely to have uncontrolled BP in non-Hispanic whites (OR = 0.71, 95% CI = 0.56-0.90, although the likelihood for uncontrolled BP is the same for smokers and never smokers in Hispanics and non-Hispanic blacks. Current smokers were 26% less likely than never smokers to have isolated uncontrolled SBP in non-Hispanic whites (OR = 0.74, 95% CI = 0.58-0.95. However, current smoking is associated with an increased likelihood of uncontrolled systolic-diastolic BP in non-Hispanic blacks, and current smokers in this group were 70% more likely to have uncontrolled systolic-diastolic BP than never smokers (OR = 1.70, 95% CI = 1.10-2.65.The associations between current smoking and uncontrolled BP differed over race/ethnicity. Health practitioners may need to be especially

  9. Anti-sense suppression of epidermal growth factor receptor expression alters cellular proliferation, cell-adhesion and tumorigenicity in ovarian cancer cells.

    Science.gov (United States)

    Alper, O; De Santis, M L; Stromberg, K; Hacker, N F; Cho-Chung, Y S; Salomon, D S

    2000-11-15

    Over-expression of epidermal growth factor receptor (EGFR) in ovarian cancer has been well documented. Human NIH:OVCAR-8 ovarian carcinoma cells were transfected with an expression vector containing the anti-sense orientation of truncated human EGFR cDNA. EGFR anti-sense over-expression resulted in decreased EGFR protein and mRNA expression, cell proliferation and tumor formation in nude mice. In accordance with the reduced levels of EGFR in EGFR anti-sense-expressing cells, tyrosine phosphorylation of EGFR was decreased compared to untransfected parental cells treated with EGF. In EGFR anti-sense-transfected cells, expression of erbB-3, but not erbB-2, was increased. In addition, basal and heregulin-beta 1-stimulated tyrosine phosphorylation of erbB-3 was higher in EGFR anti-sense vector-transfected cells. A morphological alteration in EGFR anti-sense gene-expressing cells was correlated with a decrease in the expression of E-cadherin, alpha-catenin and, to a lesser extent, beta-catenin. Changes in the expression of these proteins were associated with a reduction in complex formation among E-cadherin, beta-catenin and alpha-catenin and between beta-catenin and EGFR in EGFR anti-sense-expressing cells compared to sense-transfected control cells. These results demonstrate that EGFR expression in ovarian carcinoma cells regulates expression of cell adhesion proteins that may enhance cell growth and invasiveness. Copyright 2000 Wiley-Liss, Inc.

  10. BAG-1 enhances cell-cell adhesion, reduces proliferation and induces chaperone-independent suppression of hepatocyte growth factor-induced epidermal keratinocyte migration

    International Nuclear Information System (INIS)

    Hinitt, C.A.M.; Wood, J.; Lee, S.S.; Williams, A.C.; Howarth, J.L.; Glover, C.P.; Uney, J.B.; Hague, A.

    2010-01-01

    Cell motility is important in maintaining tissue homeostasis, facilitating epithelial wound repair and in tumour formation and progression. The aim of this study was to determine whether BAG-1 isoforms regulate epidermal cell migration in in vitro models of wound healing. In the human epidermal cell line HaCaT, endogenous BAG-1 is primarily nuclear and increases with confluence. Both transient and stable p36-Bag-1 overexpression resulted in increased cellular cohesion. Stable transfection of either of the three human BAG-1 isoforms p36-Bag-1 (BAG-1S), p46-Bag-1 (BAG-1M) and p50-Bag-1 (BAG-1L) inhibited growth and wound closure in serum-containing medium. However, in response to hepatocyte growth factor (HGF) in serum-free medium, BAG-1S/M reduced communal motility and colony scattering, but BAG-1L did not. In the presence of HGF, p36-Bag-1 transfectants retained proliferative response to HGF with no change in ERK1/2 activation. However, the cells retained E-cadherin localisation at cell-cell junctions and exhibited pronounced cortical actin. Point mutations in the BAG domain showed that BAG-1 inhibition of motility is independent of its function as a chaperone regulator. These findings are the first to suggest that BAG-1 plays a role in regulating cell-cell adhesion and suggest an important function in epidermal cohesion.

  11. Eating traits questionnaires as a continuum of a single concept. Uncontrolled eating.

    Science.gov (United States)

    Vainik, Uku; Neseliler, Selin; Konstabel, Kenn; Fellows, Lesley K; Dagher, Alain

    2015-07-01

    Research on eating behaviour has identified several potentially relevant eating-related traits captured by different questionnaires. Often, these questionnaires predict Body Mass Index (BMI), but the relationship between them has not been explicitly studied. We studied the unity and diversity of questionnaires capturing five common eating-related traits: Power of Food, Eating Impulsivity, emotional eating, Disinhibition, and binge eating in women from Estonia (n = 740) and Canada (n = 456). Using bifactor analysis, we showed that a) these questionnaires are largely explained by a single factor, and b) relative to this shared factor, only some questionnaires offered additional variance in predicting BMI. Hence, these questionnaires seemed to characterise a common factor, which we label Uncontrolled Eating. Item Response Theory techniques were then applied to demonstrate that c) within this common factor, the questionnaires could be placed on a continuum of Uncontrolled Eating. That is, Eating Impulsivity focused on the milder degree, Power of Food Scale, emotional eating scales, and Disinhibition on intermediate degrees, and the Binge Eating Scale on the most severe degrees of Uncontrolled Eating. In sum, evidence from two samples showed that questionnaires capturing five common BMI-related traits largely reflected the same underlying latent trait - Uncontrolled Eating. In Estonia, some questionnaires focused on different severities of this common construct, supporting a continuum model of Uncontrolled Eating. These findings provide a starting point for developing better questionnaires of the neurobehavioural correlates of obesity, and provide a unifying perspective from which to view the existing literature. R scripts and data used for the analysis are provided. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Deficits in episodic memory are related to uncontrolled eating in a sample of healthy adults.

    Science.gov (United States)

    Martin, A A; Davidson, T L; McCrory, M A

    2018-05-01

    Despite a substantial amount of animal data linking deficits in memory inhibition to the development of overeating and obesity, few studies have investigated the relevance of memory inhibition to uncontrolled eating in humans. Further, although memory for recent eating has been implicated as an important contributor to satiety and energy intake, the possibility that variations in episodic memory relate to individual differences in food intake control has been largely neglected. To examine these relationships, we recruited ninety-three adult subjects to attend a single lab session where we assessed body composition, dietary intake, memory performance, and eating behaviors (Three Factor Eating Questionnaire). Episodic recall and memory inhibition were assessed using a well-established measure of memory interference (Retrieval Practice Paradigm). Hierarchical regression analyses indicated that memory inhibition was largely unrelated to participants' eating behaviors; however, episodic recall was reliably predicted by restrained vs. uncontrolled eating: recall was positively associated with strategic dieting (β = 2.45, p = 0.02), avoidance of fatty foods (β = 3.41, p = 0.004), and cognitive restraint (β = 1.55, p = 0.04). In contrast, recall was negatively associated with uncontrolled eating (β = -1.15, p = 0.03) and emotional eating (β = -2.46, p = 0.04). These findings suggest that episodic memory processing is related to uncontrolled eating in humans. The possibility that deficits in episodic memory may contribute to uncontrolled eating by disrupting memory for recent eating is discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways.

    Science.gov (United States)

    Bijangi-Vishehsaraei, Khadijeh; Reza Saadatzadeh, M; Wang, Haiyan; Nguyen, Angie; Kamocka, Malgorzata M; Cai, Wenjing; Cohen-Gadol, Aaron A; Halum, Stacey L; Sarkaria, Jann N; Pollok, Karen E; Safa, Ahmad R

    2017-12-01

    OBJECTIVE Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)-a constituent of cruciferous vegetables with a multitargeted effect-as a therapeutic agent for GBM. METHODS The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models. RESULTS SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of γ-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell-induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN

  14. MicroRNA-128b suppresses tumor growth and promotes apoptosis by targeting A2bR in gastric cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ping; Guo, Xueyan; Zong, Wei [Department of Gastroenterology, The Third Affiliated Hospital, College of Medicine, Xi' an Jiaotong University, Xi' an 710068 (China); Song, Bin [Department of General Surgery, The Third Affiliated Hospital, College of Medicine, Xi' an Jiaotong University, Xi' an 710068 (China); Liu, Guisheng [Department of Gastroenterology, The Third Affiliated Hospital, College of Medicine, Xi' an Jiaotong University, Xi' an 710068 (China); He, Shuixiang, E-mail: fisrstsxianghe@163.com [Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Xi' an Jiaotong University, Xi' an 710061 (China)

    2015-11-27

    MicroRNAs (miRNAs) play crucial roles in the development and progression of human cancers, including gastric cancer (GC). The discovery of miRNAs may provide a new and powerful tool for studying the mechanism, diagnosis, and treatment of GC. In this study, we aimed to investigate the role and mechanism of miR-128b in the development and progression of GC. Quantitative real-time PCR (qRT-PCR) was used to measure the expression level of miR-128b in GC tissues and cell lines. We found that miR-128b was significantly down-regulated in GC tissues and cell lines. In addition, over-expression of miR-128b inhibited GC cell proliferation, migration and invasion of GC cells in vitro. Gain-of-function in vitro experiments further showed that the miR-128b mimic significantly promoted GC cell apoptosis. Subsequent dual-luciferase reporter assay identified one of the proto-oncogene A2bR as direct target of miR-128b. Therefore, our results indicate that miR-128b is a proto-oncogene miRNA that can suppresses GC proliferation and migration through down-regulation of the oncogene gene A2bR. Taken together, our results indicate that miR-128b could serve as a potential diagnostic biomarker and therapeutic option for human GC in the near future. - Highlights: • The expression of MiR-128b is significantly down-regulated in GC tissues and cell lines. • Ectopic expression of miR-128b directly affects cell proliferation, migration and invasion in vitro. • Overexpression of miR-128b increases apoptosis in GC cells. • A2bR is a candidate target gene of miR-128b. • MiR-128b represses cell proliferation, migration and invasion and promotes apoptosis by targeting A2bR in GC.

  15. Recombinant Newcastle disease virus (NDV/Anh-IL-2 expressing human IL-2 as a potential candidate for suppresses growth of hepatoma therapy

    Directory of Open Access Journals (Sweden)

    Yunzhou Wu

    2016-09-01

    Full Text Available Newcastle disease virus (NDV have shown oncolytic therapeutic efficacy in preclinical study and are currently approved for clinical trials. NDV Anhinga strain which is a mesogenic strain should be classified as lytic strain and has a therapeutic efficacy in hepatocellular cancer. In this study, we evaluated the capacity of NDV Anhinga strain to elicit immune reaction in vivo and the possibility for using as a vaccine vector for expressing tumor therapeutic factors. Interleukin-2 (IL-2 could boost the immune response against the tumor cells. Therefore, we use NDV Anhinga strain as backbone to construct a recombinant virus (NDV/Anh-IL-2 expressing IL-2. The virus growth curve showed that the production of recombinant NDV/Anh-IL-2 was slightly delayed compared to the wild type. The NDV/Anh-IL-2 strain could express soluble IL-2 and effectively inhibit the growth of hepatocellular carcinoma in vivo. 60 days post-treatment, mice which were completely cured by previous treatment were well protected when rechallenged with the same tumor cell. From the H&E-stained sections, intense infiltration of lymphocyte was observed in the NDV Anhinga strain treated group, especially in NDV/Anh-IL-2 group. The NDV Anhinga strain could not only kill the tumor directly, but could also elicit immune reaction and a potent immunological memory when killing tumor in vivo. In conclusion, the Anhinga strain could be an effective vector for tumor therapy; the recombinant NDV/Anh-IL-2 strain expressing soluble IL-2 is a promising candidate for hepatoma therapy.

  16. Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl-2

    Science.gov (United States)

    Yue, Wen; Zheng, Xi; Lin, Yong; Yang, Chung S.; Xu, Qing; Carpizo, Darren; Huang, Huarong; DiPaola, Robert S.; Tan, Xiang-Lin

    2015-01-01

    Metformin and aspirin have been studied extensively as cancer preventive or therapeutic agents. However, the effects of their combination on pancreatic cancer cells have not been investigated. Herein, we evaluated the effects of metformin and aspirin, alone or in combination, on cell viability, migration, and apoptosis as well as the molecular changes in mTOR, STAT3 and apoptotic signaling pathways in PANC-1 and BxPC3 cells. Metformin and aspirin, at relatively low concentrations, demonstrated synergistically inhibitory effects on cell viability. Compared to the untreated control or individual drug, the combination of metformin and aspirin significantly inhibited cell migration and colony formation of both PANC-1 and BxPC-3 cells. Metformin combined with aspirin significantly inhibited the phosphorylation of mTOR and STAT3, and induced apoptosis as measured by caspase-3 and PARP cleavage. Remarkably, metformin combined with aspirin significantly downregulated the anti-apoptotic proteins Mcl-1 and Bcl-2, and upregulated the pro-apoptotic proteins Bim and Puma, as well as interrupted their interactions. The downregulation of Mcl-1 and Bcl-2 was independent of AMPK or STAT3 pathway but partially through mTOR signaling and proteasome degradation. In a PANC-1 xenograft mouse model, we demonstrated that the combination of metformin and aspirin significantly inhibited tumor growth and downregulated the protein expression of Mcl-1 and Bcl-2 in tumors. Taken together, the combination of metformin and aspirin significantly inhibited pancreatic cancer cell growth in vitro and in vivo by regulating the pro- and anti-apoptotic Bcl-2 family members, supporting the continued investigation of this two drug combination as chemopreventive or chemotherapeutic agents for pancreatic cancer. PMID:26056043

  17. Supplementation of lactobacilli improves growth, regulates microbiota composition and suppresses skeletal anomalies in juvenile pike-perch (Sander lucioperca) reared in recirculating aquaculture system (RAS): A pilot study.

