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  1. ZLM-7 exhibits anti-angiogenic effects via impaired endothelial cell function and blockade of VEGF/VEGFR-2 signaling.

    PubMed

    Su, Min; Huang, Jingjia; Li, Jijia; Qin, Xiyuan; Tang, Xiaoning; Jin, Fang; Chen, Shali; Jiang, Chuanming; Zou, Zizheng; Peng, Kunjian; Nuruzzaman, Mohammed; Zhang, Jianting; Luo, Junli; Liu, Suyou; Luo, Zhiyong

    2016-04-05

    Inhibition of angiogenesis is a promising therapeutic strategy against cancer. In this study, we reported that ZLM-7, a combretastain A-4 (CA-4) derivative, exhibited anti-angiogenic activity in vitro and in vivo. In vitro, ZLM-7 induced microtubule cytoskeletal disassembly. It decreased VEGF-induced proliferation, migration, invasion and tube formation in endothelial cells, which are critical steps in angiogenesis. In vivo, ZLM-7 significantly inhibited neovascularization in a chicken chorioallantoic membrane (CAM) model and reduced the microvessel density in tumor tissues of MCF-7 xenograft mouse model. ZLM-7 also displayed comparable antiangiogenic and anti-tumor activities associated with the lead compound CA-4, but exhibited lower toxicity compared with CA-4. The anti-angiogenic effect of ZLM-7 was exerted via blockade of VEGF/VEGFR-2 signaling. ZLM-7 treatment suppressed the expression and secretion of VEGF in endothelial cells and MCF-7 cells under hypoxia. Further, ZLM-7 suppressed the VEGF-induced phosphorylation of VEGFR-2 and its downstream signaling mediators including activated AKT, MEK and ERK in endothelial cells. Overall, these results demonstrate that ZLM-7 exhibits anti-angiogenic activities by impairing endothelial cell function and blocking VEGF/VEGFR-2 signaling, suggesting that ZLM-7 might be a potential angiogenesis inhibitor.

  2. Effects of NVP-BEZ235 on the proliferation, migration, apoptosis and autophagy in HT-29 human colorectal adenocarcinoma cells.

    PubMed

    Yu, Yang; Yu, Xiaofeng; Ma, Jianxia; Tong, Yili; Yao, Jianfeng

    2016-07-01

    The phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of the rapamycin (mTOR) pathway plays a significant role in colorectal adenocarcinoma. NVP-BEZ235 (dactolisib) is a novel dual inhibitor of PI3K/mTOR. The effects of NVP-BEZ235 in human colorectal adenocarcinoma are still unclear. In the present study, we aimed to explore the proliferation, migration, apoptosis and autophagy in HT-29 human colorectal adenocarcinoma cells. HT-29 human colorectal adenocarcinoma cells were treated with NVP-BEZ235 (0, 0.001, 0.01, 0.1, 1 and 3 µM) for 24 and 48 h, respectively. Cells were also treated with NVP-BEZ235 (0.1 µM), DDP (100, 300 and 1,000 µM), and NVP-BEZ235 (0.1 µM) combined with DDP (100, 300 and 1,000 µM) respectively, and cultured for 24 h after treatment. MTT assay was utilized to evaluate the effects of NVP-BEZ235 alone or NVP-BEZ235 combined with cis-diamminedichloroplatinum (DDP) on proliferation of HT-29 cells. Cell wound-scratch assay was used detect cell migration. In addition, expression of microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B and LC3B) in HT-29 cells was detected by immunofluorescence at 48 h after NVP-BEZ235 (1 µM) treatment. Expression of proteins involved in cell cycle and proliferation (p-Akt, p-mTOR and cyclin D1), apoptosis (cleaved caspase-3), and autophagy (cleaved LC3B and Beclin-1) were detected by western blot analysis. NVP-BEZ235 inhibited the proliferation and migration of HT-29 human colorectal adenocarcinoma cells. NVP-BEZ235 decreased protein expression of p-Akt, p-mTOR and cyclin D1, and increased protein expression of cleaved caspase-3, cleaved LC3B and Beclin-1 as the concentrations and the incubation time of NVP-BEZ235 increased. In addition, NVP-BEZ235 and DDP had synergic effects in inhibiting cell proliferation and migration. The expression of protein involved in apoptosis (cleaved caspase-3) was higher in drug combination group compared to the NVP-BEZ235 single treatment group. NVP-BEZ235

  3. Combined therapy with RAD001 e BEZ235 overcomes resistance of PET immortalized cell lines to mTOR inhibition.

    PubMed

    Passacantilli, Ilaria; Capurso, Gabriele; Archibugi, Livia; Calabretta, Sara; Caldarola, Sara; Loreni, Fabrizio; Delle Fave, Gianfranco; Sette, Claudio

    2014-07-30

    Pancreatic endocrine tumors (PETs) are characterised by an indolent behaviour in terms of tumor growth. However, most patients display metastasis at diagnosis and no cure is currently available. Since the PI3K/AKT/mTOR axis is deregulated in PETs, the mTOR inhibitor RAD001 represents the first line treatment. Nevertheless, some patients do not respond to treatments and most acquire resistance. Inhibition of mTOR leads to feedback re-activation of PI3K activity, which may promote resistance to RAD001. Thus, PI3K represents a novel potential target for PETs. We tested the impact of three novel PI3K inhibitors (BEZ235, BKM120 and BYL719) on proliferation of PET cells that are responsive (BON-1) or unresponsive (QGP-1) to RAD001. BEZ235 was the most efficient in inhibiting proliferation in PET cells. Furthermore, combined treatment with BEZ235 and RAD001 exhibited synergic effects and was also effective in BON-1 that acquired resistance to RAD001 (BON-1 RR). Analysis of PI3K/AKT/mTOR pathway showed that RAD001 and BEZ235 only partially inhibited mTOR-dependent phosphorylation of 4EBP1. By contrast, combined therapy with the two inhibitors strongly inhibited phosphorylation of 4EBP1, assembly of the translational initiation complex and protein synthesis. Thus, combined treatment with BEZ235 may represent suitable therapy to counteract primary and acquired resistance to RAD001 in PETs.

  4. Combined therapy with RAD001 e BEZ235 overcomes resistance of PET immortalized cell lines to mTOR inhibition

    PubMed Central

    Passacantilli, Ilaria; Capurso, Gabriele; Archibugi, Livia; Calabretta, Sara; Caldarola, Sara; Loreni, Fabrizio; Fave, Gianfranco Delle; Sette, Claudio

    2014-01-01

    Pancreatic endocrine tumors (PETs) are characterised by an indolent behaviour in terms of tumor growth. However, most patients display metastasis at diagnosis and no cure is currently available. Since the PI3K/AKT/mTOR axis is deregulated in PETs, the mTOR inhibitor RAD001 represents the first line treatment. Nevertheless, some patients do not respond to treatments and most acquire resistance. Inhibition of mTOR leads to feedback re-activation of PI3K activity, which may promote resistance to RAD001. Thus, PI3K represents a novel potential target for PETs. We tested the impact of three novel PI3K inhibitors (BEZ235, BKM120 and BYL719) on proliferation of PET cells that are responsive (BON-1) or unresponsive (QGP-1) to RAD001. BEZ235 was the most efficient in inhibiting proliferation in PET cells. Furthermore, combined treatment with BEZ235 and RAD001 exhibited synergic effects and was also effective in BON-1 that acquired resistance to RAD001 (BON-1 RR). Analysis of PI3K/AKT/mTOR pathway showed that RAD001 and BEZ235 only partially inhibited mTOR-dependent phosphorylation of 4EBP1. By contrast, combined therapy with the two inhibitors strongly inhibited phosphorylation of 4EBP1, assembly of the translational initiation complex and protein synthesis. Thus, combined treatment with BEZ235 may represent suitable therapy to counteract primary and acquired resistance to RAD001 in PETs. PMID:25026292

  5. Neuroprotective effects of the anticancer drug NVP-BEZ235 (dactolisib) on amyloid-β 1–42 induced neurotoxicity and memory impairment

    PubMed Central

    Bellozi, Paula Maria Quaglio; Lima, Isabel Vieira de Assis; Dória, Juliana Guimarães; Vieira, Érica Leandro Marciano; Campos, Alline Cristina; Candelario-Jalil, Eduardo; Reis, Helton José; Teixeira, Antônio Lúcio; Ribeiro, Fabíola Mara; de Oliveira, Antônio Carlos Pinheiro

    2016-01-01

    Alzheimer’s Disease (AD) is a progressive neurodegenerative disease and the main cause of dementia. Substantial evidences indicate that there is over-activation of the PI3K/Akt/mTOR axis in AD. Therefore, the aim of the present study was to investigate the effects of NVP-BEZ235 (BEZ; dactolisib), a dual PI3K/mTOR inhibitor that is under phase I/II clinical trials for the treatment of some types of cancer, in hippocampal neuronal cultures stimulated with amyloid-β (Aβ) 1–42 and in mice injected with Aβ 1–42 in the hippocampus. In cell cultures, BEZ reduced neuronal death induced by Aβ. BEZ, but not rapamycin, a mTOR inhibitor, or LY294002, a PI3K inhibitor that also inhibits mTOR, reduced the memory impairment induced by Aβ. The effect induced by Aβ was also prevented in PI3Kγ−/− mice. Neuronal death and microgliosis induced by Aβ were reduced by BEZ. In addition, the compound increased IL-10 and TNF-α levels in the hippocampus. Finally, BEZ did not change the phosphorylation of Akt and p70s6K, suggesting that the involvement of PI3K and mTOR in the effects induced by BEZ remains controversial. Therefore, BEZ represents a potential strategy to prevent the pathological outcomes induced by Aβ and should be investigated in other models of neurodegenerative conditions. PMID:27142962

  6. A Phase II Study of BEZ235 in Patients with Everolimus-resistant, Advanced Pancreatic Neuroendocrine Tumours

    PubMed Central

    FAZIO, NICOLA; BUZZONI, ROBERTO; BAUDIN, ERIC; ANTONUZZO, LORENZO; HUBNER, RICHARD A.; LAHNER, HARALD; DE HERDER, WOUTER W.; RADERER, MARKUS; TEULÉ, ALEXANDRE; CAPDEVILA, JAUME; LIBUTTI, STEVEN K.; KULKE, MATTHEW H.; SHAH, MANISHA; DEY, DEBARSHI; TURRI, SABINE; AIMONE, PAOLA; MASSACESI, CRISTIAN; VERSLYPE, CHRIS

    2016-01-01

    Background This was a two-stage, phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours (pNETs) (NCT01658436). Patients and Methods In stage 1, 11 patients received 400 mg BEZ235 orally twice daily (bid). Due to tolerability concerns, a further 20 patients received BEZ235 300 mg bid. Stage 2 would be triggered by a 16-week progression-free survival (PFS) rate of ≥60% in stage 1. Results As of 30 June, 2014, 29/31 patients had discontinued treatment. Treatment-related grade 3/4 adverse events were reported in eight (72.7%) patients at 400 mg and eight (40.0%) patients at 300 mg, including hyperglycaemia, diarrhoea, nausea, and vomiting. The estimated 16-week PFS rate was 51.6% (90% confidence interval=35.7–67.3%). Conclusion BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses. Although evidence of disease stability was observed, the study did not proceed to stage 2. PMID:26851029

  7. Radiosensitization of Glioblastoma Cell Lines by the Dual PI3K and mTOR Inhibitor NVP-BEZ235 Depends on Drug-Irradiation Schedule12

    PubMed Central

    Kuger, Sebastian; Graus, Dorothea; Brendtke, Rico; Günther, Nadine; Katzer, Astrid; Lutyj, Paul; Polat, Bülent; Chatterjee, Manik; Sukhorukov, Vladimir L; Flentje, Michael; Djuzenova, Cholpon S

    2013-01-01

    Previous studies have shown that the dual phosphatidylinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor NVP-BEZ235 radiosensitizes tumor cells if added shortly before ionizing radiation (IR) and kept in culture medium thereafter. The present study explores the impact of inhibitor and IR schedule on the radiosensitizing ability of NVP-BEZ235 in four human glioblastoma cell lines. Two different drug-IR treatment schedules were compared. In schedule I, cells were treated with NVP-BEZ235 for 24 hours before IR and the drug was removed before IR. In schedule II, the cells were exposed to NVP-BEZ235 1 hour before, during, and up to 48 hours after IR. The cellular response was analyzed by colony counts, expression of marker proteins of the PI3K/AKT/mTOR pathway, cell cycle, and DNA damage. We found that under schedule I, NVP-BEZ235 did not radiosensitize cells, which were mostly arrested in G1 phase during IR exposure. In addition, the drug-pretreated and irradiated cells exhibited less DNA damage but increased expressions of phospho-AKT and phospho-mTOR, compared to controls. In contrast, NVP-BEZ235 strongly enhanced the radiosensitivity of cells treated according to schedule II. Possible reasons of radiosensitization by NVP-BEZ235 under schedule II might be the protracted DNA repair, prolonged G2/M arrest, and, to some extent, apoptosis. In addition, the PI3K pathway was downregulated by the NVP-BEZ235 at the time of irradiation under schedule II, as contrasted with its activation in schedule I. We found that, depending on the drug-IR schedule, the NVP-BEZ235 can act either as a strong radiosensitizer or as a cytostatic agent in glioblastoma cells. PMID:23544169

  8. Dual PI3K/mTOR inhibitor NVP-BEZ235-induced apoptosis of hepatocellular carcinoma cell lines is enhanced by inhibitors of autophagy.

    PubMed

    Chang, Zhexing; Shi, Guang; Jin, Jiqiang; Guo, Huatao; Guo, Xuefeng; Luo, Fangyue; Song, Yuguo; Jia, Xiaojing

    2013-06-01

    Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling has been found in several types of human cancer, including hepatocellular carcinoma (HCC). NVP-BEZ235 is a novel, orally bioavailable dual PI3K/mTOR inhibitor that has exhibited promising activity against HCC in preclinical models. Autophagy is a cellular lysosomal degradation pathway essential for the regulation of cell survival and death to maintain homeostasis. This process is negatively regulated by mTOR signaling and often counteracts the efficacy of certain cancer therapeutic agents. In this study, we explored the role of autophagy in apoptosis induced by NVP-BEZ235 in two HCC cell lines, Hep3B and PLC/PRF/5, and identified the mechanism of combinatorial treatment. NVP-BEZ235 was effective in inhibiting the growth of the two HCC cell lines possibly though induction of apoptosis. NVP-BEZ235 also potently increased the expression of LC3-II and decreased the expression of p62, indicating induction of autophagy. When NVP-BEZ235 was used in combination with Atg5 siRNA or the autophagy inhibitor 3-methyladenine (3-MA), enhancement of the inhibitory effects on the growth of HCC cells was detected. In addition, enhanced induction of apoptosis was observed in cells exposed to the combination of NVP-BEZ235 and Atg5 siRNA or 3-MA. Thus, induction of autophagy by NVP-BEZ235 may be a survival mechanism that counteracts its anticancer effects. Based on these data, we suggest a strategy to enhance the anticancer efficacy of BEZ235 by blockade of autophagy. Thus, our study provides a rationale for the clinical development of combinations of NVP-BEZ235 and autophagy inhibitors for the treatment of HCC and other malignancies.

  9. Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against T-cell acute lymphoblastic leukemia.

    PubMed

    Chiarini, Francesca; Grimaldi, Cecilia; Ricci, Francesca; Tazzari, Pier Luigi; Evangelisti, Camilla; Ognibene, Andrea; Battistelli, Michela; Falcieri, Elisabetta; Melchionda, Fraia; Pession, Andrea; Pagliaro, Pasqualepaolo; McCubrey, James A; Martelli, Alberto M

    2010-10-15

    Recent findings have highlighted that constitutively active phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it upregulates cell proliferation, survival, and drug resistance. These observations lend compelling weight to the application of PI3K/Akt/mTOR inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the novel dual PI3K/mTOR inhibitor NVP-BEZ235, an orally bioavailable imidazoquinoline derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. NVP-BEZ235 was cytotoxic to a panel of T-ALL cell lines as determined by MTT assays. NVP-BEZ235 treatment resulted in cell cycle arrest and apoptosis. Western blots showed a dose- and time-dependent dephosphorylation of Akt and mTORC1 downstream targets in response to NVP-BEZ235. Remarkably, NVP-BEZ235 targeted the side population of both T-ALL cell lines and patient lymphoblasts, which might correspond to leukemia-initiating cells, and synergized with chemotherapeutic agents (cyclophosphamide, cytarabine, dexamethasone) currently used for treating T-ALL patients. NVP-BEZ235 reduced chemoresistance to vincristine induced in Jurkat cells by coculturing with MS-5 stromal cells, which mimic the bone marrow microenvironment. NVP-BEZ235 was cytotoxic to T-ALL patient lymphoblasts displaying pathway activation, where the drug dephosphorylated eukaryotic initiation factor 4E-binding protein 1, at variance with rapamycin. Taken together, our findings indicate that longitudinal inhibition at two nodes of the PI3K/Akt/mTOR network with NVP-BEZ235, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment of those T-ALLs that have aberrant upregulation of this signaling pathway for their proliferation and survival. ©2010 AACR.

  10. Autophagy inhibition enhances colorectal cancer apoptosis induced by dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235

    PubMed Central

    YANG, XIAOYU; NIU, BINGXUAN; WANG, LIBO; CHEN, MEILING; KANG, XIAOCHUN; WANG, LUONAN; JI, YINGHUA; ZHONG, JIATENG

    2016-01-01

    Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway performs a central role in tumorigenesis and is constitutively activated in many malignancies. As a novel dual PI3K/mTOR inhibitor currently undergoing evaluation in a phase I/II clinical trial, NVP-BEZ235 indicates a significant antitumor efficacy in diverse solid tumors, including colorectal cancer (CRC). Autophagy is a catabolic process that maintains cellular homeostasis and reduces diverse stresses through lysosomal recycling of the unnecessary and damaged cell components. This process is also observed to antagonize the antitumor efficacy of PI3K/mTOR inhibitor agents such as NVP-BEZ235, via apoptosis inhibition. In the present study, we investigated anti-proliferative and apoptosis-inducing ability of NVP-BEZ235 in SW480 cells and the crosstalk between autophagy and apoptosis in SW480 cells treated with NVP-BEZ235 in combination with an autophagy inhibitor. The results revealed that, NVP-BEZ235 effectively inhibit the growth of SW480 cells by targeting the PI3K/mTOR signaling pathway and induced apoptosis. The inhibition of autophagy with 3-methyladenine or chloroquine inhibitors in combination with NVP-BEZ235 in SW480 cells enhanced the apoptotic rate as componets to NVP-BEZ235 alone. In conclusion, the findings provide a rationale for chemotherapy targeting the PI3K/mTOR signaling pathway presenting a potential therapeutic strategy to enhance the efficacy of dual PI3K/mTOR inhibitor NVP-BEZ235 in combination with an autophagy inhibitor in CRC treatment and treatment of other tumors. PMID:27347108

  11. Co-treatment with BEZ235 Enhances Sensitivity of BRCA1-negative Breast Cancer Cells to Olaparib.

    PubMed

    Yi, Yong Weon; Park, Jeong-Soo; Kwak, Sahng-June; Seong, Yeon-Sun

    2015-07-01

    The poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib has been reported as having preferential anti-proliferative effects on breast cancer 1 (BRCA1)-deficient breast and ovarian cancer cells and was recently approved by the US Food and Drug Administration (FDA) for advanced, BRCA1-mutated ovarian cancer. Herein, we show that BEZ235, a protein kinase inhibitor, enhanced the tumor cell-killing effect of olaparib in BRCA1-mutated breast cancer cells in vitro. BEZ235 reduced olaparib-induced phosphorylation of p53 binding protein 1 (53BP1) and 53BP1 foci formation, as well as phosphorylation of AKT (S473). Long-term colony-formation assay revealed more strong synergistic effects of this combination in SUM149PT and MDA-MB-468 breast cancer cell lines. BEZ235 treatment combined with olaparib may be a candidate for effective therapeutic treatment of BRCA1-mutated breast cancer. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

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

    SciTech Connect

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

    2009-02-01

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

  13. Dual blockade of PI3K/AKT/mTOR (NVP-BEZ235) and Ras/Raf/MEK (AZD6244) pathways synergistically inhibit growth of primary endometrioid endometrial carcinoma cultures, whereas NVP-BEZ235 reduces tumor growth in the corresponding xenograft models.