    Science.gov (United States)

    Ljubobratovic, Uros; Kosanovic, Dejana; Vukotic, Goran; Molnar, Zsuzsanna; Stanisavljevic, Nemanja; Ristovic, Tijana; Peter, Geza; Lukic, Jovanka; Jeney, Galina

    2017-12-01

    This research aimed to test the effects of lactobacilli, applied to cultured pike-perch, either through hydrolyzed OTOHIME fish diet, or through Artemia nauplii, on fish growth, microbiota balance and skeletal development. On the 12th Day Post Hatching (DPH) fish were divided into following treatment groups: two groups received the combination of OTOHIME and nauplii enriched either with Lactobacillus paracasei BGHN14+Lactobacillus rhamnosus BGT10 or with Lactobacillus reuteri BGGO6-55+Lactobacillus salivarius BGHO1, and one group received OTOHIME hydrolyzed by BGHN14+BGT10 and non-enriched nauplii. Control group received non-enriched nauplii and non-hydrolyzed OTOHIME. The treatment lasted 14days and fish were sacrificed on the 26th DPH for the assessment of digestive enzyme activity and microbiota composition. Individual total lengths and individual body weights were recorded at the end of the treatments, on the 26th DPH, and also on the 45th DPH, in parallel with the evaluation of skeletal deformities and fish survival. Our results indicated positive effect of Artemia enriched with BGGO6-55+BGHO1 on fish growth, skeletal development and trypsin to chymotrypsin activity ratio (T/C), as an indicator of protein digestibility. Hydrolysis of OTOHIME was also associated with better skeletal development, higher T/C values and lower levels of Aeromonas and Mycobacterium spp., which are important fish pathogens. Though additional testing in larger cohort studies is needed, these observations are promising in terms of usage of probiotics for improved environmentally friendly production of pike-perch in Recirculating Aquaculture System (RAS). Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Gene silencing of indoleamine 2,3-dioxygenase 2 in melanoma cells induces apoptosis through the suppression of NAD+ and inhibits in vivo tumor growth.

    Science.gov (United States)

    Liu, Yanling; Zhang, Yujuan; Zheng, Xiufen; Zhang, Xusheng; Wang, Hongmei; Li, Qin; Yuan, Keng; Zhou, Nanjing; Yu, Yanrong; Song, Na; Fu, Jiamin; Min, Weiping

    2016-05-31

    Indoleamine 2,3-dioxygenase 2 (IDO2) is a newly discovered enzyme that catalyzes the initial and rate-limiting step in the degradation of tryptophan. As a homologous protein of IDO1, IDO2 plays an inhibitory role in T cell proliferation, and it is essential for regulatory T cell (Treg) generation in healthy conditions. Little is known about the immune-independent functions of IDO2 relevant to its specific contributions to physiology and pathophysiology in cancer cells. The purpose of this study was to assess the impact of IDO2 gene silencing as a way to inhibit B16-BL6 cancer cells in a murine model. Here, for the first time, we show that knockdown of IDO2 using small interfering RNA (siRNA) inhibits cancer cell proliferation, arrests cell cycle in G1, induces greater cell apoptosis, and reduces cell migration in vitro. Knockdown of IDO2 decreased the generation of nicotinamide adenine dinucleotide (NAD+) while increasing the generation of reactive oxygen species (ROS). We further demonstrate that cell apoptosis, induced by IDO2 downregulation, can be weakened by addition of exogenous NAD+, suggesting a novel mechanism by which IDO2 promotes tumor growth through its metabolite product NAD+. In addition to in vitro findings, we also demonstrate that IDO2 silencing in tumor cells using short hairpin RNA (shRNA) delayed tumor formation and arrested tumor growth in vivo. In conclusion, this study demonstrates a new non-immune-associated mechanism of IDO2 in vitro and IDO2 expression in B16-BL6 cells contributes to cancer development and progression. Our research provides evidence of a novel target for gene silencing that has the potential to enhance cancer therapy.

  19. Use of water vapor for suppressing the growth of unstable low-{kappa} interlayer in HfTiO gate-dielectric Ge metal-oxide-semiconductor capacitors with sub-nanometer capacitance equivalent thickness

    Energy Technology Data Exchange (ETDEWEB)

    Xu, J.P. [Department of Electronic Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074 (China); Zou, X. [School of Electromachine and Architecture Engineering, Jianghan University, Wuhan, 430056 (China); Lai, P.T. [Department of Electrical and Electronic Engineering, University of Hong Kong, Pokfulam Road (Hong Kong)], E-mail: laip@eee.hku.hk; Li, C.X.; Chan, C.L. [Department of Electrical and Electronic Engineering, University of Hong Kong, Pokfulam Road (Hong Kong)

    2009-03-02

    Annealing of high-permittivity HfTiO gate dielectric on Ge substrate in different gases (N{sub 2}, NH{sub 3}, NO and N{sub 2}O) with or without water vapor is investigated. Analysis by transmission electron microscopy indicates that the four wet anneals can greatly suppress the growth of a GeO{sub x} interlayer at the dielectric/Ge interface, and thus decrease interface states, oxide charges and gate leakage current. Moreover, compared with the wet N{sub 2} anneal, the wet NH{sub 3}, NO and N{sub 2}O anneals decrease the equivalent permittivity of the gate dielectric due to the growth of a GeO{sub x}N{sub y} interlayer. Among the eight anneals, the wet N{sub 2} anneal produces the best dielectric performance with an equivalent relative permittivity of 35, capacitance equivalent thickness of 0.81 nm, interface-state density of 6.4 x 10{sup 11} eV{sup -1} cm{sup -2} and gate leakage current of 2.7 x 10{sup -4} A/cm{sup 2} at V{sub g} = 1 V.

  20. Use of water vapor for suppressing the growth of unstable low-κ interlayer in HfTiO gate-dielectric Ge metal-oxide-semiconductor capacitors with sub-nanometer capacitance equivalent thickness

    International Nuclear Information System (INIS)

    Xu, J.P.; Zou, X.; Lai, P.T.; Li, C.X.; Chan, C.L.

    2009-01-01

    Annealing of high-permittivity HfTiO gate dielectric on Ge substrate in different gases (N 2 , NH 3 , NO and N 2 O) with or without water vapor is investigated. Analysis by transmission electron microscopy indicates that the four wet anneals can greatly suppress the growth of a GeO x interlayer at the dielectric/Ge interface, and thus decrease interface states, oxide charges and gate leakage current. Moreover, compared with the wet N 2 anneal, the wet NH 3 , NO and N 2 O anneals decrease the equivalent permittivity of the gate dielectric due to the growth of a GeO x N y interlayer. Among the eight anneals, the wet N 2 anneal produces the best dielectric performance with an equivalent relative permittivity of 35, capacitance equivalent thickness of 0.81 nm, interface-state density of 6.4 x 10 11 eV -1 cm -2 and gate leakage current of 2.7 x 10 -4 A/cm 2 at V g = 1 V

  1. Cordycepin (3'-deoxyadenosine) inhibits the growth of B16-BL6 mouse melanoma cells through the stimulation of adenosine A3 receptor followed by glycogen synthase kinase-3beta activation and cyclin D1 suppression.

    Science.gov (United States)

    Yoshikawa, Noriko; Yamada, Shizuo; Takeuchi, Chihiro; Kagota, Satomi; Shinozuka, Kazumasa; Kunitomo, Masaru; Nakamura, Kazuki

    2008-06-01

    Cordyceps sinensis, a parasitic fungus on the larvae of Lepidoptera, has been used as a traditional Chinese medicine. We previously reported that the growth of B16-BL6 mouse melanoma (B16-BL6) cells was inhibited by cordycepin (3'-deoxyadenosine), an active ingredient of C. sinensis, and its effect was antagonized by MRS1191, a selective adenosine A3 receptor antagonist. In this study, the radioligand binding assay using [125I]-AB-MECA (a selective adenosine A3 receptor agonist) has shown that B16-BL6 cells express adenosine A3 receptors and that cordycepin binds to these receptors. We also confirmed the involvement of adenosine A3 receptors in the action of cordycepin using MRS1523 and MRS1220, specific adenosine A3 receptor antagonists. Next, indirubin, a glycogen synthase kinase-3beta (GSK-3beta) inhibitor, antagonized the growth suppression induced by cordycepin. Furthermore, the level of cyclin D1 protein in B16-BL6 cells was decreased by cordycepin using Western blot analysis. In conclusion, this study demonstrated that cordycepin inhibits the proliferation of B16-BL6 cells by stimulating adenosine A3 receptors followed by the Wnt signaling pathway, including GSK-3beta activation and cyclin D1 inhibition.

  2. Presumed consent for organ preservation in uncontrolled donation after cardiac death in the United States: a public policy with serious consequences

    Directory of Open Access Journals (Sweden)

    Rady Mohamed Y

    2009-09-01

    Full Text Available Abstract Organ donation after cessation of circulation and respiration, both controlled and uncontrolled, has been proposed by the Institute of Medicine as a way to increase opportunities for organ procurement. Despite claims to the contrary, both forms of controlled and uncontrolled donation after cardiac death raise significant ethical and legal issues. Identified causes for concern include absence of agreement on criteria for the declaration of death, nonexistence of universal guidelines for duration before stopping resuscitation efforts and techniques, and assumption of presumed intent to donate for the purpose of initiating temporary organ-preservation interventions when no expressed consent to donate is present. From a legal point of view, not having scientifically valid criteria of cessation of circulation and respiration for declaring death could lead to a conclusion that organ procurement itself is the proximate cause of death. Although the revised Uniform Anatomical Gift Act of 2006 provides broad immunity to those involved in organ-procurement activities, courts have yet to provide an opinion on whether persons can be held liable for injuries arising from the determination of death itself. Preserving organs in uncontrolled donation after cardiac death requires the administration of life-support systems such as extracorporeal membrane oxygenation. These life-support systems can lead to return of signs of life that, in turn, have to be deliberately suppressed by the administration of pharmacological agents. Finally, allowing temporary organ-preservation interventions without expressed consent is inherently a violation of the principle of respect for a person's autonomy. Proponents of organ donation from uncontrolled donation after cardiac death, on the other hand, claim that these nonconsensual interventions enhance respect for autonomy by allowing people, through surrogate decision making, to execute their right to donate organs

  3. Presumed consent for organ preservation in uncontrolled donation after cardiac death in the United States: a public policy with serious consequences

    Science.gov (United States)

    Verheijde, Joseph L; Rady, Mohamed Y; McGregor, Joan

    2009-01-01

    Organ donation after cessation of circulation and respiration, both controlled and uncontrolled, has been proposed by the Institute of Medicine as a way to increase opportunities for organ procurement. Despite claims to the contrary, both forms of controlled and uncontrolled donation after cardiac death raise significant ethical and legal issues. Identified causes for concern include absence of agreement on criteria for the declaration of death, nonexistence of universal guidelines for duration before stopping resuscitation efforts and techniques, and assumption of presumed intent to donate for the purpose of initiating temporary organ-preservation interventions when no expressed consent to donate is present. From a legal point of view, not having scientifically valid criteria of cessation of circulation and respiration for declaring death could lead to a conclusion that organ procurement itself is the proximate cause of death. Although the revised Uniform Anatomical Gift Act of 2006 provides broad immunity to those involved in organ-procurement activities, courts have yet to provide an opinion on whether persons can be held liable for injuries arising from the determination of death itself. Preserving organs in uncontrolled donation after cardiac death requires the administration of life-support systems such as extracorporeal membrane oxygenation. These life-support systems can lead to return of signs of life that, in turn, have to be deliberately suppressed by the administration of pharmacological agents. Finally, allowing temporary organ-preservation interventions without expressed consent is inherently a violation of the principle of respect for a person's autonomy. Proponents of organ donation from uncontrolled donation after cardiac death, on the other hand, claim that these nonconsensual interventions enhance respect for autonomy by allowing people, through surrogate decision making, to execute their right to donate organs. However, the lack of transparency

  4. Growth suppression of colorectal cancer by plant-derived multiple mAb CO17-1A × BR55 via inhibition of ERK1/2 phosphorylation.