    PubMed

    Schrauwen, Stefanie; Depreeuw, Jeroen; Coenegrachts, Lieve; Hermans, Els; Lambrechts, Diether; Amant, Frédéric

    2015-07-01

    Endometrial carcinoma (EC) is the most common gynecological cancer in the Western World. Treatment options are limited for advanced and recurrent disease. Therefore, new treatment options are necessary. Inhibition of the PI3K/AKT/mTOR and/or the Ras/Raf/MEK pathways is suggested to be clinically relevant. However, the knowledge about the effect of combination targeted therapy in EC is limited. The aim of this study was to investigate the effect of these therapies on primary endometrioid EC cell cultures in vitro and in vivo. Primary endometrioid EC cell cultures were incubated with Temsirolimus (mTORC1 inhibitor), NVP-BKM120 (pan-PI3K inhibitor), NVP-BEZ235 (pan-PI3K/mTOR inhibitor), or AZD6244 (MEK1/2 inhibitor) as single treatment. In vitro, the effect of NVP-BEZ235 with or without AZD6244 was determined for cell viability, cell cycle arrest, apoptosis induction, and cell signaling. In vivo, the effect of NVP-BEZ35 was investigated for 2 subcutaneous xenograft models of the corresponding primary cultures. NVP-BEZ235 was the most potent PI3K/AKT/mTOR pathway inhibitor. NVP-BEZ235 and AZD6244 reduced cell viability and induced cell cycle arrest and apoptosis, by reduction of p-AKT, p-S6, and p-ERK levels. Combination treatment showed a synergistic effect. In vivo, NVP-BEZ235 reduced tumor growth and inhibited p-S6 expression. The effects of the compounds were independent of the mutation profile of the cell cultures used. A synergistic antitumor effect was shown for NVP-BEZ235 and AZD6244 in primary endometrioid EC cells in vitro. In addition, NVP-BEZ235 induced reduction of tumor growth in vivo. Therefore, targeted therapies seem an interesting strategy to further evaluate in clinical trials. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Novel PI3K and mTOR Inhibitor NVP-BEZ235 Radiosensitizes Breast Cancer Cell Lines under Normoxic and Hypoxic Conditions

    PubMed Central

    Kuger, Sebastian; Cörek, Emre; Polat, Bülent; Kämmerer, Ulrike; Flentje, Michael; Djuzenova, Cholpon S.

    2014-01-01

    In the present study, we assessed, if the novel dual phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 radiosensitizes triple negative (TN) MDA-MB-231 and estrogen receptor (ER) positive MCF-7 cells to ionizing radiation under various oxygen conditions, simulating different microenvironments as occurring in the majority of breast cancers (BCs). Irradiation (IR) of BC cells cultivated in hypoxic conditions revealed increased radioresistance compared to normoxic controls. Treatment with NVP-BEZ235 completely circumvented this hypoxia-induced effects and radiosensitized normoxic, reoxygenated, and hypoxic cells to similar extents. Furthermore, NVP-BEZ235 treatment suppressed HIF-1α expression and PI3K/mTOR signaling, induced autophagy, and caused protracted DNA damage repair in both cell lines in all tested oxygen conditions. Moreover, after incubation with NVP-BEZ235, MCF-7 cells revealed depletion of phospho-AKT and considerable signs of apoptosis, which were significantly enhanced by radiation. Our findings clearly demonstrate that NVP-BEZ235 has a clinical relevant potential as a radiosensitizer in BC treatment. PMID:24678241

  15. Molecular analysis of a male breast cancer patient with prolonged stable disease under mTOR/PI3K inhibitors BEZ235/everolimus

    PubMed Central

    Brannon, A. Rose; Frizziero, Melissa; Chen, David; Hummel, Jennifer; Gallo, Jorge; Riester, Markus; Patel, Parul; Cheung, Wing; Morrissey, Michael; Carbone, Carmine; Cottini, Silvia; Tortora, Giampaolo; Melisi, Davide

    2016-01-01

    The mTORC1 inhibitor everolimus (Afinitor/RAD001) has been approved for multiple cancer indications, including ER+/HER2− metastatic breast cancer. However, the combination of everolimus with the dual PI3K/mTOR inhibitor BEZ235 was shown to be more efficacious than either everolimus or BEZ235 alone in preclinical models. Herein, we describe a male breast cancer (MBC) patient who was diagnosed with hormone receptor-positive (HR+)/HER2− stage IIIA invasive ductal carcinoma and sequentially treated with chemoradiotherapy and hormonal therapy. Upon the development of metastases, the patient began a 200 mg twice-daily BEZ235 and 2.5 mg weekly everolimus combination regimen. The patient sustained a prolonged stable disease of 18 mo while undergoing the therapy, before his tumor progressed again. Therefore, we sought to both better understand MBC and investigate the underlying molecular mechanisms of the patient's sensitivity and subsequent resistance to the BEZ235/everolimus combination therapy. Genomic and immunohistochemical analyses were performed on samples collected from the initial invasive ductal carcinoma pretreatment and a metastasis postprogression on the BEZ235/everolimus combination treatment. Both tumors were relatively quiet genomically with no overlap to recurrent MBC alterations in the literature. Markers of PI3K/mTOR pathway hyperactivation were not identified in the pretreatment sample, which complements previous reports of HR+ female breast cancers being responsive to mTOR inhibition without this activation. The postprogression sample, however, demonstrated greater than fivefold increased estrogen receptor and pathogenesis-related protein expression, which could have constrained the PI3K/mTOR pathway inhibition by BEZ235/everolimus. Overall, these analyses have augmented the limited episteme on MBC genetics and treatment. PMID:27148582

  16. Superior efficacy of co-treatment with the dual PI3K/mTOR inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A against NSCLC

    PubMed Central

    Quan, Taihao; Li, Longshan; Quan, Chunji; Piao, Yingshi; Jin, Tiefeng; Lin, Zhenhua

    2016-01-01

    Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. NSCLC development and progression have recently been correlated with the heightened activation of histone deacetylases (HDACs) and PI3K/Akt signaling pathways. Targeted inhibition of these proteins is promising approach for the development of novel therapeutic strategies to treat patients with advanced NSCLC. For this reason, we combined a dual PI3K and mTOR inhibitor, BEZ235 with the HDAC inhibitor Trichostatin A (TSA), to determine their combined effects on human NSCLC. In this study, we initially discovered that co-treatment with BEZ235 and TSA showed a synergistic effect on inhibition of NSCLC cell proliferation and induction of apoptosis. The combination treatment also synergistically suppressed NSCLC migration, invasion and the NSCLC epithelial-mesenchymal transition (EMT) in vitro. The synergistic effect was also evidenced by declines in xenograft growth and metastasis rates and in ki-67 protein expression in vivo. Together, these results indicated that BEZ235 and TSA combination treatment significantly increased anti-tumor activities compared with BEZ235 and TSA alone, supporting a further evaluation of combination treatment for NSCLC. PMID:27507059

  17. The PI3K/mTOR dual inhibitor BEZ235 suppresses proliferation and migration and reverses multidrug resistance in acute myeloid leukemia

    PubMed Central

    Deng, Lan; Jiang, Ling; Lin, Xiang-hua; Tseng, Kuo-Fu; Liu, Yuan; Zhang, Xing; Dong, Rui-hong; Lu, Zhi-gang; Wang, Xiu-ju

    2017-01-01

    Aberrant activation of the PI3K/Akt/mTOR pathway contributes to the proliferation of malignant cells, and may confer resistance to chemotherapy in various malignancies, including acute myeloid leukemia (AML). Chemoresistance is the major reason for relapse in AML. RAD001 (everolimus) has been used at d1 and d7 of an induction chemotherapy regimen for AML, which has acceptable toxicity and may improve conventional chemotherapeutic treatment. Dual inhibitors of PI3K and mTOR overcome some of the intrinsic disadvantages of rapamycin and its derivatives. In this study, we evaluated the effects of BEZ235, a PI3K/mTOR dual inhibitor, on the multidrug-resistant AML cell lines HL-60/VCR and K562/ADR in vitro. BEZ235 dose-dependently inhibited the viability of HL-60/VCR and K562/ADR cells with the IC50 values of 66.69 and 71.44 nmol/L, respectively. BEZ235 (25–100 nmol/L) dose-dependently inhibited the migration of the two AML cell lines, and it also significantly sensitized the two AML cell lines to VCR and ADR. After treatment with BEZ235, the miR-1-3p levels were markedly increased in HL-60/VCR cells. Using TargetScan analysis and luciferase assays, we showed that miR-1-3p targeted BAG4, EDN1 and ABCB1, the key regulators of cell apoptosis, migration and multidrug resistance, and significantly decreased their levels in the two AML cell lines. Transfection of HL-60/VCR and K562/ADR cells with miR-1-3p-AMO to inhibit miR-1-3p could reverse the anti-proliferation effects of BEZ235. In conclusion, the PI3K/mTOR dual inhibitor BEZ235 effectively chemosensitizes AML cells via increasing miR-1-3p and subsequently down-regulating BAG4, EDN1 and ABCB1. PMID:28042875

  18. Effects of the mTOR inhibitor everolimus and the PI3K/mTOR inhibitor NVP-BEZ235 in murine acute lung injury models.

    PubMed

    Üstün, Sevdican; Lassnig, Caroline; Preitschopf, Andrea; Mikula, Mario; Müller, Mathias; Hengstschläger, Markus; Weichhart, Thomas

    2015-09-01

    The mammalian target of rapamycin (mTOR) is a key signaling kinase associated with a variety of cellular functions including the regulation of immunological and inflammatory responses. Classic mTOR inhibitors such as rapamycin or everolimus are commonly used in transplant as well as cancer patients to prevent transplant rejection or cancer progression, respectively. Noninfectious drug-induced pneumonitis is a frequent side effect in mTOR-inhibitor-treated patients. Therefore, we tested the effects of the mTOR inhibitor everolimus and the novel dual PI3K/mTOR inhibitor NVP-BEZ235 in a murine lipopolysaccharide (LPS)-induced acute lung injury model. C57BL/6 mice were treated with either everolimus or NVP-BEZ235 on two consecutive days prior to intratracheal administration of LPS. LPS administration induced a significant increase in total cell, neutrophil and erythrocyte numbers in the bronchoalveolar lavage fluid. Histological examination revealed a serious lung injury as shown by interstitial edema, vascular congestion and mononuclear cell infiltration in these mice after 24h. Everolimus as well as NVP-BEZ235 did not noticeably affect overall histopathology of the lungs in the lung injury model. However, NVP-BEZ235 enhanced IL-6 and TNF-α expression after 24h. In contrast, everolimus did not affect IL-6 and TNF-α levels. Interestingly, both inhibitors reduced inflammatory cytokines in an LPS/oleic acid-induced lung injury model. In conclusion, the mTOR inhibitors did not worsen the overall histopathological severity, but they exerted distinct effects on proinflammatory cytokine expression in the lung depending on the lung injury model applied.

  19. Beyond the Gallery Forest: Contrasting Habitat and Diet in Lemur catta Troops at Bezà Mahafaly Special Reserve.

    PubMed

    Yamashita, Nayuta; Sauther, Michelle L; Cuozzo, Frank P; Youssouf Jacky, Ibrahim Antho

    2015-01-01

    Ring-tailed lemurs have been studied intensively in the Parcel 1 gallery forest of Bezà Mahafaly Special Reserve. Here, we report on lemur groups in a mixture of deciduous dry forest and spiny forest just 5 km to the west. Compared to Parcel 1, Parcel 2 (P2) has a lower density of Tamarindus indica, a major dietary plant species for gallery forest lemurs. Recent studies in drier habitats have called into question the association of lemur density and tamarind presence. In order to address this question, we measured forest structure and composition of plant plots between parcels and conducted lemur feeding observations. The trees and shrubs within the parcels did not differ in height or diameter at breast height, but the frequencies of plant species that were common between parcels were significantly different. Numbers of feeding observations on foods common to both parcels did not differ, but their relative rankings within parcels did. Frequencies of food plants corresponded to earlier reports of lemur population densities. However, we found that the ring-tailed lemur diet is a mixture of plants that are eaten in abundance regardless of frequency and those that are locally available. In terms of their reliance on Tamarindus, P2 animals appear intermediate between those in gallery forests and nontamarind sites.

  20. GSK3β-dependent cyclin D1 and cyclin E1 degradation is indispensable for NVP-BEZ235 induced G0/G1 arrest in neuroblastoma cells.

    PubMed

    Liu, Shan-Ling; Liu, Zhen; Zhang, Li-Di; Zhu, Han-Qing; Guo, Jia-Hui; Zhao, Mei; Wu, Yingli; Liu, Feng; Gao, Feng-Hou

    2017-10-05

    Cyclin D1 and cyclin E1, as vital regulatory factors of G1-S phase cell cycle progression, are frequently constitutive expressed and associated with pathogenesis and tumorigenesis in most human cancers and they have been regarded as promising targets for cancer therapy. In this study, we established NVP-BEZ235, a potent dual kinase inhibitor, could induce neuroblastoma cells proliferation inhibition without apoptosis activation. Moreover, we showed NVP-BEZ235 could induce neuroblastoma cells arrested at G0/G1 phase accompanied with significant reduction of the cyclin D1 and E1 proteins in a dose dependent manner at nanomole concentration. Additionally we found that GSK3β was dephosphorylated and activated by NVP-BEZ235 and then triggered cyclin D1 and cyclin E1 degradation through ubiquitination proteasome pathway, based on the evidences that NVP-BEZ235 induced downregulation of cyclin D1 and cyclin E1 were obviously recovered by proteasome inhibitor and the blockade of GSK3β contributed to remarkable rescue of cyclin D1 and cyclin E1. Analogous results about its anti-proliferation effects and molecular mechanism were observed on neuroblastoma xenograft mouse model in vivo. Therefore, these results indicate that NVP-BEZ235-induced cyclin D1 and cyclin E1 degradation, which happened through activating GSK3β, and GSK3β-dependent down-regulation of cyclin D1 and cyclin E1 should be available for anticancer therapeutics.

  1. MRI reveals the in vivo cellular and vascular response to BEZ235 in ovarian cancer xenografts with different PI3-kinase pathway activity

    PubMed Central

    Cebulla, J; Huuse, E M; Pettersen, K; van der Veen, A; Kim, E; Andersen, S; Prestvik, W S; Bofin, A M; Pathak, A P; Bjørkøy, G; Bathen, T F; Moestue, S A

    2015-01-01

    Background: The phosphoinositide-3 kinase (PI3K) pathway is an attractive therapeutic target. However, difficulty in predicting therapeutic response limits the clinical implementation of PI3K inhibitors. This study evaluates the utility of clinically relevant magnetic resonance imaging (MRI) biomarkers for noninvasively assessing the in vivo response to the dual PI3K/mTOR inhibitor BEZ235 in two ovarian cancer models with differential PI3K pathway activity. Methods: The PI3K signalling activity of TOV-21G and TOV-112D human ovarian cancer cells was investigated in vitro. Cellular and vascular response of the xenografts to BEZ235 treatment (65 mg kg−1, 3 days) was assessed in vivo using diffusion-weighted (DW) and dynamic contrast-enhanced (DCE)-MRI. Micro-computed tomography was performed to investigate changes in vascular morphology. Results: The TOV-21G cells showed higher PI3K signalling activity than TOV-112D cells in vitro and in vivo. Treated TOV-21G xenografts decreased in volume and DW-MRI revealed an increased water diffusivity that was not found in TOV-112D xenografts. Treatment-induced improvement in vascular functionality was detected with DCE-MRI in both models. Changes in vascular morphology were not found. Conclusions: Our results suggest that DW- and DCE-MRI can detect cellular and vascular response to PI3K/mTOR inhibition in vivo. However, only DW-MRI could discriminate between a strong and weak response to BEZ235. PMID:25535727

  2. The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Induces Tumor Regression in a Genetically Engineered Mouse Model of PIK3CA Wild-Type Colorectal Cancer

    PubMed Central

    Wang, Wei Vivian; Richard, Larissa Georgeon; Chen, Wei; Coffee, Erin M.; Sinnamon, Mark J.; Lee, Lydia; Chen, Peng-Chieh; Bronson, Roderick T.; Martin, Eric S.; Hung, Kenneth E.

    2011-01-01

    Purpose To examine the in vitro and in vivo efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type colorectal cancer (CRC). Experimental Design PIK3CA mutant and wild-type human CRC cell lines were treated in vitro with NVP-BEZ235, and the resulting effects on proliferation, apoptosis, and signaling were assessed. Colonic tumors from a genetically engineered mouse (GEM) model for sporadic wild-type PIK3CA CRC were treated in vivo with NVP-BEZ235. The resulting effects on macroscopic tumor growth/regression, proliferation, apoptosis, angiogenesis, and signaling were examined. Results In vitro treatment of CRC cell lines with NVP-BEZ235 resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (median IC50 = 9.0–14.3 nM). Similar effects were seen in paired isogenic CRC cell lines that differed only in the presence or absence of an activating PIK3CA mutant allele. In vivo treatment of colonic tumor-bearing mice with NVP-BEZ235 resulted in transient PI3K inhibition and sustained blockade of mTORC1/mTORC2 signaling. Longitudinal tumor surveillance by optical colonoscopy demonstrated a 97% increase in tumor size in control mice (p = 0.01) vs. a 43% decrease (p = 0.008) in treated mice. Ex vivo analysis of the NVP-BEZ235-treated tumors demonstrated a 56% decrease in proliferation (p = 0.003), no effects on apoptosis, and a 75% reduction in angiogenesis (p = 0.013). Conclusions These studies provide the preclinical rationale for studies examining the efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type CRC. PMID:21966435

  3. Effective inhibition of colon cancer cell growth with MgAl-layered double hydroxide (LDH) loaded 5-FU and PI3K/mTOR dual inhibitor BEZ-235 through apoptotic pathways.

    PubMed

    Chen, Jiezhong; Shao, Renfu; Li, Li; Xu, Zhi Ping; Gu, Wenyi

    2014-01-01

    Colon cancer is the third most common cancer and the third largest cause of cancer-related death. Fluorouracil (5-FU) is the front-line chemotherapeutic agent for colon cancer. However, its response rate is less than 60%, even in combination with other chemotherapeutic agents. The side effects of 5-FU also limit its application. Nanoparticles have been used to deliver 5-FU, to increase its effectiveness and reduce side effects. Another common approach for colon cancer treatment is targeted therapy against the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. A recently-invented inhibitor of this pathway, BEZ-235, has been tested in several clinical trials and has shown effectiveness and low side effects. Thus, it is a very promising drug for colon cancer treatment. The combination of these two drugs, especially nanoparticle-packed 5-FU and BEZ-235, has not been studied. In the present study, we demonstrated that nanoparticles of layered double hydroxide (LDH) loaded with 5-FU were more effective than a free drug at inhibiting colon cancer cell growth, and that a combination treatment with BEZ-235 further increased the sensitivity of colon cancer cells to the treatment of LDH-packed 5-FU (LDH-5-FU). BEZ-235 alone can decrease colon cancer HCT-116 cell viability to 46% of the control, and the addition of LDH-5-FU produced a greater effect, reducing cell survival to 8% of the control. Our data indicate that the combination therapy of nanodelivered 5-FU with a PI3K/Akt inhibitor, BEZ-235, may promise a more effective approach for colon cancer treatment.

  4. A Phase Ib Study of BEZ235, a Dual Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR), in Patients With Advanced Renal Cell Carcinoma

    PubMed Central

    Molina, Ana M.; Lakhman, Yulia; Patil, Sujata; Woo, Kaitlin; DeLuca, John; Lee, Chung-Han; Hsieh, James J.; Feldman, Darren R.; Motzer, Robert J.; H. Voss, Martin

    2016-01-01

    Lessons Learned Our results highlight additional toxicities of dual PI3K/mTOR inhibition in the clinical setting that were unforeseen from preclinical models. Because of toxicity and lack of efficacy, BEZ235 should not be further developed in the current formulation for patients with renal cell carcinoma. Background. Allosteric inhibitors of the mammalian target of rapamycin complex 1 (mTORC1) are approved for advanced renal cell carcinoma (RCC). Preclinical models have suggested that dual inhibition of phosphatidylinositol 3-kinase (PI3K) and mTOR kinase may establish superior anticancer effect. We aimed to establish safety for BEZ235, a potent inhibitor of both PI3K and mTOR, in advanced RCC. Methods. Patients with advanced RCC who had previously failed standard therapy received escalating doses of BEZ235 in sachet formulation twice daily until progression or unacceptable toxicity. Primary endpoints were to identify the maximally tolerated dose (MTD) and to determine the recommended dose for the phase II study. Results. The study was terminated early because of high incidence of dose-limiting toxicities (DLTs) across all dose levels tested. Ten patients were treated with BEZ235—six with clear cell and four with non-clear cell subtypes. Five of these patients suffered DLTs: 2 of 2 patients in the original 400 mg b.i.d. cohort, 1 of 6 in the 200 mg b.i.d. cohort, and 2 of 2 in the 300 mg b.i.d. cohort. DLTs included fatigue, rash, nausea and vomiting, diarrhea, mucositis, anorexia, and dysgeusia. Five patients were evaluable for response: Two had stable disease as best response, and three had progressive disease. Conclusion. BEZ235 twice daily resulted in significant toxicity without objective responses; further development of this compound will not be pursued in this disease. PMID:27286790

  5. Anti-tumor efficacy of BEZ235 is complemented by its anti-angiogenic effects via downregulation of PI3K-mTOR-HIF1alpha signaling in HER2-defined breast cancers

    PubMed Central

    Dey, Nandini; Sun, Yuliang; Carlson, Jennifer H; Wu, Hui; Lin, Xiaoqian; Leyland-Jones, Brian; De, Pradip