    Science.gov (United States)

    Kwak, Dong Hoon; Moussavou, Ghislain; Lee, Ju Hyoung; Heo, Sung Youn; Ko, Kisung; Hwang, Kyung-A; Jekal, Seung-Joo; Choo, Young-Kug

    2014-11-14

    We have generated the transgenic Tabaco plants expressing multiple monoclonal antibody (mAb) CO7-1A × BR55 by cross-pollinating with mAb CO17-1A and mAb BR55. We have demonstrated the anti-cancer effect of plant-derived multiple mAb CO17-1A × BR55. We find that co-treatment of colorectal mAbs (anti-epithelial cellular adhesion molecule (EpCAM), plant-derived monoclonal antibody (mAb(P)) CO17-1A and mAb(P) CO17-1A × BR55) with RAW264.7 cells significantly inhibited the cell growth in SW620 cancer cells. In particular, multi mAb(P) CO17-1A × BR55 significantly and efficiently suppressed the growth of SW620 cancer cells compared to another mAbs. Apoptotic death-positive cells were significantly increased in the mAb(P) CO17-1A × BR55-treated. The mAb(P) CO17-1A × BR55 treatment significantly decreased the expression of B-Cell lymphoma-2 (BCl-2), but the expression of Bcl-2-associated X protein (Bax), and cleaved caspase-3 were markedly increased. In vivo, the mAb(P) CO17-1A × BR55 significantly and efficiently inhibited the growth of colon tumors compared to another mAbs. The apoptotic cell death and inhibition of pro-apoptotic proteins expression were highest by treatment with mAb(P) CO17-1A × BR55. In addition, the mAb(P) CO17-1A × BR55 significantly inhibited the extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation in cancer cells and tumors. Therefore, this study results suggest that multiple mAb(P) CO17-1A × BR55 has a significant effect on apoptosis-mediated anticancer by suppression of ERK1/2 phosphorylation in colon cancer compared to another mAbs. In light of these results, further clinical investigation should be conducted on mAb(P) CO17-1A × BR55 to determine its possible chemopreventive and/or therapeutic efficacy against human colon cancer.

  5. Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer.

    Directory of Open Access Journals (Sweden)

    Ibrahim Tekedereli

    Full Text Available Eukaryotic elongation factor 2 kinase (eEF-2K, through its phosphorylation of elongation factor 2 (eEF2, provides a mechanism by which cells can control the rate of the elongation phase of protein synthesis. The activity of eEF-2K is increased in rapidly proliferating malignant cells, is inhibited during mitosis, and may contribute to the promotion of autophagy in response to anti-cancer therapies. The purpose of this study was to examine the therapeutic potential of targeting eEF-2K in breast cancer tumors. Through the systemic administration of liposomal eEF-2K siRNA (twice a week, i.v. 150 µg/kg, the expression of eEF-2K was down-regulated in vivo in an orthotopic xenograft mouse model of a highly aggressive triple negative MDA-MB-231 tumor. This targeting resulted in a substantial decrease in eEF2 phosphorylation in the tumors, and led to the inhibition of tumor growth, the induction of apoptosis and the sensitization of tumors to the chemotherapy agent doxorubicin. eEF-2K down-modulation in vitro resulted in a decrease in the expression of c-Myc and cyclin D1 with a concomitant increase in the expression of p27(Kip1. A decrease in the basal activity of c-Src (phospho-Tyr-416, focal adhesion kinase (phospho-Tyr-397, and Akt (phospho-Ser-473 was also detected following eEF-2K down-regulation in MDA-MB-231 cells, as determined by Western blotting. Where tested, similar results were seen in ER-positive MCF-7 cells. These effects were also accompanied by a decrease in the observed invasive phenotype of the MDA-MB-231 cells. These data support the notion that the disruption of eEF-2K expression in breast cancer cells results in the down-regulation of signaling pathways affecting growth, survival and resistance and has potential as a therapeutic approach for the treatment of breast cancer.

  6. Sunitinib significantly suppresses the proliferation, migration, apoptosis resistance, tumor angiogenesis and growth of triple-negative breast cancers but increases breast cancer stem cells.

    Science.gov (United States)

    Chinchar, Edmund; Makey, Kristina L; Gibson, John; Chen, Fang; Cole, Shelby A; Megason, Gail C; Vijayakumar, Srinivassan; Miele, Lucio; Gu, Jian-Wei

    2014-01-01

    The majority of triple-negative breast cancers (TNBCs) are basal-like breast cancers. However there is no reported study on anti-tumor effects of sunitinib in xenografts of basal-like TNBC (MDA-MB-468) cells. In the present study, MDA-MB-231, MDA-MB-468, MCF-7 cells were cultured using RPMI 1640 media with 10% FBS. Vascular endothelia growth factor (VEGF) protein levels were detected using ELISA (R & D Systams). MDA-MB-468 cells were exposed to sunitinib for 18 hours for measuring proliferation (3H-thymidine incorporation), migration (BD Invasion Chamber), and apoptosis (ApopTag and ApoScreen Anuexin V Kit). The effect of sunitinib on Notch-1 expression was determined by Western blot in cultured MDA-MB-468 cells. 10(6) MDA-MB-468 cells were inoculated into the left fourth mammary gland fat pad in athymic nude-foxn1 mice. When the tumor volume reached 100 mm(3), sunitinib was given by gavage at 80 mg/kg/2 days for 4 weeks. Tumor angiogenesis was determined by CD31 immunohistochemistry. Breast cancer stem cells (CSCs) isolated from the tumors were determined by flow cytometry analysis using CD44(+)/CD24(-) or low. ELISA indicated that VEGF was much more highly expressed in MDA-MB-468 cells than MDA-MB-231 and MCF-7 cells. Sunitinib significantly inhibited the proliferation, invasion, and apoptosis resistance in cultured basal like breast cancer cells. Sunitinib significantly increased the expression of Notch-1 protein in cultured MDA-MB-468 or MDA-MB-231 cells. The xenograft models showed that oral sunitinib significantly reduced the tumor volume of TNBCs in association with the inhibition of tumor angiogeneisis, but increased breast CSCs. These findings support the hypothesis that the possibility should be considered of sunitinib increasing breast CSCs though it inhibits TNBC tumor angiogenesis and growth/progression, and that effects of sunitinib on Notch expression and hypoxia may increase breast cancer stem cells. This work provides the groundwork for an

  7. In vivo targeting of ADAM9 gene expression using lentivirus-delivered shRNA suppresses prostate cancer growth by regulating REG4 dependent cell cycle progression.

    Directory of Open Access Journals (Sweden)

    Che-Ming Liu

    Full Text Available Cancer cells respond to stress by activating a variety of survival signaling pathways. A disintegrin and metalloproteinase (ADAM 9 is upregulated during cancer progression and hormone therapy, functioning in part through an increase in reactive oxygen species. Here, we present in vitro and in vivo evidence that therapeutic targeting of ADAM9 gene expression by lentivirus-delivered small hairpin RNA (shRNA significantly inhibited proliferation of human prostate cancer cell lines and blocked tumor growth in a murine model of prostate cancer bone metastasis. Cell cycle studies confirmed an increase in the G1-phase and decrease in the S-phase population of cancer cells under starvation stress conditions, which correlated with elevated intracellular superoxide levels. Microarray data showed significantly decreased levels of regenerating islet-derived family member 4 (REG4 expression in prostate cancer cells with knockdown of ADAM9 gene expression. This REG4 downregulation also resulted in induction of expression of p21(Cip1/WAF1, which negatively regulates cyclin D1 and blocks the G1/S transition. Our data reveal a novel molecular mechanism of ADAM9 in the regulation of prostate cancer cell proliferation, and suggests a combined modality of ADAM9 shRNA gene therapy and cytotoxic agents for hormone refractory and bone metastatic prostate cancer.

  8. Elevated serum milk fat globule-epidermal growth factor 8 levels in type 2 diabetic patients are suppressed by overweight or obese status.

    Science.gov (United States)

    Li, Yuanyuan; Ran, Wenzhuo; Zhang, Jiaqiang; Chen, Shi; Li, Yihang; Luo, Deng; Wang, Chen; Jia, Weiping

    2017-02-01

    Inflammation is the most important link between obesity and type 2 diabetes (T2D). Although milk fat globule-epidermal growth factor 8 (MFG-E8) is a key mediator in anti-inflammatory responses, its role in obesity and diabetes is not yet completely understood. We aimed to measure MFG-E8 serum levels and to explore the role of MFG-E8 in obesity and T2D. Fasting serum MFG-E8 levels were quantified by enzyme-linked immunosorbent assay for 168 individuals, whose oral glucose tolerance test was conducted, and levels of inflammatory factors, including tumor necrosis factor-α (TNF-α) and C-reactive protein, were measured. The participants were subdivided into 66 newly diagnosed T2D individuals, 44 impaired glucose tolerance (IGT) subjects and 58 healthy controls. Their characteristics were further classified as lean or nonlean for investigation. MFG-E8 levels were significantly higher in T2D subjects than in healthy controls (P = 0.028). Decreased levels of MFG-E8 were found in overweight or obese individuals, compared to those in lean subjects, in both the T2D and IGT groups (P obesity and T2D in the clinical setting. © 2017 IUBMB Life, 69(2):63-71, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

  9. 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.

  10. 1,4-Naphthoquinone derivatives potently suppress Candida albicans growth, inhibit formation of hyphae and show no toxicity toward zebrafish embryos.

    Science.gov (United States)

    Janeczko, Monika; Kubiński, Konrad; Martyna, Aleksandra; Muzyczka, Angelika; Boguszewska-Czubara, Anna; Czernik, Sławomir; Tokarska-Rodak, Małgorzata; Chwedczuk, Marta; Demchuk, Oleg M; Golczyk, Hieronim; Masłyk, Maciej

    2018-04-01

    In this study, we applied various assays to find new activities of 1,4-naphthoquinone derivatives for potential anti-Candida albicans applications. These assays determined (a) the antimicrobial effect on growth/cell multiplication in fungal cultures, (b) the effect on formation of hyphae and biofilm, (c) the influence on cell membrane integrity, (d) the effect on cell morphology using atomic force microscopy, and (e) toxicity against zebrafish embryos. We have demonstrated the activity of these compounds against different Candida species and clinical isolates of C. albicans. 1,4-Naphthoquinones significantly affected fungal strains at 8-250 mg l -1 of MIC. Interestingly, at concentrations below MICs, the chemicals showed effectiveness in inhibition of hyphal formation and cell aggregation in Candida. Of note, atomic force microscopy (AFM) analysis revealed an influence of the compounds on cell morphological properties. However, at low concentrations (0.8-31.2 mg l -1 ), it did not exert any evident toxic effects on zebrafish embryos. Our research has evidenced the effectiveness of 1,4-naphthoquinones as potential anti-Candida agents.

  11. Saw palmetto extract suppresses insulin-like growth factor-I signaling and induces stress-activated protein kinase/c-Jun N-terminal kinase phosphorylation in human prostate epithelial cells.

    Science.gov (United States)

    Wadsworth, Teri L; Carroll, Julie M; Mallinson, Rebecca A; Roberts, Charles T; Roselli, Charles E

    2004-07-01

    A common alternative therapy for benign prostatic hyperplasia (BPH) is the extract from the fruit of saw palmetto (SPE). BPH is caused by nonmalignant growth of epithelial and stromal elements of the prostate. IGF action is important for prostate growth and development, and changes in the IGF system have been documented in BPH tissues. The main signaling pathways activated by the binding of IGF-I to the IGF-I receptor (IGF-IR) are the ERK arm of the MAPK cascade and the phosphoinositol-3-kinase (PI3K)/protein kinase B (PKB/Akt) cascade. We tested the hypothesis that SPE suppresses growth and induces apoptosis in the P69 prostate epithelial cell line by inhibiting IGF-I signaling. Treatment with 150 microg/ml SPE for 24 h decreased IGF-I-induced proliferation of P69 cells and induced cleavage of the enzyme poly(ADP-ribose)polymerase (PARP), an index of apoptosis. Treatment of serum-starved P69 cells with 150 microg/ml SPE for 6 h reduced IGF-I-induced phosphorylation of Akt (assessed by Western blot) and Akt activity (assessed by an Akt kinase assay). Western blot analysis showed that SPE reduced IGF-I-induced phosphorylation of the adapter protein insulin receptor substrate-1 and decreased downstream effects of Akt activation, including increased cyclin D1 levels and phosphorylation of glycogen synthase kinase-3 and p70(s6k). There was no effect on IGF-I-induced phosphorylation of MAPK, IGF-IR, or Shc. Treatment of starved cells with SPE alone induced phosphorylation the proapoptotic protein JNK. SPE treatment may relieve symptoms of BPH, in part, by inhibiting specific components of the IGF-I signaling pathway and inducing JNK activation, thus mediating antiproliferative and proapoptotic effects on prostate epithelia.