    2016-01-01

    Activation of the PI3K-mTOR pathway via HER2: HER3-mediated signaling in HER2+ breast cancers pose one of the major threats towards the success of trastuzumab. First, trastuzumab cannot perturb survival/proliferative signals following HER2: HER3 heterodimerization in HER2+ tumor cells. Second, trastuzumab treatment has been reported to cause drug-mediated resistance in over 50% of HER2+ breast cancers. We have reported that treatment with an anti-angiogenic drug imparted a significant anti-tumor advantage when combined with trastuzumab plus pertuzumab in the trastuzumab-resistant model of HER2+ breast cancers (PMID: 23959459). The very fact as revealed by our study that an inclusion of anti-angiogenic drug conferred a significant anti-tumor advantage when combined with dual anti-HER2 therapy clearly indicated a critical and indispensable role of angiogenesis in these tumors. Hence, we hypothesized that BEZ235 a dual PI3K/mTOR inhibitor will have an effect on the tumor as well as the angiogenic stromal compartments. In vitro and in vivo efficacy of BEZ235 was determined in HER2+ trastuzumab-sensitive, trastuzumab-resistant and HER2 amplified/PIK3CA mutated cell lines. BEZ235 alone and in combination with trastuzumab was tested on the tumor as well as stromal compartments. AKT-mTOR signal was suppressed following BEZ235 treatment in a concentration and time-dependent manner. AnnexinV, cl-CASPASE3, SURVIVIN and p-FOXO1 indicated that BEZ235-induced cell death occurred predominantly via an apoptotic pathway. Heregulin-induced HIF1α synthesis was also significantly decreased. Oncoprint data (cBioPortal) representing PAM50 Her2 enriched tumors (TCGA, Nature 2012) and Her2-positive breast tumors (TCGA, cell 2015) showed 91.4% genetic alterations and 79.2% genetic alterations in a set of four genes comprised of PIK3CA, ERBB2, VEGFA and HIF1alpha. The co-occurrence of HIF1alpha with VEGFA in PAM50 Her2 enriched tumors (TCGA, Nature 2012) and the co-occurrence of HIF1alpha

  6. Antitumor activity of selective MEK1/2 inhibitor AZD6244 in combination with PI3K/mTOR inhibitor BEZ235 in gefitinib-resistant NSCLC xenograft models

    PubMed Central

    2014-01-01

    Purpose Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, MET amplification, and KRAS mutation, thereafter relapsing. AZD6244 is a potent, selective, and orally available MEK1/2 inhibitor. In this study, we evaluated the therapeutic efficacy of AZD6244 alone or with BEZ235, an orally available potent inhibitor of phosphatidylinositol 3–kinase (PI3K) and mammalian target of rapamycin (mTOR), in gefitinib-resistant non-small cell lung carcinoma (NSCLC) models. Experimental design NCI-H1975 with EGFR-T790M mutation, NCI-H1993 with MET amplification and NCI-H460 with KRAS/PIK3CA mutation human NSCLC cells were subcutaneous injected into the athymic nude mice respectively. Mice were randomly assigned to treatment with AZD6244, BEZ235, AZD6244 plus BEZ235, or control for 3 weeks, then all mice were sacrificed and tumor tissues were subjected to western blot analyses and immunohistochemical staining. Results AZD6244 could inhibit the tumor growth of NCI-H1993, but slightly inhibit the tumor growth of NCI-1975 and NCI-H460. Combining AZD6244 with BEZ235 markedly enhanced their antitumor effects and without any marked adverse events. Western blot analysis and immunohistochemical staining revealed that AZD6244 alone reduced ERK1/2 phosphorylation, angiogenesis, and tumor cell proliferation. Moreover, MEK1/2 inhibition resulted in decreased AKT phosphorylation in NCI-H1993 tumor model. BEZ235 also inhibited AKT phosphorylation as well as their downstream molecules in all three tumor models. The antiangiogenic effects were substantially enhanced when the agents were combined, which may due to the reduced expression of matrix metallopeptidase-9 in tumor tissues (MMP-9). Conclusions In this study, we evaluated therapy directed against MEK and PI3K/mTOR in distinct gefitinib-resistant NSCLC xenograft

  7. Antitumor activity of selective MEK1/2 inhibitor AZD6244 in combination with PI3K/mTOR inhibitor BEZ235 in gefitinib-resistant NSCLC xenograft models.

    PubMed

    Qu, Yiqing; Wu, Xiuxiu; Yin, Yunhong; Yang, Yan; Ma, Dedong; Li, Hao

    2014-06-17

    Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, MET amplification, and KRAS mutation, thereafter relapsing. AZD6244 is a potent, selective, and orally available MEK1/2 inhibitor. In this study, we evaluated the therapeutic efficacy of AZD6244 alone or with BEZ235, an orally available potent inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR), in gefitinib-resistant non-small cell lung carcinoma (NSCLC) models. NCI-H1975 with EGFR-T790M mutation, NCI-H1993 with MET amplification and NCI-H460 with KRAS/PIK3CA mutation human NSCLC cells were subcutaneous injected into the athymic nude mice respectively. Mice were randomly assigned to treatment with AZD6244, BEZ235, AZD6244 plus BEZ235, or control for 3 weeks, then all mice were sacrificed and tumor tissues were subjected to western blot analyses and immunohistochemical staining. AZD6244 could inhibit the tumor growth of NCI-H1993, but slightly inhibit the tumor growth of NCI-1975 and NCI-H460. Combining AZD6244 with BEZ235 markedly enhanced their antitumor effects and without any marked adverse events. Western blot analysis and immunohistochemical staining revealed that AZD6244 alone reduced ERK1/2 phosphorylation, angiogenesis, and tumor cell proliferation. Moreover, MEK1/2 inhibition resulted in decreased AKT phosphorylation in NCI-H1993 tumor model. BEZ235 also inhibited AKT phosphorylation as well as their downstream molecules in all three tumor models. The antiangiogenic effects were substantially enhanced when the agents were combined, which may due to the reduced expression of matrix metallopeptidase-9 in tumor tissues (MMP-9). In this study, we evaluated therapy directed against MEK and PI3K/mTOR in distinct gefitinib-resistant NSCLC xenograft models. Combining AZD6244 with BEZ235 enhanced their

  8. The pan-BCL-2-blocker obatoclax (GX15-070) and the PI3-kinase/mTOR-inhibitor BEZ235 produce cooperative growth-inhibitory effects in ALL cells.

    PubMed

    Stefanzl, Gabriele; Berger, Daniela; Cerny-Reiterer, Sabine; Blatt, Katharina; Eisenwort, Gregor; Sperr, Wolfgang R; Hoermann, Gregor; Lind, Karin; Hauswirth, Alexander W; Bettelheim, Peter; Sill, Heinz; Melo, Junia V; Jäger, Ulrich; Valent, Peter

    2017-09-15

    Acute lymphoblastic leukemia (ALL) is characterized by leukemic expansion of lymphoid blasts in hematopoietic tissues. Despite improved therapy only a subset of patients can be cured. Therefore, current research is focusing on new drug-targets. Members of the BCL-2 family and components of the PI3-kinase/mTOR pathway are critically involved in the regulation of growth and survival of ALL cells. We examined the effects of the pan-BCL-2 blocker obatoclax and the PI3-kinase/mTOR-inhibitor BEZ235 on growth and survival of ALL cells. In (3)H-thymidine uptake experiments, both drugs suppressed the in vitro proliferation of leukemic cells in all patients with Philadelphia chromosome-positive (Ph(+)) ALL and Ph(-) ALL (obatoclax IC50: 0.01-5 μM; BEZ235, IC50: 0.01-1 μM). Both drugs were also found to produce growth-inhibitory effects in all Ph(+) and all Ph(-) cell lines tested. Moreover, obatoclax and BEZ235 induced apoptosis in ALL cells. In drug-combination experiments, obatoclax and BEZ235 exerted synergistic growth-inhibitory effects on ALL cells. Finally, we confirmed that ALL cells, including CD34(+)/CD38(-) stem cells and all cell lines express transcripts for PI3-kinase, mTOR, BCL-2, MCL-1, and BCL-xL. Taken together, this data shows that combined targeting of the PI3-kinase/mTOR-pathway and BCL-2 family-members is a potent approach to counteract growth and survival of ALL cells.

  9. Curcumin Significantly Enhances Dual PI3K/Akt and mTOR Inhibitor NVP-BEZ235-Induced Apoptosis in Human Renal Carcinoma Caki Cells through Down-Regulation of p53-Dependent Bcl-2 Expression and Inhibition of Mcl-1 Protein Stability

    PubMed Central

    Cho, Il Je; Kim, Sang Chan; Kwon, Taeg Kyu

    2014-01-01

    The PI3K/Akt and mTOR signaling pathways are important for cell survival and growth, and they are highly activated in cancer cells compared with normal cells. Therefore, these signaling pathways are targets for inducing cancer cell death. The dual PI3K/Akt and mTOR inhibitor NVP-BEZ235 completely inhibited both signaling pathways. However, NVP-BEZ235 had no effect on cell death in human renal carcinoma Caki cells. We tested whether combined treatment with natural compounds and NVP-BEZ235 could induce cell death. Among several chemopreventive agents, curcumin, a natural biologically active compound that is extracted from the rhizomes of Curcuma species, markedly induced apoptosis in NVP-BEZ235-treated cells. Co-treatment with curcumin and NVP-BEZ235 led to the down-regulation of Mcl-1 protein expression but not mRNA expression. Ectopic expression of Mcl-1 completely inhibited curcumin plus NVP-NEZ235-induced apoptosis. Furthermore, the down-regulation of Bcl-2 was involved in curcumin plus NVP-BEZ235-induced apoptosis. Curcumin or NVP-BEZ235 alone did not change Bcl-2 mRNA or protein expression, but co-treatment reduced Bcl-2 mRNA and protein expression. Combined treatment with NVP-BEZ235 and curcumin reduced Bcl-2 expression in wild-type p53 HCT116 human colon carcinoma cells but not p53-null HCT116 cells. Moreover, Bcl-2 expression was completely reversed by treatment with pifithrin-α, a p53-specific inhibitor. Ectopic expression of Bcl-2 also inhibited apoptosis in NVP-BE235 plus curcumin-treated cells. In contrast, NVP-BEZ235 combined with curcumin did not have a synergistic effect on normal human skin fibroblasts and normal human mesangial cells. Taken together, combined treatment with NVP-BEZ235 and curcumin induces apoptosis through p53-dependent Bcl-2 mRNA down-regulation at the transcriptional level and Mcl-1 protein down-regulation at the post-transcriptional level. PMID:24743574

  10. Inhibition of autophagy enhances apoptosis induced by the PI3K/AKT/mTor inhibitor NVP-BEZ235 in renal cell carcinoma cells.