  12. Weight loss in obese men by caloric restriction and high-dose diazoxide-mediated insulin suppression.

    NARCIS (Netherlands)

    Boekel, G.A.J van; Loves, S.; Sorge, A.A. van; Ruinemans-Koerts, J.; Rijnders, T.; Boer, H. de

    2008-01-01

    OBJECTIVE: To examine the concept whether high-dose diazoxide (DZX)-mediated insulin suppression, in combination with moderate caloric restriction and increased physical activity, can establish a weight loss of at least 15% in obese hyperinsulinaemic men. DESIGN: Open, uncontrolled, 6-month pilot

  13. Branched-Chain Amino Acids Ameliorate Fibrosis and Suppress Tumor Growth in a Rat Model of Hepatocellular Carcinoma with Liver Cirrhosis

    Science.gov (United States)

    Cha, Jung Hoon; Bae, Si Hyun; Kim, Hye Lim; Park, Na Ri; Choi, Eun Suk; Jung, Eun Sun; Choi, Jong Young; Yoon, Seung Kew

    2013-01-01

    Purpose Recent studies have revealed that branched-chain amino acids (BCAA) reduce the development of hepatocellular carcinoma (HCC) in patients with obesity and hepatitis C virus infection by improving insulin resistance (IR). The aim of this study was to examine the anti-cancer and anti-fibrotic effects of BCAA on the development of diethylnitrosamine (DEN)-induced HCC and liver cirrhosis in a rat model. Methods Male SD rats received weekly intraperitoneal injections of DEN (50 mg/kg of body weight) for 16 weeks to induce HCC. They were fed a diet containing 3% casein, 3% or 6% BCAA for 13 weeks beginning 6 weeks after DEN administration. DEN was used to induce HCC through stepwise development from cirrhosis to HCC. The effect of BCAA was evaluated in tumor tissues by histopathologic analyses, reverse transcription-polymerase chain reaction, and Western blotting. Results The mean area and number of dysplastic nodules (DNs) and tumors in the casein group tended to be larger than those in the BCAA group 16 weeks after DEN administration. The mean fibrotic area in the BCAA group was smaller than that in the casein group. The BCAA group showed decreased mRNA levels for markers of fibrosis, angiogenesis, and apoptosis inhibition. Compared with the casein group, the BCAA group had lower levels of α-smooth muscle actin, vascular endothelial growth factor, p-β-catenin, p-p38 mitogen-activated protein kinase, proliferating cell nuclear antigen, and caspase-3 protein expression, as well as a higher level of cleaved caspase-3 protein expression. Conclusions BCAA supplementation of the diet ameliorated liver fibrosis and HCC development in a DEN-induced rat model of HCC with liver cirrhosis, but not in the IR model. These results provide a rationale for anti-fibrosis and chemoprevention using BCAA treatment for HCC with liver cirrhosis, as well as decreasing the ammonia level. PMID:24223741

  14. Suppression of the Epidermal Growth Factor-like Domain 7 and Inhibition of Migration and Epithelial-Mesenchymal Transition in Human Pancreatic Cancer PANC-1 Cells.

    Science.gov (United States)

    Wang, Yun-Liang; Dong, Feng-Lin; Yang, Jian; Li, Zhi; Zhi, Qiao-Ming; Zhao, Xin; Yang, Yong; Li, De-Chun; Shen, Xiao-Chun; Zhou, Jin

    2015-01-01

    Epidermal growth factor-like domain multiple 7 (EGFL7), a secreted protein specifically expressed by endothelial cells during embryogenesis, recently was identified as a critical gene in tumor metastasis. Epithelial-mesenchymal transition (EMT) was found to be closely related with tumor progression. Accordingly, it is important to investigate the migration and EMT change after knock-down of EGFL7 gene expression in human pancreatic cancer cells. EGFL7 expression was firstly testified in 4 pancreatic cancer cell lines by real-time polymerase chain reaction (Real-time PCR) and western blot, and the highest expression of EGFL7 was found in PANC-1 cell line. Then, PANC-1 cells transfected with small interference RNA (siRNA) of EGFL7 using plasmid vector were named si-PANC-1, while transfected with negative control plasmid vector were called NC-PANC-1. Transwell assay was used to analyze the migration of PANC-1 cells. Real-time PCR and western blotting were used to detect the expression change of EGFL7 gene, EMT markers like E-Cadherin, N-Cadherin, Vimentin, Fibronectin and transcription factors like snail, slug in PANC-1, NC- PANC-1, and si-PANC-1 cells, respectively. After successful plasmid transfection, EGFL7 gene were dramatically knock-down by RNA interference in si-PANC-1 group. Meanwhile, migration ability decreased significantly, compared with PANC-1 and NC-PANC-1 group. Meanwhile, the expression of epithelial phenotype marker E-Cadherin increased and that of mesenchymal phenotype markers N-Cadherin, Vimentin, Fibronectin dramatically decreased in si-PANC-1 group, indicating a reversion of EMT. Also, transcription factors snail and slug decreased significantly after RNA interference. Current study suggested that highly-expressed EGFL7 promotes migration of PANC-1 cells and acts through transcription factors snail and slug to induce EMT, and further study is needed to confirm this issue.

  15. Dietary agent, benzyl isothiocyanate inhibits signal transducer and activator of transcription 3 phosphorylation and collaborates with sulforaphane in the growth suppression of PANC-1 cancer cells

    Directory of Open Access Journals (Sweden)

    Deangelis Stephanie

    2009-08-01

    Full Text Available Abstract The Signal Transducer and Activator of Transcription (STAT proteins comprise a family of latent transcription factors with diverse functions. STAT3 has well established roles in cell proliferation, growth and survival, and its persistent activation has been detected with high frequency in many human cancers. As constitutive activation of STAT3 appears to be vital for the continued survival of these cancerous cells, it has emerged as an attractive target for chemotherapeutics. We examined whether the inhibitory activities of bioactive compounds from cruciferous vegetables, such as Benzyl isothiocyanate (BITC and sulforaphane, extended to STAT3 activation in PANC-1 human pancreatic cancer cells. BITC and sulforaphane were both capable of inhibiting cell viability and inducing apoptosis in PANC-1. Sulforaphane had minimal effect on the direct inhibition of STAT3 tyrosine phosphorylation, however, suggesting its inhibitory activities are most likely STAT3-independent. Conversely, BITC was shown to inhibit the tyrosine phosphorylation of STAT3, but not the phosphorylation of ERK1/2, MAPK and p70S6 kinase. These results suggest that STAT3 may be one of the targets of BITC-mediated inhibition of cell viability in PANC-1 cancer cells. In addition, we show that BITC can prevent the induction of STAT3 activation by Interleukin-6 in MDA-MB-453 breast cancer cells. Furthermore, combinations of BITC and sulforaphane inhibited cell viability and STAT3 phosphorylation more dramatically than either agent alone. These findings suggest that the combination of the dietary agents BITC and sulforaphane has potent inhibitory activity in pancreatic cancer cells and that they may have translational potential as chemopreventative or therapeutic agents.

  16. Retinoic acid suppresses growth of lesions, inhibits peritoneal cytokine secretion, and promotes macrophage differentiation in an immunocompetent mouse model of endometriosis.

    Science.gov (United States)

    Wieser, Friedrich; Wu, Juanjuan; Shen, Zhaoju; Taylor, Robert N; Sidell, Neil

    2012-06-01

    To determine the effects of all-trans-retinoic acid (RA) on establishment and growth of endometrial lesions, peritoneal interleukin-6 (IL-6) and macrophage chemotactic factor-1 (MCP-1) concentrations, and CD38, CD11b, and F4/80 expression on peritoneal macrophages in an immunocompetent mouse model of endometriosis. Experimental transplantation study using mice. Academic medical center. C57BL/6 recipient mice and syngeneic green fluorescent protein transgenic (GFP+) mice. Recipient mice were inoculated with GFP+ minced uterine tissue to induce endometriosis and treated with RA (400 nmol/day) or vehicle for 17 days (3 days before to 14 days after tissue injection). Total number of GFP+ implants in recipient mice, number of implants showing visible blood vessels, total volume of established lesions per mouse, concentrations of IL-6 and MCP-1 in peritoneal fluid, and expression of CD11b, F4/80, and CD38 on peritoneal macrophages. Retinoic acid treatment for 17 days reduced the number of implants versus controls and decreased the frequency of lesions with vessels. Peritoneal washings in RA-treated animals had lower concentrations of IL-6 and MCP-1 than controls 3 days after endometrial inoculation and lower levels of IL-6 on day 14 after inoculation. Concomitant with these effects on day 14, CD38, CD11b, and F4/80 were higher on macrophages from RA-treated mice versus controls. The development of endometriotic implants is inhibited by RA. This effect may be caused, at least in part, by reduced IL-6 and MCP-1 production and enhanced differentiation of peritoneal macrophages. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  17. Branched-chain amino acids ameliorate fibrosis and suppress tumor growth in a rat model of hepatocellular carcinoma with liver cirrhosis.

    Directory of Open Access Journals (Sweden)

    Jung Hoon Cha

    Full Text Available PURPOSE: Recent studies have revealed that branched-chain amino acids (BCAA reduce the development of hepatocellular carcinoma (HCC in patients with obesity and hepatitis C virus infection by improving insulin resistance (IR. The aim of this study was to examine the anti-cancer and anti-fibrotic effects of BCAA on the development of diethylnitrosamine (DEN-induced HCC and liver cirrhosis in a rat model. METHODS: Male SD rats received weekly intraperitoneal injections of DEN (50 mg/kg of body weight for 16 weeks to induce HCC. They were fed a diet containing 3% casein, 3% or 6% BCAA for 13 weeks beginning 6 weeks after DEN administration. DEN was used to induce HCC through stepwise development from cirrhosis to HCC. The effect of BCAA was evaluated in tumor tissues by histopathologic analyses, reverse transcription-polymerase chain reaction, and Western blotting. RESULTS: The mean area and number of dysplastic nodules (DNs and tumors in the casein group tended to be larger than those in the BCAA group 16 weeks after DEN administration. The mean fibrotic area in the BCAA group was smaller than that in the casein group. The BCAA group showed decreased mRNA levels for markers of fibrosis, angiogenesis, and apoptosis inhibition. Compared with the casein group, the BCAA group had lower levels of α-smooth muscle actin, vascular endothelial growth factor, p-β-catenin, p-p38 mitogen-activated protein kinase, proliferating cell nuclear antigen, and caspase-3 protein expression, as well as a higher level of cleaved caspase-3 protein expression. CONCLUSIONS: BCAA supplementation of the diet ameliorated liver fibrosis and HCC development in a DEN-induced rat model of HCC with liver cirrhosis, but not in the IR model. These results provide a rationale for anti-fibrosis and chemoprevention using BCAA treatment for HCC with liver cirrhosis, as well as decreasing the ammonia level.

  18. APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model.

    Science.gov (United States)

    Jin, Guoguo; Yao, Ke; Guo, Zhiping; Zhao, Zhenjiang; Liu, Kangdong; Liu, Fangfang; Chen, Hanyong; Gorja, Dhilli Rao; Reddy, Kanamata; Bode, Ann M; Dong, Ziming; Dong, Zigang

    2017-08-08

    Esophageal cancer (EC) is one of the most aggressive malignancies of the upper aerodigestive tract. Over the past three decades, with advances in surgical techniques and treatment, the prognosis of esophageal cancer has only slowly improved. Thus identifying novel molecular targets and developing therapeutic agents are critical. Aurora kinases play a crucial role in mitosis and selective inhibitors might provide an effective therapeutic treatment for cancer. However, the role of Aurora kinases in EC is still inadequately studied. Here, we identified a novel compound, referred to as APIO-EE-9, which inhibits growth and colony formation and induces apoptosis of esophageal cancer cells. Using computer modeling, we found that APIO-EE-9 interacted with both Aurora A and B in the ATP-binding pocket. APIO-EE-9 inhibited both Aurora A and B kinase activities in a dose-dependent manner. Treatment with APIO-EE-9 substantially reduced the downstream Aurora kinase phosphorylation of histone H3 (Ser10), resulting in formation of multiple nuclei and centrosomes. Additionally, esophageal cancer cells expressing shAurora A or shAurora B kinase exhibited a dramatic reduction in proliferation and colony formation. Injection of these cells as xenografts in mice reduced tumor formation compared to wildtype cells. Importantly, APIO-EE-9 significantly decreased the size of esophageal patient-derived xenograft (PDX) tumors implanted in SCID mice. These results demonstrated that APIO-EE-9 is a specific Aurora kinase inhibitor that could be developed as a therapeutic agent against esophageal cancer.

  19. Risk Assessment During the Final Phase of an Uncontrolled Re-Entry

    Science.gov (United States)

    Gaudel, A.; Hourtolle, C.; Goester, J. F.; Fuentes, N.

    2013-09-01

    As French National Space Agency, CNES is empowered to monitor compliance with technical regulations of the French Space Operation Act, FSOA, and to take all necessary measures to ensure the safety of people, property, public health and environment for all space operations involving French responsibility at international level.Therefore, CNES developed ELECTRA that calculates the risk for ground population involved in three types of events: rocket launching, controlled re-entry and uncontrolled re-entry. For the first two cases, ELECTRA takes into account degraded cases due to a premature stop of propulsion.Major evolutions were implemented recently on ELECTRA to meet new users' requirements, like the risk assessment during the final phase of uncontrolled re-entry, that can be combined with the computed risk for each country involved by impacts.The purpose of this paper is to provide an overview of the ELECTRA method and main functionalities, and then to highlight these recent improvements.