    PubMed

    Li, Hongyan; Jin, Xuefei; Zhang, Zhuo; Xing, Yuanyuan; Kong, Xiangbo

    2013-07-01

    The PI3K/AKT/mTOR pathway plays a key role in the development of the hypervascular tumor renal cell carcinoma (RCC). NVP-BEZ235 (NVP), a novel dual PI3K/mTOR inhibitor, showed great antitumor benefit and provided a treatment strategy in RCC. In this study, we test the effect of NVP on survival rate, apoptosis and autophagy in the RCC cell line, 786-0. We also explore the hypothesis that NVP, in combination with autophagy inhibitors, leads to apoptosis enhancement in 786-0 cells. The results showed that the PI3K/AKT/mTOR pathway proteins p-AKT and p-P70S6K were highly expressed in RCC tissue. We also showed that NVP inhibited cell growth and induced apoptosis and autophagy in RCC cells. The combination treatment of NVP with autophagy inhibitors enhanced the effect of NVP on suppressing 786-0 growth and induction of apoptosis. This study proposes a novel treatment paradigm where combining PI3K/AKT/mTOR pathway inhibitors and autophagy inhibitors lead to enhanced RCC cell apoptosis.

  11. Synergistic anti-tumor effect of 17AAG with the PI3K/mTOR inhibitor NVP-BEZ235 on human melanoma.

    PubMed

    Calero, R; Morchon, E; Martinez-Argudo, I; Serrano, R

    2017-10-10

    Drug resistance by MAPK signaling recovery or activation of alternative signaling pathways, such as PI3K/AKT/mTOR, is an important factor that limits the long-term efficacy of targeted therapies in melanoma patients. In the present study, we investigated the phospho-proteomic profile of RTKs and its correlation with downstream signaling pathways in human melanoma. We found that tyrosine kinase receptors expression correlated with the expression of pivotal downstream components of the RAS/RAF/MAPK and PI3K/AKT/mTOR pathways in melanoma cell lines and tumors. We also found high expression of HSP90 and the PI3K/AKT/mTOR pathway proteins, 4EBP1 and AKT compared with healthy tissue and this correlated with poor overall survival of melanoma patients. The combination of the HSP90 inhibitor 17AAG with the PI3K/mTOR inhibitor NVP-BEZ235 showed a synergistic activity decreasing melanoma cell growth, inducing apoptosis and targeting simultaneously the MAPK and PI3K/AKT/mTOR pathways. These results demonstrate that the combination of HSP90 and PI3K/mTOR inhibitors could be an effective therapeutic strategy that target the main survival pathways in melanoma and must be considered to overcome resistance to BRAF inhibitors in melanoma patients. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Ring-Tailed Lemur (Lemur catta) Health Parameters across Two Habitats with Varied Levels of Human Disturbance at the Bezà Mahafaly Special Reserve, Madagascar.

    PubMed

    Singleton, Cora L; Norris, Aimee M; Sauther, Michelle L; Cuozzo, Frank P; Youssouf Jacky, Ibrahim Antho

    2015-01-01

    The health of 36 wild, free-ranging ring-tailed lemurs (Lemur catta) at the Bezà Mahafaly Special Reserve was assessed across 2 habitats of varied human impact: a reserve riverine gallery forest, and a degraded mixed dry deciduous and Alluaudia-dominated spiny forest. While there were no statistically significant differences in leukocyte count or differential between habitats, female lemurs in the reserve gallery forest had significantly higher percentages of monocytes and eosinophils than male lemurs in the gallery forest. Lemurs from the degraded spiny habitat had significantly higher mean packed cell volume, hematocrit, hemoglobin, total protein, blood urea nitrogen, chloride, ionized calcium and urine specific gravity than lemurs from the reserve gallery forest. These findings may reflect lower hydration levels in lemurs living in degraded habitat, providing evidence that environmental degradation has identifiable impacts on the physiology and health of wild, free-ranging ring-tailed lemurs living in nearby habitats. Given the greater evidence of human impact in the mixed dry deciduous/spiny forest habitat, a pattern seen throughout southern Madagascar, biomedical markers suggestive of decreased hydration can provide empirical data to inform new conservation policies facilitating the long-term survival of this lemur community.

  13. Sources of tooth wear variation early in life among known-aged wild ring-tailed lemurs (Lemur catta) at the Bezà Mahafaly Special Reserve, Madagascar.

    PubMed

    Cuozzo, Frank P; Head, Brian R; Sauther, Michelle L; Ungar, Peter S; O'Mara, M Teague

    2014-11-01

    Ring-tailed lemurs (Lemur catta) at the Bezà Mahafaly Special Reserve (BMSR), Madagascar display a high frequency of individuals with notable and sometimes extreme tooth wear. Adult lemurs display a range of tooth wear even among individuals of the same age, but we do not know at what age this variation first appears. This study's goal was to determine whether wear variation occurs in younger wild lemurs. Based on the decade-long study of ring-tailed lemur feeding and dental ecology at BMSR, we hypothesized that younger, natal lemurs (under 5 years of age), would display variation in their degree of tooth wear that would correspond to microhabitat differences, given differences in food availability in different troops' home ranges. We also hypothesized that wear would differ between sexes at this young age, given differences in feeding between males and females in this population. Hypotheses were tested using dental topographic analyses using dental impressions collected from known-aged lemurs across 10 years at BMSR. Results illustrate significant differences in wear-related tooth topography (i.e., relief and slope, presented here as "occlusal lift") for microhabitat, sex and troop affiliation among lemurs under 5 years of age in this population. Although, all lemurs in this population consume mechanically challenging tamarind fruit, those in more disturbed habitats eat additional introduced foods, some of which are also mechanically challenging. Thus, dietary variation is the likely cause of variation in tooth wear. The wear variation we show at a young age suggests caution when assigning age based on tooth wear in living and fossil primates. These wear-related tooth shape changes early in life, which reflects sex, habitat variation and levels of anthropogenic disturbance, may potentially impact reproductive fitness later in life. © 2014 Wiley Periodicals, Inc.

  14. Seasonal variation in the abundance and distribution of ticks that parasitize Microcebus griseorufus at the Bezà Mahafaly Special Reserve, Madagascar.

    PubMed

    Rodriguez, Idalia A; Rasoazanabary, Emilienne; Godfrey, Laurie R

    2015-12-01

    At Bezà Mahafaly Special Reserve (BMSR), Madagascar, mouse lemurs (Microcebus griseorufus) are parasitized by multiple species of haemaphysaline ticks. At present we know little about the role ticks play in wild lemur populations and how they can alter interspecies relationships within communities or impact host fitness. In order to better understand these dynamics at BMSR, we examined parasite-host interactions as well as the ecology of mouse lemurs and their infesting ticks, Haemaphysalis lemuris and H. sp. cf. simplex. We show that season, host sex, and habitat influence the relative abundance of ticks on mouse lemurs. Specifically, infestations occur only during the dry season (May-October), are higher in males, and are higher at the study site with the most ground cover and with greater density of large-bodied hosts. Microcebus likely experience decreased susceptibility to tick infestations during the wet season because at that time they rarely if ever descend to the ground. Similarly, male mouse lemurs have higher infestation rates than females because of the greater time they spend traveling and foraging on the ground. During the dry season, Microcebus likely serve as hosts for the tenrec tick, H. sp. cf. simplex, when tenrecs hibernate. In turn, during the wet season when mouse lemurs rarely descend to the ground, other small mammals at the reserve may serve as maintenance hosts for populations of immature ticks. The synchronous development of larvae and nymphs could present high risk for vector-borne disease in Microcebus. This study also provides a preliminary description of the ecology and life cycle of the most common lemur tick, H. lemuris.

  15. Seasonal variation in the abundance and distribution of ticks that parasitize Microcebus griseorufus at the Bezà Mahafaly Special Reserve, Madagascar

    PubMed Central

    Rodriguez, Idalia A.; Rasoazanabary, Emilienne; Godfrey, Laurie R.

    2015-01-01

    At Bezà Mahafaly Special Reserve (BMSR), Madagascar, mouse lemurs (Microcebus griseorufus) are parasitized by multiple species of haemaphysaline ticks. At present we know little about the role ticks play in wild lemur populations and how they can alter interspecies relationships within communities or impact host fitness. In order to better understand these dynamics at BMSR, we examined parasite-host interactions as well as the ecology of mouse lemurs and their infesting ticks, Haemaphysalis lemuris and H. sp. cf. simplex. We show that season, host sex, and habitat influence the relative abundance of ticks on mouse lemurs. Specifically, infestations occur only during the dry season (May–October), are higher in males, and are higher at the study site with the most ground cover and with greater density of large-bodied hosts. Microcebus likely experience decreased susceptibility to tick infestations during the wet season because at that time they rarely if ever descend to the ground. Similarly, male mouse lemurs have higher infestation rates than females because of the greater time they spend traveling and foraging on the ground. During the dry season, Microcebus likely serve as hosts for the tenrec tick, H. sp. cf. simplex, when tenrecs hibernate. In turn, during the wet season when mouse lemurs rarely descend to the ground, other small mammals at the reserve may serve as maintenance hosts for populations of immature ticks. The synchronous development of larvae and nymphs could present high risk for vector-borne disease in Microcebus. This study also provides a preliminary description of the ecology and life cycle of the most common lemur tick, H. lemuris. PMID:26767168

  16. Establishment of a Structure–Activity Relationship of 1H-Imidazo[4,5-c]quinoline-Based Kinase Inhibitor NVP-BEZ235 as a Lead for African Sleeping Sickness

    PubMed Central

    2014-01-01

    Compound NVP-BEZ235 (1) is a potent inhibitor of human phospoinositide-3-kinases and mammalian target of rapamycin (mTOR) that also showed high inhibitory potency against Trypanosoma brucei cultures. With an eye toward using 1 as a starting point for anti-trypanosomal drug discovery, we report efforts to reduce host cell toxicity, to improve the physicochemical properties, and to improve the selectivity profile over human kinases. In this work, we have developed structure–activity relationships for analogues of 1 and have prepared analogues of 1 with improved solubility properties and good predicted central nervous system exposure. In this way, we have identified 4e, 9, 16e, and 16g as the most promising leads to date. We also report cell phenotype and phospholipidomic studies that suggest that these compounds exert their anti-trypanosomal effects, at least in part, by inhibition of lipid kinases. PMID:24805946

  17. Deinococcus soli sp. nov., a gamma- and uv-radiation-resistant bacterium from north-west China.

    PubMed

    Zhang, Lei; Qin, Bao-Fu; Wang, Yang; Fang, Cheng-Xiang

    2011-01-01

    An ionizing- and UV-radiation-resistant bacterial strain, designated ZLM-202T, was isolated from an arid soil sample collected from Xinjiang Province, north-west China. The soil sample was irradiated before serial dilution plating was performed using twofold-diluted marine agar. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain ZLM-202T was a member of the genus Deinococcus, exhibiting sequence similarities of 86.3-92.2% to the type strains of recognized Deinococcus species. Strain-ZLM-202 was strictly aerobic and showed optimum growth at 30-37 degrees C and pH 7.0. The major respiratory menaquinone was MK-8. The major fatty acids were 16:1 omega7c, 16:0, 15:1 omega6c, 15:0 iso and 16:1 omega5c. L-ornithine was detected in its peptidoglycan. The polar lipid profile consisted mainly of various unknown phosphoglycolipids, aminophospholipids, glycolipids and phospholipids. The DNA G + C content was 65.5 mol. %. The strain was shown to be extremely resistant to gamma radiation (> 10 kGy) and UV light (> 600 J m(-2)). On the basis of the phylogenetic, chemotaxonomic and phenotypic data, strain ZLM-202T represents a novel species of the genus Deinococcus, for which the name Deinococcus soli sp. nov. is proposed. The type strain is ZLM-202T (= CCTCC AB 208223T = KCTC 13419T).