  20. Transfer Pricing: Is the Comparable Uncontrolled Price Method the Best Method in all Cases?

    Directory of Open Access Journals (Sweden)

    Pranvera Dalloshi

    2012-12-01

    Full Text Available The transfer price scope is becoming a very important issue for all companies that comprise from different departments or have a network of branches. These companies are obliged to present the way of price determination for transactions that they have with their branches or other relevant members of their network. The establishment of the multinational companies that develop their activities in various countries is being increased. It has increased the need to supervise their transactions and approval of laws and administrative orders that do not leave space for misuses. The paper is focused in the response to the question if the Comparable Uncontrolled Price Method is the best method to be used in all cases. It is presented through a concrete example that shows how the price of a product determined through the Comparable Uncontrolled Price Method or market price has an impact to the profit of the mother company and other subsidiaries.

  1. Relationship of left ventricular, elastic and muscular arteries remodeling in patients with uncontrolled arterial hypertension

    Directory of Open Access Journals (Sweden)

    S. Ya. Dotsenko

    2013-04-01

    Full Text Available Introduction. Uncontrolled hypertension is observed in 65-92% of hypertensive patients. It plays an important role in the development of adverse cardiovascular events and survival, which depend on subclinical target organ damage. There are reports on the relationship between ineffective hypertension control and left ventricular (LV hypertrophy or large arteries stiffness. However, the nature of the remodeling in uncontrolled hypertension remains poorly understood. Objective: to study the character and relationship of left ventricular and arterial remodeling depending on effectiveness of hypertension control. Design and method. We performed a study of 363 hypertensive patients (160 men and 203 women aged 50,8 ± 1,2 years without comorbidities, which were divided into 3 groups according to the effectiveness of blood pressure (BP control: 160 patients with controlled hypertension, 142 patients with uncontrolled hypertension and 61 patients with resistant hypertension. Uncontrolled BP based on measured systolic BP≥140 mmHg and diastolic BP≥90 mmHg. Remodeling indexes of left ventricular, elastic (common carotid and muscular (brachial artery were evaluated by the ultrasonic method. The severity and character of diastolic dysfunction, hypertrophy, types of remodeling and stiffness were assessed. Statistical processing of the results was performed using Student's t criterion and Pearson correlation analysis. Results and discussion. According to the results of the study, uncontrolled hypertension affected the development of subclinical cardiovascular lesions negatively. Thus, LV hypertrophy was detected more frequently in the third group (91,8% in resistant hypertension versus 46,8% in controlled hypertension, p<0,05. Differences in LV geometry with increasing of concentric remodeling types were also observed more frequently in the third group, where concentric remodeling and concentric hypertrophy types were founded in 14,8% and 59

  2. Bakri balloon as a uterus preserving treatment of uncontrollable haemorrhage one month post-partum

    DEFF Research Database (Denmark)

    Bonnici, Mia; Markauskas, Algirdas; Munk, Torben

    2014-01-01

    In this case Bakri balloon was used to stop haemorrhage one month post-partum. The case introduces the use of this device outside usual indications. A 27-year-old woman was admitted several times with vaginal bleeding after caesarean section. She was treated pharmacologically and with curettage. ....... One month post-partum hysteroscopic removal of placental tissue was done. During this uncontrollable haemorrhage occurred and hysterectomy was considered. An attempt to save the uterus with Bakri balloon was made succesfully....

  3. Personality and Cognitive Abilities: Predictors of Restrained, Uncontrolled and Emotional Eating Behaviours?

    OpenAIRE

    Howard, Kirstie

    2014-01-01

    Abstract The psychology of eating behaviour merits more attention, due to the increasing prevalence of eating disorders, obesity and other eating related issues. There is a need for a more grounded understanding of the behavioural, emotional and cognitive aspects of dietary habits. Aim: To examine the relationship between personality, cognitive abilities and eating behaviours; Restrained Eating (RE), Uncontrolled Eating (UE) and Emotional Eating (EE). This was based on a series of pre...

  4. Factors Associated with Uncontrolled Hypertension among Renal Transplant Recipients Attending Nephrology Clinics in Nairobi, Kenya

    Directory of Open Access Journals (Sweden)

    Mary N. Kubo

    2015-01-01

    Full Text Available Objective. To determine the factors associated with poor blood pressure control among renal transplant recipients in a resource-limited setting. Methods. A cross-sectional study was carried out on renal transplant recipients at the Kenyatta National Hospital. Sociodemographic details, blood pressure, urine albumin : creatinine ratio, and adherence using the MMAS-8 questionnaire were noted. Independent factors associated with uncontrolled hypertension were determined using logistic regression analysis. Results. 85 subjects were evaluated. Mean age was 42.4 (SD ± 12.2 years, with a male : female ratio of 1.9 : 1. Fifty-five patients (64.7% had uncontrolled hypertension (BP ≥ 130/80 mmHg. On univariate analysis, male sex (OR 3.7, 95% CI 1.4–9.5, p=0.006, higher levels of proteinuria (p=0.042, and nonadherence to antihypertensives (OR 18, 95% CI 5.2–65.7, p<0.001 were associated with uncontrolled hypertension. On logistic regression analysis, male sex (adjusted OR 4.6, 95% CI 1.1–19.0, p=0.034 and nonadherence (adjusted OR 33.8, 95% CI 8.6–73.0, p<0.001 were independently associated with uncontrolled hypertension. Conclusion. Factors associated with poor blood pressure control in this cohort were male sex and nonadherence to antihypertensives. Emphasis on adherence to antihypertensive therapy must be pursued within this population.

  5. Harnessing happiness? Uncontrollable positive emotion in bipolar disorder, major depression, and healthy adults.

    Science.gov (United States)

    Kang, Yoona; Gruber, June

    2013-04-01

    The ability to adaptively exert control over negative emotions is associated with beneficial mental health outcomes. Less is known about the associated emotional sequelae surrounding controllable versus uncontrollable positive emotional experiences. The ability to harness positive emotions is of particular importance in populations involving disrupted positive emotion functioning. In the present study, participants engaged in a relived memory task in which they recalled either a controllable or uncontrollable past positive emotional experience in counterbalanced order, while concurrent experiential and autonomic responses were measured. Participants included adults with bipolar I disorder (BD; n = 32), major depression (MDD; n = 32), and or nonpsychiatric controls (CTLs; n = 31). Across all participants, reliving a controllable positive emotion experience was associated with exhibited increased respiratory sinus arrhythmia, an autonomic marker of regulatory control. Interestingly, only the MDD group reported increased positive emotion and decreased cardiovascular arousal when reliving an event involving uncontrollable positive emotion, compared to the BD and CTL groups. No other group differences emerged. These findings suggest that although controllable positive emotion experiences may be adaptive for most, individuals with a history of restricted affect and depressed mood may actually derive more pleasure from times of unharnessed happiness. PsycINFO Database Record (c) 2013 APA, all rights reserved.

  6. Surgical Outcomes of Ahmed or Baerveldt Tube Shunt Implantation for medically Uncontrolled Traumatic Glaucoma.

    Science.gov (United States)

    Yadgarov, Arkadiy; Liu, Dan; Crane, Elliot S; Khouri, Albert S

    2017-01-01

    To describe postoperative surgical success of either Ahmed or Baerveldt tube shunt implantation for eyes with medically uncontrolled traumatic glaucoma. A review was carried out to identify patients with traumatic glaucoma that required tube shunt implantation between 2009 and 2015 at Rutgers University in Newark, New Jersey, USA. Seventeen eyes from 17 patients met inclusion criteria, including at least 3-month postoperative follow-up. The main outcome measure was surgical success at 1-year follow-up after tube implantation. Mean preoperative intraocular pressure (IOP) was 34.1 ± 8.2 mm Hg on 3.1 ± 1.6 ocular hypotensive medications. Nine eyes (53%) sustained closed globe injury. Ten eyes (59%) received an Ahmed valve shunt and seven eyes (41%) received a Baerveldt tube shunt. Surgical success rate at 1 year postoperatively was 83%. Compared to preoperative, the mean postoperative IOP was significantly lower (16.1 ± 3.5 mm Hg, p Ahmed or Baerveldt tube shunt provided successful control of IOP in patients with medically uncontrollable traumatic glaucoma. Yadgarov A, Liu D, Crane ES, Khouri AS. Surgical Outcomes of Ahmed or Baerveldt Tube Shunt Implantation for medically Uncontrolled Traumatic Glaucoma. J Curr Glaucoma Pract 2017;11(1):16-21.

  7. Dexamethasone suppression test

    Science.gov (United States)

    DST; ACTH suppression test; Cortisol suppression test ... During this test, you will receive dexamethasone. This is a strong man-made (synthetic) glucocorticoid medicine. Afterward, your blood is drawn ...

  8. Modeling posttraumatic growth among cancer patients: The roles of social support, appraisals, and adaptive coping.

    Science.gov (United States)

    Cao, Weidan; Qi, Xiaona; Cai, Deborah A; Han, Xuanye

    2018-01-01

    The purpose of the study was to build a model to explain the relationships between social support, uncontrollability appraisal, adaptive coping, and posttraumatic growth (PTG) among cancer patients in China. The participants who were cancer patients in a cancer hospital in China filled out a survey. The final sample size was 201. Structural equation modeling was used to build a model explaining PTG. Structural equation modeling results indicated that higher levels of social support predicted higher levels of adaptive coping, higher levels of uncontrollability appraisal predicted lower levels of adaptive coping, and higher levels of adaptive coping predicted higher levels of PTG. Moreover, adaptive coping was a mediator between social support and growth, as well as a mediator between uncontrollability and growth. The direct effects of social support and uncontrollability on PTG were insignificant. The model demonstrated the relationships between social support, uncontrollability appraisal, adaptive coping, and PTG. It could be concluded that uncontrollability appraisal was a required but not sufficient condition for PTG. Neither social support nor uncontrollability appraisal had direct influence on PTG. However, social support and uncontrollability might indirectly influence PTG, through adaptive coping. It implies that both internal factors (eg, cognitive appraisal and coping) and external factors (eg, social support) are required in order for growth to happen. Copyright © 2017 John Wiley & Sons, Ltd.

  9. Deconstructing continuous flash suppression

    OpenAIRE

    Yang, Eunice; Blake, Randolph

    2012-01-01

    In this paper, we asked to what extent the depth of interocular suppression engendered by continuous flash suppression (CFS) varies depending on spatiotemporal properties of the suppressed stimulus and CFS suppressor. An answer to this question could have implications for interpreting the results in which CFS influences the processing of different categories of stimuli to different extents. In a series of experiments, we measured the selectivity and depth of suppression (i.e., elevation in co...

  10. RNA interference suppression of A100A4 reduces the growth and metastatic phenotype of human renal cancer cells via NF-kB-dependent MMP-2 and bcl-2 pathway.

    Science.gov (United States)

    Yang, X-C; Wang, X; Luo, L; Dong, D-H; Yu, Q-C; Wang, X-S; Zhao, K

    2013-06-01

    S100A4 is a well established marker and mediator of metastatic disease, but the exact mechanisms responsible for the metastasis promoting effects are less well defined. We tested a hypothesis that the S100A4 gene plays a role in the proliferation and invasiveness of human renal cancer cells (RCC) and may be associated with its metastatic spread. The small interference RNA vector pcDNA3.1-S100A4 siRNA was transfected in to the human renal cancer cell lines ACHN, Ketr-3, OS-RC-2, CaKi-2 and HTB-47, then treated with ABT-737 or BB94. Cell apoptosis and cell viability was detected by flow cytometry and MTT assay. Matrigel was used for cell motility and invasion assay. MMP-2, bcl-2 and S100A4 was detected by RT-PCR and western blot assay. NF-kB subunit p65 activity was detected by confocal microscopy assay. We then determine the effect S100A4 sliencing on tumor growth, lung metastasis development in vivo. Immunohistochemistry was used to detected the expression of S100A4, bcl-2, MMP-2, p65 and CD31. S100A4 silencing in ACHN cells by RNA interference significantly inhibited NF-kB and NF-kB-mediated MMP-2 and bcl-2 activation and cellular migration, proliferation, and promoted apoptosis. Furthermore, re-expression of S100A4 in S100A4-siRNA-transfected ACHN cells by transient S100A4 cDNA transfection restored the NF-kB and NF-kB-mediated MMP-2 and bcl-2 activation and their high migratory and cellular proliferative ability. An inhibitor ABT-737 (the Bcl-2 antagonist targets Bcl-2) against Bcl-2 suppressed cellular proliferation and promoted apoptosis induced by S100A4 re-expression in S100A4-siRNA-transfected ACHN cells. A inhibitor BB94 against MMPs to neutralize MMP-2 protein suppressed cellular invasion and migration induced by S100A4 re-expression in S100A4-siRNA-transfected ACHN cells. In the prevention model, S100A4 silencing inhibited primary tumor growth by (tumor weight) (76 ± 8%) and (tumor volum) (78 ± 4%) respectively and promoted apoptosis and the formation

  11. Vitamin K2 and cotylenin A synergistically induce monocytic differentiation and growth arrest along with the suppression of c-MYC expression and induction of cyclin G2 expression in human leukemia HL-60 cells.

    Science.gov (United States)

    Maniwa, Yasuhisa; Kasukabe, Takashi; Kumakura, Shunichi

    2015-08-01

    Although all-trans retinoic acid (ATRA) is a standard and effective drug used for differentiation therapy in acute promyelocytic leukemia, ATRA-resistant leukemia cells ultimately emerge during this treatment. Therefore, the development of new drugs or effective combination therapy is urgently needed. We demonstrate that the combined treatment of vitamin K2 and cotylenin A synergistically induced monocytic differentiation in HL-60 cells. This combined treatment also synergistically induced NBT-reducing activity and non-specific esterase-positive cells as well as morphological changes to monocyte/macrophage-like cells. Vitamin K2 and cotylenin A cooperatively inhibited the proliferation of HL-60 cells in short-term and long-term cultures. This treatment also induced growth arrest at the G1 phase. Although 5 µg/ml cotylenin A or 5 µM vitamin K2 alone reduced c-MYC gene expression in HL-60 cells to approximately 45% or 80% that of control cells, respectively, the combined treatment almost completely suppressed c-MYC gene expression. We also demonstrated that the combined treatment of vitamin K2 and cotylenin A synergistically induced the expression of cyclin G2, which had a positive effect on the promotion and maintenance of cell cycle arrest. These results suggest that the combination of vitamin K2 and cotylenin A has therapeutic value in the treatment of acute myeloid leukemia.

  12. Anti-progestins suppress the growth of established tumors induced by 7,12-dimethylbenz(a)anthracene: comparison between RU486 and a new 21-substituted-19-nor-progestin.

    Science.gov (United States)

    Wiehle, Ronald D; Christov, Konstantin; Mehta, Rajendra

    2007-07-01

    In this report, we evaluate the effects of a 21-substituted-19-nor-progestin, CDB-4124, on 7,12,-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in rats in comparison with RU486. Sprague-Dawley female rats were treated with DMBA at 50 days of age in order to induce mammary tumors. When the tumors reached the size of 10-12 mm, the animals were treated for 28 days with the vehicle, RU486, progesterone, CDB-4124 at various doses, or CDB-4124 plus progesterone. Anti-progestins resulted in the regression in the size of the existing tumors, and in the suppressed development of new tumors and tumor multiplicity. Progesterone treatment, however, increased the size and multiplicity. Progesterone rendered an increased number of growing tumors as compared to the regression in the anti-progesterone treatment groups. The combination of CDB-4124 and high doses of progesterone opposed the efficacy of CDB-4124. The growth inhibitory effects of the anti-progestins were correlated with increased apoptosis and reduced cell proliferation. These results indicate that anti-progestins should be developed for the chemoprevention and treatment of hormone-responsive breast cancer.

  13. Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial.

    LENUS (Irish Health Repository)

    Lobo, Melvin D

    2015-01-22

    Hypertension contributes to cardiovascular morbidity and mortality. We assessed the safety and efficacy of a central iliac arteriovenous anastomosis to alter the mechanical arterial properties and reduce blood pressure in patients with uncontrolled hypertension.

  14. The Role of Salivary Gland Scintigraphy in the Evaluation of Salivary Gland Dysfunction in Uncontrolled Type II Diabetic Patients

    OpenAIRE

    Senthilkumar, B.; Sathasivasubramanian, S.

    2013-01-01

    The aim of the present study was to evaluate the salivary gland dysfunction in patients with uncontrolled type II diabetes using salivary gland scintigraphy and then to compare these ratios with quantitative whole salivary secretion rates. Using a gamma camera (siemens-diacam) equipped with a low energy all-purpose collimator, 32 uncontrolled type II diabetic patients and 30 normal healthy patients were studied by injecting a radio isotope (technetium 99m pertechnetate) about 5 mCi was inject...

  15. Uncontrolled hypertension secondary to leukemic cell infiltration of kidneys in a hemodialysis patient

    Directory of Open Access Journals (Sweden)

    Kultigin Turkmen

    2010-06-01

    Full Text Available Kultigin Turkmen1, Lutfullah Altintepe2, Ibrahim Guney2, Ismet Aydogdu3, Osman Koc4, Mehmet Ali Erkut5, Halil Zeki Tonbul11Department of Nephrology, Meram School of Medicine, Selcuk University, 2Meram Training and Research Hospital, Selcuk University, 3Department of Hematology, Meram School of Medicine, Selcuk University, 4Department of Radiology, Meram School of Medicine, Selcuk University, 5Department of Hematology, Meram Training and Research Hospital, Selcuk UniversityAbstract: Leukemic infiltration of the kidney is usually silent, and the admission of the patients with renal dysfunction or acute kidney injury is uncommon. We present a 34-year old hemodialysis patient with new onset of uncontrolled hypertension, erythropoietin-resistant anemia, thrombocytopenia, and Bell’s palsy. On admission, his blood pressure (BP was 210/110 mmHg and he had petechiae and purpura at upper and lower extremities. Renal ultrasonography (USG showed bilaterally enlarged kidneys without hydronephrosis, unlike his previous USG, which determined bilaterally atrophic kidneys. Acute lymphoblastic leukemia, hypertensive crisis due to bilateral leukemic cell infiltration of kidneys, tumor lysis syndrome, and leukemic involvement of the facial nerve were diagnosed. Despite intense antihypertensive management, his BP was not controlled. After prednisolone, daunorubicine, and vincristine therapy, the size of kidneys diminished and his BP dropped under normal range. In conclusion, pathological findings such as uncontrolled hypertension, flank pain, skin rashes, and abnormal blood count should be considered carefully, even in patients with end-stage renal disease receiving renal replacement therapy.Keywords: leukemic cell infiltration, uncontrolled hypertension, hemodialysis

  16. Prevalence of Recommendations Made Within Dental Research Articles Using Uncontrolled Intervention or Observational Study Designs.

    Science.gov (United States)

    Wilson, M K; Chestnutt, I G

    2016-03-01

    Evidence to inform clinical practice is reliant on research carried out using appropriate study design. The objectives of this work were to (i) identify the prevalence of articles reporting on human studies using uncontrolled intervention or observational research designs published in peer-reviewed dental journals and (ii) determine the nature of recommendations made by these articles. Six peer-reviewed dental journals were selected. Issues published in January to June 2013 were examined and the types of articles published categorized. Following pre-defined inclusion/exclusion criteria, human studies classified as using uncontrolled intervention or observational research designs were subject to detailed review by two independent investigators, to examine if they presented clinical, policy or research recommendations and if these recommendations were supported by the data presented. 52.9% (n = 156) of studies published during the time period met the inclusion criteria. Studies with uncontrolled intervention or observational research designs comprised a larger proportion of the primary research studies published in the journals with lower impact factors (73.3%; n = 107) compared to the high impact journals (38.9%; n = 49). Analysis showed that 60.9% (n = 95) of the included studies made recommendations for clinical practice/dental policy. In 28.2% (n = 44) of studies, the clinical/policy recommendations made were judged to not be fully supported by the data presented. Many studies published in the current dental literature, which are not considered to produce strong evidence, make recommendations for clinical practice or policy. There were some cases when the recommendations were not fully supported by the data presented. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Molecular characterization of transforming growth factor-beta3

    NARCIS (Netherlands)

    Dijke, ten P.

    1991-01-01

    Normal tissue homeostasis is controlled by a critical balance of positive and negative modulators. Chapter 2 gives an overview of the molecular aspects of growth control, in particular the role of growth factors and oncogene and anti-oncogene products. Uncontrolled growth of cancer cells

  18. Mobile robot multi-sensor unit for unsupervised gas discrimination in uncontrolled environments

    OpenAIRE

    Xing, Yuxin; Vincent, Timothy A.; Cole, Marina; Gardner, Julian W.; Fan, Han; Hernandez Bennetts, Victor; Schaffernicht, Erik; Lilienthal, Achim

    2017-01-01

    In this work we present a novel multi-sensor unit to detect and discriminate unknown gases in uncontrolled environments. The unit includes three metal oxide (MOX) sensors with CMOS micro heaters, a plasmonic enhanced non-dispersive infra-red (NDIR) sensor, a commercial temperature humidity sensor, and a flow sensor. The proposed sensing unit was evaluated with plumes of gases (propanol, ethanol and acetone) in both, a laboratory setup on a gas testing bench and on-board a mobile robot operati...

  19. Causal Analysis of The Uncontrolled Moderator In The HFEF Main Cell

    Energy Technology Data Exchange (ETDEWEB)

    Posegate, Charles R. [Idaho National Lab. (INL), Idaho Falls, ID (United States); Crofts, Bryan P. [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2012-12-01

    On 11/07/2012 while investigating the cause of defects in neutron radiography film at HFEF, oil was discovered near the elevator shaft located at the 4M location within the Main Cell. Subsequent investigation identified oil (untracked moderator) in several locations ofthe HFEF Main Cell. Initial analysis determined that oil leaking from a 1M shielding window had leaked past a compensatory containment system resulting in a thin layer of oil found in several locations on the main cell floor. The result of this condition is uncontrolled moderator in moderator controlled zones, which is a violation of Criticality Hazard Control Statements (CHCS) for HFEF.

  20. Data on the oral CRTh2 antagonist QAW039 (fevipiprant in patients with uncontrolled allergic asthma

    Directory of Open Access Journals (Sweden)

    Veit J. Erpenbeck

    2016-12-01

    Full Text Available This article contains data on clinical endpoints (Peak Flow Expiratory Rate, fractional exhaled nitric oxide and total IgE serum levels and plasma pharmacokinetic parameters concerning the use of the oral CRTh2 antagonist QAW039 (fevipiprant in mild to moderate asthma patients. Information on experimental design and methods on how this data was obtained is also described. Further interpretation and discussion of this data can be found in the article “The oral CRTh2 antagonist QAW039 (fevipiprant: a phase II study in uncontrolled allergic asthma” (Erpenbeck et al., in press [1].

  1. Evidence of Human Health Impacts from Uncontrolled Coal Fires in Jharia, India

    Science.gov (United States)

    Dhar, U.; Balogun, A. H.; Finkelman, R.; Chakraborty, S.; Olanipekun, O.; Shaikh, W. A.

    2017-12-01

    Uncontrolled coal fires and burning coal waste piles have been reported from dozens of countries. These fires can be caused by spontaneous combustion, sparks from machinery, lightning strikes, grass or forest fires, or intentionally. Both underground and surface coal fires mobilize potentially toxic elements such as sulfur, arsenic, selenium, fluorine, lead, and mercury as well as dangerous organic compounds such as benzene, toluene, xylene, ethylbenzene and deadly gases such as CO2 and CO. Despite the serious health problems that can be caused by uncontrolled coal fires it is rather surprising that there has been so little research and documentation of their health impacts. Underground coal fires in the Jharia region of India where more than a million people reside, have been burning for 100 years. Numerous villages exist above the underground fires exposing the residents daily to dangerous emissions. Local residents near the fire affected areas do their daily chores without concern about the intensity of nearby fires. During winter children enjoy the heat of the coal fires oblivious to the potentially harmful emissions. To determine if these uncontrolled coal fires have caused health problems we developed a brief questionnaire on general health indices and administered it to residents of the Jharia region. Sixty responses were obtained from residents of two villages, one proximal to the coal fires and one about 5 miles away from the fires. The responses were statistically analyzed using SAS 9.4. It was observed that at a significance level of 5%, villagers who lived more than 5 miles away from the fires had a 98.3% decreased odds of having undesirable health outcomes. This brief survey indicates the risk posed by underground coal fires and how it contributes to the undesirable health impacts. What remains is to determine the specific health issues, what components of the emissions cause the health problems, and what can be done to minimize these problems

  2. Complete suppression of viral gene expression is associated with the onset and progression of lymphoid malignancy: observations in Bovine Leukemia Virus-infected sheep

    Directory of Open Access Journals (Sweden)

    Burny Arsène

    2007-07-01

    Full Text Available Abstract Background During malignant progression, tumor cells need to acquire novel characteristics that lead to uncontrolled growth and reduced immunogenicity. In the Bovine Leukemia Virus-induced ovine leukemia model, silencing of viral gene expression has been proposed as a mechanism leading to immune evasion. However, whether proviral expression in tumors is completely suppressed in vivo was not conclusively demonstrated. Therefore, we studied viral expression in two selected experimentally-infected sheep, the virus or the disease of which had features that made it possible to distinguish tumor cells from their nontransformed counterparts. Results In the first animal, we observed the emergence of a genetically modified provirus simultaneously with leukemia onset. We found a Tax-mutated (TaxK303 replication-deficient provirus in the malignant B-cell clone while functional provirus (TaxE303 had been consistently monitored over the 17-month aleukemic period. In the second case, both non-transformed and transformed BLV-infected cells were present at the same time, but at distinct sites. While there was potentially-active provirus in the non-leukemic blood B-cell population, as demonstrated by ex-vivo culture and injection into naïve sheep, virus expression was completely suppressed in the malignant B-cells isolated from the lymphoid tumors despite the absence of genetic alterations in the proviral genome. These observations suggest that silencing of viral genes, including the oncoprotein Tax, is associated with tumor onset. Conclusion Our findings suggest that silencing is critical for tumor progression and identify two distinct mechanisms-genetic and epigenetic-involved in the complete suppression of virus and Tax expression. We demonstrate that, in contrast to systems that require sustained oncogene expression, the major viral transforming protein Tax can be turned-off without reversing the transformed phenotype. We propose that suppression