  18. The Andreev reflection of zero line mode in graphene-superconductor hybrid junction.

    PubMed

    Feng, Li; Cheng, Shu-guang

    2015-04-01

    The zero line mode (ZLM) in two dimensional materials provides a quasi-one dimensional path for electronic transport. We report the theoretical investigation of the Andreev reflection of ZLM by using the staggered graphene-superconductor based models. For a two-terminal system in which the valley index is well preserved, when graphene is zigzag edged, the Andreev reflection coefficient can be either large or strongly suppressed depending on the symmetric properties of the transverse wave function in graphene ribbon. However, the Andreev reflection coefficient, independent of the staggering profile in the armchair edged model, is large due to the absence of wave function symmetry. When ZLM changes its direction in a vertical path, a perfect Andreev reflection could happen when the incident ZLM stems from a zigzag edged graphene ribbon. In a zigzag edged four-terminal hybrid model, the interference of reflected holes leads to perfect Andreev reflection with probability unity and the annihilation of the crossed Andreev reflection. For the armchair edged model, the interference effect disappears because the Andreev reflection from one of the paths is prohibited. The interference of Andreev reflections in four-terminal models is investigated by spacial local density of states in the central scattering region as well.

  19. Bezafibrate ameliorates diabetes via reduced steatosis and improved hepatic insulin sensitivity in diabetic TallyHo mice.

    PubMed

    Franko, Andras; Neschen, Susanne; Rozman, Jan; Rathkolb, Birgit; Aichler, Michaela; Feuchtinger, Annette; Brachthäuser, Laura; Neff, Frauke; Kovarova, Marketa; Wolf, Eckhard; Fuchs, Helmut; Häring, Hans-Ulrich; Peter, Andreas; Hrabě de Angelis, Martin

    2017-03-01

    Recently, we have shown that Bezafibrate (BEZ), the pan-PPAR (peroxisome proliferator-activated receptor) activator, ameliorated diabetes in insulin deficient streptozotocin treated diabetic mice. In order to study whether BEZ can also improve glucose metabolism in a mouse model for fatty liver and type 2 diabetes, the drug was applied to TallyHo mice. TallyHo mice were divided into an early (ED) and late (LD) diabetes progression group and both groups were treated with 0.5% BEZ (BEZ group) or standard diet (SD group) for 8 weeks. We analyzed plasma parameters, pancreatic beta-cell morphology, and mass as well as glucose metabolism of the BEZ-treated and control mice. Furthermore, liver fat content and composition as well as hepatic gluconeogenesis and mitochondrial mass were determined. Plasma lipid and glucose levels were markedly reduced upon BEZ treatment, which was accompanied by elevated insulin sensitivity index as well as glucose tolerance, respectively. BEZ increased islet area in the pancreas. Furthermore, BEZ treatment improved energy expenditure and metabolic flexibility. In the liver, BEZ ameliorated steatosis, modified lipid composition and increased mitochondrial mass, which was accompanied by reduced hepatic gluconeogenesis. Our data showed that BEZ ameliorates diabetes probably via reduced steatosis, enhanced hepatic mitochondrial mass, improved metabolic flexibility and elevated hepatic insulin sensitivity in TallyHo mice, suggesting that BEZ treatment could be beneficial for patients with NAFLD and impaired glucose metabolism.

  20. In Vitro Biotransformation of Two Human CYP3A Probe Substrates and Their Inhibition during Early Zebrafish Development

    PubMed Central

    Verbueken, Evy; Alsop, Derek; Saad, Moayad A.; Pype, Casper; Van Peer, Els M.; Casteleyn, Christophe R.; Van Ginneken, Chris J.; Wilson, Joanna; Van Cruchten, Steven J.

    2017-01-01

    At present, the zebrafish embryo is increasingly used as an alternative animal model to screen for developmental toxicity after exposure to xenobiotics. Since zebrafish embryos depend on their own drug-metabolizing capacity, knowledge of their intrinsic biotransformation is pivotal in order to correctly interpret the outcome of teratogenicity assays. Therefore, the aim of this in vitro study was to assess the activity of cytochrome P450 (CYP)—a group of drug-metabolizing enzymes—in microsomes from whole zebrafish embryos (ZEM) of 5, 24, 48, 72, 96 and 120 h post-fertilization (hpf) by means of a mammalian CYP substrate, i.e., benzyloxy-methyl-resorufin (BOMR). The same CYP activity assays were performed in adult zebrafish liver microsomes (ZLM) to serve as a reference for the embryos. In addition, activity assays with the human CYP3A4-specific Luciferin isopropyl acetal (Luciferin-IPA) as well as inhibition studies with ketoconazole and CYP3cide were carried out to identify CYP activity in ZLM. In the present study, biotransformation of BOMR was detected at 72 and 96 hpf; however, metabolite formation was low compared with ZLM. Furthermore, Luciferin-IPA was not metabolized by the zebrafish. In conclusion, the capacity of intrinsic biotransformation in zebrafish embryos appears to be lacking during a major part of organogenesis. PMID:28117738

  1. Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice.

    PubMed

    Franko, Andras; Huypens, Peter; Neschen, Susanne; Irmler, Martin; Rozman, Jan; Rathkolb, Birgit; Neff, Frauke; Prehn, Cornelia; Dubois, Guillaume; Baumann, Martina; Massinger, Rebecca; Gradinger, Daniel; Przemeck, Gerhard K H; Repp, Birgit; Aichler, Michaela; Feuchtinger, Annette; Schommers, Philipp; Stöhr, Oliver; Sanchez-Lasheras, Carmen; Adamski, Jerzy; Peter, Andreas; Prokisch, Holger; Beckers, Johannes; Walch, Axel K; Fuchs, Helmut; Wolf, Eckhard; Schubert, Markus; Wiesner, Rudolf J; Hrabě de Angelis, Martin

    2016-09-01

    Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in mice with streptozotocin (STZ)-induced diabetes, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin-positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes. © 2016 by the American Diabetes Association.

  2. Targeting PI3K/mTOR signaling exerts potent antitumor activity in pheochromocytoma in vivo.

    PubMed

    Lee, Misu; Minaskan, Ninelia; Wiedemann, Tobias; Irmler, Martin; Beckers, Johannes; Yousefi, Behrooz H; Kaissis, Georgios; Braren, Rickmer; Laitinen, Iina; Pellegata, Natalia S

    2017-01-01

    Pheochromocytomas (PCCs) are mostly benign tumors, amenable to complete surgical resection. However, 10-17% of cases can become malignant, and once metastasized, there is no curative treatment for this disease. Given the need to identify the effective therapeutic approaches for PCC, we evaluated the antitumor potential of the dual-PI3K/mTOR inhibitor BEZ235 against these tumors. We employed an in vivo model of endogenous PCCs (MENX mutant rats), which closely recapitulate the human tumors. Mutant rats with PCCs were treated with 2 doses of BEZ235 (20 and 30 mg/kg), or with placebo, for 2 weeks. Treatment with BEZ235 induced cytostatic and cytotoxic effects on rat PCCs, which could be appreciated by both staining the tumors ex vivo with appropriate markers and non-invasively by functional imaging (diffusion-weighted magnetic resonance imaging) in vivo Transcriptomic analyses of tumors from rats treated with BEZ235 or placebo-identified potential mediators of therapy response were performed. Slc6a2, encoding the norepinephrine transporter (NET), was downregulated in a dose-dependent manner by BEZ235 in rat PCCs. Moreover, BEZ235 reduced Slc6a2/NET expression in PCC cell lines (MPC) also. Studies of a BEZ235-resistant derivative of the MPC cell line confirmed that the reduction of NET expression associates with the response to the drug. Reduction of NET expression after BEZ235 treatment in vivo could be monitored by positron emission tomography (PET) using a tracer targeting NET. Altogether, here we demonstrate the efficacy of BEZ235 against PCC in vivo, and show that functional imaging can be employed to monitor the response of PCC to PI3K/mTOR inhibition therapy.

  3. Co-Targeting the PI3K and RAS Pathways for the Treatment of Neuroendocrine Tumors

    PubMed Central

    Valentino, Joseph D.; Li, Jing; Zaytseva, Yekaterina Y.; Mustain, W. Conan; Elliott, Victoria A.; Kim, Ji Tae; Harris, Jennifer W.; Campbell, Katherine; Weiss, Heidi; Wang, Chi; Song, Jun; Anthony, Lowell; Townsend, Courtney M.; Evers, B. Mark

    2014-01-01

    Background The precise involvement of the PI3K/mTOR and RAS/MEK pathways in carcinoid tumors is not well defined. Therefore, the purpose of our study was to evaluate the role these pathways play in carcinoid cell proliferation, apoptosis, and secretion and to determine the effects of combined treatment on carcinoid tumor inhibition. Methods The human neuroendocrine cell lines BON (pancreatic carcinoid), NCI-H727 (lung carcinoid), and QGP-1 (somatostatinoma) were treated with either the pan-PI3K inhibitor, BKM120, or the dual PI3K-mTOR inhibitor, BEZ235, alone or in combination with the MEK inhibitor, PD0325901; proliferation, apoptosis, and protein expression were assessed. Peptide secretion was evaluated in BON and QGP-1 cells. The anti-proliferative effect of BEZ235, alone or combined with PD0325901, was then tested in vivo. Results Both BKM120 and BEZ235 decreased proliferation and increased apoptosis; combination with PD0325901 significantly enhanced the antineoplastic effects of either treatment alone. In contrast, neurotensin (NT) peptide secretion was markedly stimulated with BKM120 treatment, but not BEZ235. The combination of BEZ235 + PD0325901 significantly inhibited the growth of BON xenografts without systemic toxicity. Conclusions Both BKM120 and BEZ235 effectively inhibited NET cell proliferation and stimulated apoptosis. However, inhibition of the PI3K pathway alone with BKM120 significantly stimulated NT peptide secretion; this did not occur with the dual inhibition of both PI3K and mTOR using BEZ235 suggesting that this would be a more effective treatment regimen for NETs. Moreover, the combination of BEZ235 and the MEK inhibitor PD0325901 was a safe and more effective therapy in vivo compared with single agents alone. PMID:24443523

  4. Fehlertoleranzanalyse des FlexRay Startup-Prozesses

    NASA Astrophysics Data System (ADS)

    Bünte, Sven; Milbredt, Paul

    Die PlexfiRay-Prozeduren Wakeup und Startup sollen eine konsistent-synchrone Kommunikation bezüglich eines TDMA verwandten Verfuhrens herstellen. Beide Algorithmen werden in dieser Arbeit ubstrukt modelliert und mit Hilfe des Model Checkers SPIN bezüglich Terminierung analysiert. Die Ergebnisse zeigen, dass in bestimmten Fehlerszenarios die Verwendung von Central Bus Guardians, die Clusterkonfiguration und das Verhalten des Hosts darüber entscheiden, ob Fehlertoleranz und Laufzeitbeschränkungen garantiert werden können.