  3. Deconstructing continuous flash suppression.

    Science.gov (United States)

    Yang, Eunice; Blake, Randolph

    2012-03-08

    In this paper, we asked to what extent the depth of interocular suppression engendered by continuous flash suppression (CFS) varies depending on spatiotemporal properties of the suppressed stimulus and CFS suppressor. An answer to this question could have implications for interpreting the results in which CFS influences the processing of different categories of stimuli to different extents. In a series of experiments, we measured the selectivity and depth of suppression (i.e., elevation in contrast detection thresholds) as a function of the visual features of the stimulus being suppressed and the stimulus evoking suppression, namely, the popular "Mondrian" CFS stimulus (N. Tsuchiya & C. Koch, 2005). First, we found that CFS differentially suppresses the spatial components of the suppressed stimulus: Observers' sensitivity for stimuli of relatively low spatial frequency or cardinally oriented features was more strongly impaired in comparison to high spatial frequency or obliquely oriented stimuli. Second, we discovered that this feature-selective bias primarily arises from the spatiotemporal structure of the CFS stimulus, particularly within information residing in the low spatial frequency range and within the smooth rather than abrupt luminance changes over time. These results imply that this CFS stimulus operates by selectively attenuating certain classes of low-level signals while leaving others to be potentially encoded during suppression. These findings underscore the importance of considering the contribution of low-level features in stimulus-driven effects that are reported under CFS.

  4. Attenuation of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation.

    Directory of Open Access Journals (Sweden)

    Chi Zhang

    Full Text Available BACKGROUND: Lipotoxicity is a key feature of the pathogenesis of diabetic kidney disease, and is attributed to excessive lipid accumulation (hyperlipidemia. Increasing evidence suggests that fibroblast growth factor (FGF21 has a crucial role in lipid metabolism under diabetic conditions. OBJECTIVE: The present study investigated whether FGF21 can prevent hyperlipidemia- or diabetes-induced renal damage, and if so, the possible mechanism. METHODS: Mice were injected with free fatty acids (FFAs, 10 mg/10 g body weight or streptozotocin (150 mg/kg to establish a lipotoxic model or type 1 diabetic model, respectively. Simultaneously the mice were treated with FGF21 (100 µg/kg for 10 or 80 days. The kidney weight-to-tibia length ratio and renal function were assessed. Systematic and renal lipid levels were detected by ELISA and Oil Red O staining. Renal apoptosis was examined by TUNEL assay. Inflammation, oxidative stress, and fibrosis were assessed by Western blot. RESULTS: Acute FFA administration and chronic diabetes were associated with lower kidney-to-tibia length ratio, higher lipid levels, severe renal apoptosis and renal dysfunction. Obvious inflammation, oxidative stress and fibrosis also observed in the kidney of both mice models. Deletion of the fgf21 gene further enhanced the above pathological changes, which were significantly prevented by administration of exogenous FGF21. CONCLUSION: These results suggest that FFA administration and diabetes induced renal damage, which was further enhanced in FGF21 knock-out mice. Administration of FGF21 significantly prevented both FFA- and diabetes-induced renal damage partially by decreasing renal lipid accumulation and suppressing inflammation, oxidative stress, and fibrosis.

  5. Kaempferol Suppresses Transforming Growth Factor-β1-Induced Epithelial-to-Mesenchymal Transition and Migration of A549 Lung Cancer Cells by Inhibiting Akt1-Mediated Phosphorylation of Smad3 at Threonine-179.

    Science.gov (United States)

    Jo, Eunji; Park, Seong Ji; Choi, Yu Sun; Jeon, Woo-Kwang; Kim, Byung-Chul

    2015-07-01

    Kaempferol, a natural dietary flavonoid, is well known to possess chemopreventive and therapeutic anticancer efficacy; however, its antimetastatic effects have not been mechanistically studied so far in any cancer model. This study was aimed to investigate the inhibitory effect and accompanying mechanisms of kaempferol on epithelial-to-mesenchymal transition (EMT) and cell migration induced by transforming growth factor-β1 (TGF-β1). In human A549 non-small lung cancer cells, kaempferol strongly blocked the enhancement of cell migration by TGF-β1-induced EMT through recovering the loss of E-cadherin and suppressing the induction of mesenchymal markers as well as the upregulation of TGF-β1-mediated matrix metalloproteinase-2 activity. Interestingly, kaempferol reversed TGF-β1-mediated Snail induction and E-cadherin repression by weakening Smad3 binding to the Snail promoter without affecting its C-terminus phosphorylation, complex formation with Smad4, and nuclear translocation under TGF-β1 stimulation. Mechanism study revealed that the phosphorylation of Smad3 linker region induced by TGF-β1 was required for the induction of EMT and cell migration, and selective downregulation of the phosphorylation of Smad3 at Thr179 residue (not Ser204, Ser208, and Ser213) in the linker region was responsible for the inhibition by kaempferol of TGF-β1-induced EMT and cell migration. Furthermore, Akt1 was required for TGF-β1-mediated induction of EMT and cell migration and directly phosphorylated Smad3 at Thr179, and kaempferol completely abolished TGF-β1-induced Akt1 phosphorylation. In summary, kaempferol blocks TGF-β1-induced EMT and migration of lung cancer cells by inhibiting Akt1-mediated phosphorylation of Smad3 at Thr179 residue, providing the first evidence of a molecular mechanism for the anticancer effect of kaempferol. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  6. A smart pH-responsive nano-carrier as a drug delivery system for the targeted delivery of ursolic acid: suppresses cancer growth and metastasis by modulating P53/MMP-9/PTEN/CD44 mediated multiple signaling pathways.

    Science.gov (United States)

    Jiang, Kai; Chi, Ting; Li, Tao; Zheng, Guirong; Fan, Lulu; Liu, Yajun; Chen, Xiufen; Chen, Sijia; Jia, Lee; Shao, Jingwei

    2017-07-13

    Ursolic acid (UA) has been recently used as a promising anti-tumor and cancer metastatic chemo-preventive agent due to its low toxicity and liver-protecting property. However, the low bioavailability and nonspecific tumor targeting restrict its further clinical application. To address the problem, a silica-based mesoporous nanosphere (MSN) controlled-release drug delivery system (denoted UA@M-CS-FA) was designed and successfully synthesized, and was functionalized with folic acid (FA) and pH-sensitive chitosan (CS) for the targeted delivery of UA to folate receptor (FR) positive tumor cells. UA@M-CS-FA were spherical with mean diameter below 150 nm, and showed about -20 mV potential. Meanwhile, UA@M-CS-FA exhibited a pH-sensitive release manner and high cellular uptake in FR over-expressing HeLa cancer cells. Also, in vitro cellular assays suggested that UA@M-CS-FA inhibited cancer cell growth, invasion and migration. Mechanistically, UA@M-CS-FA induced cancer cell apoptosis and inhibited migration via cell cycle arrest in the G0/G1 stage, regulating the PARP/Bcl-2/MMP-9/CD44/PTEN/P53. Importantly, in vivo experiments further confirmed that UA@M-CS-FA significantly suppressed the tumor progression and lung metastasis in tumor-bearing nude mice. Immunohistochemical analysis revealed that UA@M-CS-FA treatment regulated CD44, a biomarker of cancer metastasis. Overall, our data demonstrated that a CS and FA modified MSN controlled-release drug delivery system could help broaden the usage of UA and reflect the great application potential of the UA as an anticancer or cancer metastatic chemopreventive agent.

  7. Kaempferol Suppresses Transforming Growth Factor-β1–Induced Epithelial-to-Mesenchymal Transition and Migration of A549 Lung Cancer Cells by Inhibiting Akt1-Mediated Phosphorylation of Smad3 at Threonine-1791

    Science.gov (United States)

    Jo, Eunji; Park, Seong Ji; Choi, Yu Sun; Jeon, Woo-Kwang; Kim, Byung-Chul

    2015-01-01

    Kaempferol, a natural dietary flavonoid, is well known to possess chemopreventive and therapeutic anticancer efficacy; however, its antimetastatic effects have not been mechanistically studied so far in any cancer model. This study was aimed to investigate the inhibitory effect and accompanying mechanisms of kaempferol on epithelial-to-mesenchymal transition (EMT) and cell migration induced by transforming growth factor-β1 (TGF-β1). In human A549 non–small lung cancer cells, kaempferol strongly blocked the enhancement of cell migration by TGF-β1–induced EMT through recovering the loss of E-cadherin and suppressing the induction of mesenchymal markers as well as the upregulation of TGF-β1–mediated matrix metalloproteinase-2 activity. Interestingly, kaempferol reversed TGF-β1–mediated Snail induction and E-cadherin repression by weakening Smad3 binding to the Snail promoter without affecting its C-terminus phosphorylation, complex formation with Smad4, and nuclear translocation under TGF-β1 stimulation. Mechanism study revealed that the phosphorylation of Smad3 linker region induced by TGF-β1 was required for the induction of EMT and cell migration, and selective downregulation of the phosphorylation of Smad3 at Thr179 residue (not Ser204, Ser208, and Ser213) in the linker region was responsible for the inhibition by kaempferol of TGF-β1–induced EMT and cell migration. Furthermore, Akt1 was required for TGF-β1–mediated induction of EMT and cell migration and directly phosphorylated Smad3 at Thr179, and kaempferol completely abolished TGF-β1–induced Akt1 phosphorylation. In summary, kaempferol blocks TGF-β1–induced EMT and migration of lung cancer cells by inhibiting Akt1-mediated phosphorylation of Smad3 at Thr179 residue, providing the first evidence of a molecular mechanism for the anticancer effect of kaempferol. PMID:26297431

  8. Suppression of the invasive plant mile-a-minute (Mikania micrantha) by local crop sweet potato (Ipomoea batatas) by means of higher growth rate and competition for soil nutrients.

    Science.gov (United States)

    Shen, Shicai; Xu, Gaofeng; Clements, David Roy; Jin, Guimei; Chen, Aidong; Zhang, Fudou; Kato-Noguchi, Hisashi

    2015-01-28

    There are a variety of ways of increasing crop diversity to increase agricultural sustainability and in turn having a positive influence on nearby natural ecosystems. Competitive crops may provide potent management tools against invasive plants. To elucidate the competitive mechanisms between a sweet potato crop (Ipomoea batatas) and an invasive plant, mile-a-minute (Mikania micrantha), field experiments were carried out in Longchuan County of Yunnan Province, Southwest China, utilizing a de Wit replacement series. The trial incorporated seven ratios of sweet potato and mile-a-minute plants in 25 m(2) plots. In monoculture, the total biomass, biomass of adventitious root, leafstalk length, and leaf area of sweet potato were all higher than those of mile-a-minute, and in mixed culture the plant height, branch, leaf, stem node, adventitious root, flowering and biomass of mile-a-minute were suppressed significantly (P competition was less than interspecific competition. The competitive balance index of sweet potato demonstrated a higher competitive ability than mile-a-minute. Except pH, other soil nutrient contents of initial soil (CK) were significantly higher than those of seven treatments. The concentrations of soil organic matter, total N, total K, available N, available P, available K, exchange Ca, exchange Mg, available Mn, and available B were significantly greater (P competition of sweet potato in the mixture. Evidently sweet potato has a competitive advantage in terms of plant growth characteristics and greater absorption of soil nutrients. Thus, planting sweet potato is a promising technique for reducing infestations of mile-a-minute, providing weed management benefits and economic returns from harvest of sweet potatoes. This study also shows the potential value of replacement control methods which may apply to other crop-weed systems or invaded natural ecosystems.

  9. A Novel Ras Effector Pathway Found to Play Significant Role in Tumor Suppression | Poster

    Science.gov (United States)

    By Nancy Parrish, Staff Writer; photo by Richard Frederickson, Staff Photographer Normal cells have mechanisms to prevent the development of cancer. Among these is a type of tumor suppressor mechanism known as oncogene-induced senescence, or OIS, which halts the uncontrolled growth of cells caused by mutations in oncogenes. The oncogene Ras plays a crucial role in inducing OIS

  10. Temporary balloon occlusion as therapy for uncontrollable arterial hemorrhage in multiply injured patients

    International Nuclear Information System (INIS)

    Rieger, J.; Linsenmaier, U.; Rock, C.; Pfeifer, K.J.; Euler, E.

    1999-01-01

    Purpose: Presentation of temporary balloon occlusion as an interventional radiological method for managing hemorrhage in multiply injured patients with uncontrollable loss of blood. Method: Temporary, non-selective arterial occlusion by introduction of a balloon catheter contralaterally to the source of bleeding has been performed since 1992 on 7 patients with multiple injuries, hemorrhagic shock requiring reanimation, and angiographic demonstration of an arterial hemorrhage in the supply region of the internal iliac artery with complex pelvic fracture. In each case a PTA balloon catheter was introduced transfemorally, non-selectively positioned proximal to the bleeding source, and left in place for 24-48 h under manometric control. Control angiographies were performed prior to catheter removal. Results: The bleeding was stopped immediately in all 7 patients. The hemodynamic stability made transport and thus further surgical management and/or a short-term treatment in the intensive-care station possible. Control angiographies confirmed that the bleeding had stopped in all patients. Conclusions: We recommend temporary balloon occlusion as a rapid and effective method for the management of bleeding in otherwise uncontrollable traumatic hemorrhages in the supply region of the internal iliac artery. (orig.) [de

  11. [Perception of insulin therapy in uncontrolled patients with type 2 diabetes mellitus].

    Science.gov (United States)

    Leyva Jiménez, Rafael; Hernández Zambrano, Gustavo; Ibarra Maldonado, Silvia; Ibarra Ramírez, Carlos Tomás

    2016-10-01

    To determine the perception of insulin therapy by patients with uncontrolled type2 diabetes mellitus, who have been treated with oral hypoglycaemic agents or insulin. Prospective comparative cross-sectional study. Family Medicine Unit No. 53 León, Guanajuato of Mexican Institute of Social Security. Patients between 40 and 80years old with uncontrolled type2 mellitus diabetes, treated with insulin or oral hypoglycaemic agents. Perception was assessed using the insulin treatment appraisal scale (ITAS). The rating of the survey is from 20 to 100 points, as such that when score increases the greater is the negative opinion. A sample of 459 diabetes patients were interviewed and split into 2 groups of patients according to their treatment. The OH group were patients treated with oral hypoglycaemic drugs only (56.9%), and the IN group were patients treated with insulin alone or combined with an oral hypoglycaemic (43.1%). Perception score was significantly higher in OH group (56.95±7.78 versus 49.55±8.89 points) than in the IN group (P1). The perception of insulin therapy was worse in patients treated with only oral hypoglycaemic agents than in patients using insulin. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  12. Intention-Aware Autonomous Driving Decision-Making in an Uncontrolled Intersection

    Directory of Open Access Journals (Sweden)

    Weilong Song

    2016-01-01

    Full Text Available Autonomous vehicles need to perform social accepted behaviors in complex urban scenarios including human-driven vehicles with uncertain intentions. This leads to many difficult decision-making problems, such as deciding a lane change maneuver and generating policies to pass through intersections. In this paper, we propose an intention-aware decision-making algorithm to solve this challenging problem in an uncontrolled intersection scenario. In order to consider uncertain intentions, we first develop a continuous hidden Markov model to predict both the high-level motion intention (e.g., turn right, turn left, and go straight and the low level interaction intentions (e.g., yield status for related vehicles. Then a partially observable Markov decision process (POMDP is built to model the general decision-making framework. Due to the difficulty in solving POMDP, we use proper assumptions and approximations to simplify this problem. A human-like policy generation mechanism is used to generate the possible candidates. Human-driven vehicles’ future motion model is proposed to be applied in state transition process and the intention is updated during each prediction time step. The reward function, which considers the driving safety, traffic laws, time efficiency, and so forth, is designed to calculate the optimal policy. Finally, our method is evaluated in simulation with PreScan software and a driving simulator. The experiments show that our method could lead autonomous vehicle to pass through uncontrolled intersections safely and efficiently.

  13. The medical antigravity suit for management of surgically uncontrollable bleeding associated with abdominal pregnancy.

    Science.gov (United States)

    Sandberg, E C; Pelligra, R

    1983-07-01

    Three patients with abdominal pregnancy have been treated at Stanford University Hospital in recent years. Common to each was surgically uncontrolled hemorrhage for which circumferential pneumatic compression (supplied by a medical antigravity suit) was used to stop the bleeding. In each patient, the hemostatic effect of treatment was dramatic. In published accounts of the use of the garment in other severely hemorrhaging patients, the effects have been similarly dramatic and equally successful. These observations lead to a compelling consideration in regard to optimum management of patients with abdominal pregnancy. If our experience is confirmed by others, optimum management in abdominal pregnancy hereafter should regularly and routinely include removal of the placenta at the primary operation. This approach would anticipate use of the medical antigravity suit to provide hemostasis if surgically uncontrollable bleeding is encountered. Theoretically, the complications and long-term morbidity associated with retention of the placenta would be eliminated by this means while the previous disadvantage of placental removal, the potential for exsanguinating hemorrhage, would be circumvented.

  14. Planning for the closure of uncontrolled landfills in Turkey to reduce environmental impacts.

    Science.gov (United States)

    Ergene Şentürk, Didar; Alp, Emre

    2016-11-01

    Landfilling is the most preferred solid waste disposal method in Turkey owing to both economic and technical reasons. However, beside the sanitary landfills there are also hundreds of uncontrolled waste sites located throughout Turkey, which are often left either abandoned or burning. Because there is a lack of legislative guidelines governing the closure and rehabilitation of these dumpsites, the municipalities that are responsible for waste management do not initiate the proactive strategies required for the closure of these sites. In this study, a method based on a multi-criteria analysis is conducted for different dumpsites in Turkey to evaluate the level of negative impacts on the environment. This method is based on the use of environmental indices for a quantitative assessment of the landfills, such as environmental interaction between the source and the receptors, environmental values of the receptors, and operational conditions. It was possible to assess the robustness of the proposed methodology since the pre- and post-groundwater quality monitoring data was available from the study sites that were closed and rehabilitated in 2014. The results of this study show that the method based on a multi-criteria analysis is an effective tool while in the preliminary planning stages of closure and rehabilitation activities of uncontrolled waste landfills. © The Author(s) 2016.

  15. Patient Perspectives on Quality of Life With Uncontrolled Type 1 Diabetes Mellitus: A Systematic Review and Qualitative Meta-synthesis.

    Science.gov (United States)

    Vanstone, Meredith; Rewegan, Alex; Brundisini, Francesca; Dejean, Deirdre; Giacomini, Mita

    2015-01-01

    Patients with uncontrolled type 1 diabetes mellitus may be candidates for pancreatic islet cell transplantation. This report synthesizes qualitative research on how patients with uncontrolled type 1 diabetes perceive their quality of life. The objective of this analysis was to examine the perceptions of patients with uncontrolled type 1 diabetes on how it affects their lived experience and quality of life. This report synthesizes 31 primary qualitative studies to examine quality of life from the perspectives of adult patients with type 1 diabetes mellitus and their families or partners. We performed a qualitative meta-synthesis to integrate findings across primary research studies. Long- and short-term negative consequences of uncontrolled type 1 diabetes affect all aspects of patients' lives: physical, emotional, practical, and social. The effect on each domain is far-reaching, and effects interact across domains. Uncontrolled blood sugar levels lead to substantial psychological distress, negative moods, cognitive difficulties, irritable or aggressive behaviour, and closely associated problems with relationships, self-image, and confidence. Emotional distress is pervasive and under-addressed by health care providers. Patients live in fear of complications from diabetes over the long term. In the shorter term, they are anxious about the personal, social, and professional consequences of hypoglycemic episodes (e.g., injury, humiliation), and may curtail normal activities such as driving or socializing because they are worried about having an episode. The quality of life for patients' family members is also negatively impacted by uncontrolled type 1 diabetes. Uncontrolled type 1 diabetes has significant negative impacts on the quality of life of both people with the disease and their families.

  16. Uncontrolled Hypertension and Its Determinants in Patients with Concomitant Type 2 Diabetes Mellitus (T2DM in Rural South Africa.

    Directory of Open Access Journals (Sweden)

    Oladele Vincent Adeniyi

    Full Text Available Paucity of data on the prevalence, treatment and control of hypertension in individuals living with type 2 diabetes mellitus (T2DM in the rural communities of South Africa may undermine efforts to reduce the morbidity and mortality associated with cardiovascular diseases. This study examines the socio-demographic and clinical determinants of uncontrolled hypertension among individuals living with T2DM in the rural communities of Mthatha, South Africa.This cross-sectional study involved a serially selected sample of 265 individuals living with T2DM and hypertension at Mthatha General Hospital, Mthatha. Uncontrolled hypertension was defined as systolic blood pressure greater than or equal to 140 mmHg and diastolic blood pressure greater than or equal to 90mmHg in accordance with the Eight Joint National Committee Report (JNC 8 (2014. We performed univariate and multivariate logistic regression analyses to identify the significant determinants of uncontrolled hypertension.Of the total participants (n = 265, the prevalence of uncontrolled hypertension was 75.5% (n = 200. In univariate analysis of all participants, male gender (p = 0.029, age≥65 years (p = 0.016, unemployed status (p<0.0001, excessive alcohol intake (p = 0.005 and consumption of western-type diet (p<0.0001 were positively associated with uncontrolled hypertension. In multivariate logistic regression (LR method analysis, unemployed status (p<0.0001, excessive alcohol intake (p = 0.007 and consumption of western-type diet (p<0.0001 were independently and significantly associated with uncontrolled hypertension. There is significant association between increasing number and classes of anti-hypertensive drugs and uncontrolled hypertension (p = 0.05 and 0.02, respectively.Prevalence of uncontrolled hypertension was high in individuals with concomitant hypertension and T2DM in the study population. Male sex, aging, clinic inertia, unemployed status and nutritional transitions are the most

  17. Glycated hemoglobin correlates with arterial stiffness and endothelial dysfunction in patients with resistant hypertension and uncontrolled diabetes mellitus.

    Science.gov (United States)

    Moreno, Beatriz; de Faria, Ana Paula; Ritter, Alessandra Mileni Versuti; Yugar, Lara Buonalumi Tacito; Ferreira-Melo, Silvia Elaine; Amorim, Rivadavio; Modolo, Rodrigo; Fattori, André; Yugar-Toledo, Juan Carlos; Coca, Antonio; Moreno, Heitor

    2018-05-01

    This study aimed to evaluate the effects of glycated hemoglobin (HbA 1c ) on flow-mediated dilation, intima-media thickness, pulse wave velocity, and left ventricular mass index in patients with resistant hypertension (RHTN) comparing RHTN-controlled diabetes mellitus and RHTN-uncontrolled type 2 diabetes mellitus. Two groups were formed: HbA 1c diabetes mellitus: n = 98) and HbA 1c ≥7.0% (RHTN-uncontrolled diabetes mellitus: n = 122). Intima-media thickness and flow-mediated dilation were measured by high-resolution ultrasound, left ventricular mass index by echocardiography, and arterial stiffness by carotid-femoral pulse wave velocity. No differences in blood pressure levels were found between the groups but body mass index was higher in patients with RHTN-uncontrolled diabetes mellitus. Endothelial dysfunction and arterial stiffness were worse in patients with RHTN-uncontrolled diabetes mellitus. Intima-media thickness and left ventricular mass index measurements were similar between the groups. After adjustments, multiple linear regression analyses showed that HbA 1c was an independent predictor of flow-mediated dilation and pulse wave velocity in all patients with RHTN. In conclusion, HbA 1c may predict the grade of arterial stiffness and endothelial dysfunction in patients with RHTN, and superimposed uncontrolled diabetes mellitus implicates further impairment of vascular function. ©2018 Wiley Periodicals, Inc.

  18. Emotional and uncontrolled eating styles and chocolate chip cookie consumption. A controlled trial of the effects of positive mood enhancement.

    Science.gov (United States)

    Turner, Sally Ann; Luszczynska, Aleksandra; Warner, Lisa; Schwarzer, Ralf

    2010-02-01

    The study tested the effects of positive mood enhancement on chocolate chip cookie consumption in the context of emotional and uncontrolled eating styles. The relationship between emotional eating style and chocolate chip cookie intake was assumed to be mediated by uncontrolled eating style. Further, it was hypothesized that the effectiveness of the positive mood enhancement may be more salient among those who have effective control of their eating. In this experimental study, respondents (N=106, 70% women, aged 16-45 years old) were assigned by means of cluster randomization to the control or positive mood enhancement condition (a comedy movie clip). Compared to the control condition, positive mood enhancement resulted in consuming on average 53.86 kcal less. Relationships between emotional eating style and cookie intake were mediated by uncontrolled eating. Moderated mediation analysis indicated that the effect of a mediator (uncontrolled eating) on cookie intake was moderated by the group assignment. Positive mood enhancement resulted in eating on average 3.3 cookies less among individuals with a more controlled eating style. By contrast, among those who presented uncontrolled eating, positive mood enhancement led to consuming an average of 1.7 cookies more. 2009 Elsevier Ltd. All rights reserved.

  19. Real-life efficacy and safety of omalizumab in Portuguese patients with persistent uncontrolled asthma.

    Science.gov (United States)

    Pereira Barbosa, M; Bugalho de Almeida, A; Pereira, C; Chen, C-W; Georgiou, P; Peachey, G