  5. Investigation of Quantum Effects in Heterostructures.

    DTIC Science & Technology

    2014-09-26

    identlty by block number) .j --) InAs/GaSb and GaSb/AlSb superlattices, GaSb/InAs/GaSb quantum wells and GaAs / GaA #As heterojunctions were prepared by MBE...MBE technique. Two MBE systems were available: Riber 1000 for InAs/GaSb/ASb; and Varian GEN-I for GaAs /GaAlAs. The figure shown below (taken frurn VG...studies are GaAs , GaAIAs, InAs, GaSb, AISb, Si and Ge. 3.0- Uase AlP CS0.5 2.0 ,. •b Eg CdTe (ZLm) -Si 1 -Oi 1.00 In~s kSb S 0F I I I I I I I I I I I T e

  6. Adequate vitamin D status and adiposity contribute to bone health in peripubertal nonobese children.

    PubMed

    Lee, Young Ah; Kim, Ji Young; Kang, Min Jae; Chung, Seung Joon; Shin, Choong Ho; Yang, Sei Won

    2013-05-01

    The dietary reference intake (DRI) of vitamin D for Korean children was reduced from 400 IU/day in 2005 to 200 IU/day in 2010. We evaluated the risk factors for low 25-hydroxyvitamin D [25(OH)D] status and its relationships with bone health in peripubertal nonobese children living in Seoul or Gyeonggi-do. One hundred children (9.3 ± 1.9 years, 71 prepubertal, 45 boys) participated in the winter (n = 38, December through March) and summer (June through September). Bone mineral content (Z_BMC), fat mass (Z_FM), lean mass (Z_LM), and bone mineral density for the total body (Z_TB) and lumbar spine (Z_L1-4) were measured using dual-energy X-ray absorptiometry. Twenty-nine percent of children (47.4 % in winter, 17.7 % in summer) were vitamin D deficient (25(OH)D level of <20 ng/mL). The winter season (P = 0.008) and low vitamin D intake (P = 0.044) were associated with low 25(OH)D level. The 25(OH)D level correlated positively with Z_BMC (P = 0.040), Z_TB (P = 0.027), and Z_L1-4 (P = 0.045) independently of sex, puberty, Z_FM, Z_LM, physical activity level, and calcium intake. Z_FM correlated independently with Z_BMC (P < 0.001), Z_TB (P = 0.037), and Z_L1-4 (P < 0.001). In conclusion, almost half of peripubertal nonobese children were vitamin D deficient in winter. Adequate vitamin D status and adiposity contributed to good bone health in nonobese children. Considering the beneficial effects of adequate vitamin D status on bone health, the current DRI may be insufficient for preventing vitamin D deficiency in winter among Korean children.

  7. Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development.

    PubMed

    Herrero-Sánchez, Mª Carmen; Rodríguez-Serrano, Concepción; Almeida, Julia; San Segundo, Laura; Inogés, Susana; Santos-Briz, Ángel; García-Briñón, Jesús; Corchete, Luis Antonio; San Miguel, Jesús F; Del Cañizo, Consuelo; Blanco, Belén

    2016-10-20

    Graft-versus-host disease (GvHD) remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect. The effects of a selective PI3K inhibitor (BKM120) and a dual PI3K/mTOR inhibitor (BEZ235) on human T cell proliferation, expression of activation-related molecules, and phosphorylation of PI3K/AKT/mTOR pathway proteins were analyzed. Besides, the ability of BEZ235 to prevent GvHD development in mice was evaluated. Simultaneous inhibition of PI3K and mTOR was efficient at lower concentrations than PI3K specific targeting. Importantly, BEZ235 prevented naïve T cell activation and induced tolerance of alloreactive T cells, while maintaining an adequate response against cytomegalovirus, more efficiently than BKM120. Finally, BEZ235 treatment significantly improved the survival and decreased the GvHD development in mice. These results support the use of PI3K inhibitors to control T cell responses and show the potential utility of the dual PI3K/mTOR inhibitor BEZ235 in GvHD prophylaxis.

  8. MET and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma

    PubMed Central

    Kanteti, Rajani; Dhanasingh, Immanuel; Kawada, Ichiro; Lennon, Frances E.; Arif, Qudsia; Bueno, Raphael; Hasina, Rifat; Husain, Aliya N.; Vigneswaran, Wickii; Seiwert, Tanguy; Kindler, Hedy L.; Salgia, Ravi

    2014-01-01

    Malignant pleural mesothelioma (MPM) is an aggressive disease with a poor prognosis. Studies have shown that both MET and its key downstream intracellular signaling partners, PI3K and mTOR, are overexpressed in MPM. Here we determined the combinatorial therapeutic efficacy of a new generation small molecule inhibitor of MET, ARQ 197, and dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 in mesothelioma cell and mouse xenograft models. Cell viability results show that mesothelioma cell lines were sensitive to ARQ 197, NVP-BEZ235 and GDC-0980 inhibitors. The combined use of ARQ 197 with either NVP-BEZ235 or GDC-0980, was synergistic (CI<1). Significant delay in wound healing was observed with ARQ 197 (p<0.001) with no added advantage of combining it with either NVP-BEZ235 or GDC-0980. ARQ 197 alone mainly induced apoptosis (20±2.36%) that was preceded by suppression of MAPK activity, while all the three suppressed cell cycle progression. Both GDC-0980 and NVP-BEZ235 strongly inhibited activities of PI3K and mTOR as evidenced from the phosphorylation status of AKT and S6 kinase. The above observation was further substantiated by the finding that a majority of the MPM archival samples tested revealed highly active AKT. While the single use of ARQ 197 and GDC-0980 inhibited significantly the growth of MPM xenografts (p<0.05, p<0.001 respectively) in mice, the combination of the above two drugs was highly synergistic (p<0.001). Our results suggest that the combined use of ARQ 197/NVP-BEZ235 and ARQ 197/GDC-0980 is far more effective than the use of the drugs singly in suppressing MPM tumor growth and motility and therefore merit further translational studies. PMID:25221930

  9. MET and PI3K/mTOR as a potential combinatorial therapeutic target in malignant pleural mesothelioma.

    PubMed

    Kanteti, Rajani; Dhanasingh, Immanuel; Kawada, Ichiro; Lennon, Frances E; Arif, Qudsia; Bueno, Raphael; Hasina, Rifat; Husain, Aliya N; Vigneswaran, Wickii; Seiwert, Tanguy; Kindler, Hedy L; Salgia, Ravi

    2014-01-01

    Malignant pleural mesothelioma (MPM) is an aggressive disease with a poor prognosis. Studies have shown that both MET and its key downstream intracellular signaling partners, PI3K and mTOR, are overexpressed in MPM. Here we determined the combinatorial therapeutic efficacy of a new generation small molecule inhibitor of MET, ARQ 197, and dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 in mesothelioma cell and mouse xenograft models. Cell viability results show that mesothelioma cell lines were sensitive to ARQ 197, NVP-BEZ235 and GDC-0980 inhibitors. The combined use of ARQ 197 with either NVP-BEZ235 or GDC-0980, was synergistic (CI<1). Significant delay in wound healing was observed with ARQ 197 (p<0.001) with no added advantage of combining it with either NVP-BEZ235 or GDC-0980. ARQ 197 alone mainly induced apoptosis (20±2.36%) that was preceded by suppression of MAPK activity, while all the three suppressed cell cycle progression. Both GDC-0980 and NVP-BEZ235 strongly inhibited activities of PI3K and mTOR as evidenced from the phosphorylation status of AKT and S6 kinase. The above observation was further substantiated by the finding that a majority of the MPM archival samples tested revealed highly active AKT. While the single use of ARQ 197 and GDC-0980 inhibited significantly the growth of MPM xenografts (p<0.05, p<0.001 respectively) in mice, the combination of the above two drugs was highly synergistic (p<0.001). Our results suggest that the combined use of ARQ 197/NVP-BEZ235 and ARQ 197/GDC-0980 is far more effective than the use of the drugs singly in suppressing MPM tumor growth and motility and therefore merit further translational studies.

  10. Combination effects of sorafenib with PI3K inhibitors under hypoxia in colorectal cancer

    PubMed Central

    Bhatia, Dimple R; Thiagarajan, Padma

    2016-01-01

    Aim This study reports the influence of hypoxia on response of colorectal cancer cells to anticancer effects of sorafenib in combination with PI3K inhibitors GDC-0941 and BEZ-235. Materials and methods All hypoxic exposures were carried out at 1% O2/5% CO2. Antiproliferation activity was evaluated by 48 hours propidium iodide and 14 days clonogenic assay. Protein levels were evaluated by fluorescence ELISA. Metabolites lactate and glucose were evaluated biochemically. Results In the 48-hour proliferation assay, sorafenib acted synergistically with GDC-0941 but not with BEZ-235. In long-term colony-forming assays, both GDC-0941 and BEZ-235 were shown to potentiate the antiproliferative activity of sorafenib. At the molecular level, the synergism is mediated through inhibition of pAKT, pS6, p4EBP1, pERK, cyclin D1, and Bcl-2. No change in hypoxia-inducible factor-1α (HIF-1α) levels was observed in cells treated with the combination of compounds under hypoxia. A significant reduction in glucose uptake and lactate release was observed in cells treated with the combination of compounds under normoxia and hypoxia. Conclusion Combinations of sorafenib with PI3K inhibitors BEZ-235 and GDC-0941 are efficacious under hypoxia. Thus, these anticancer combinations have a potential to overcome the hypoxia-mediated resistance mechanisms to antiproliferative agents in cancer therapy. PMID:27995152

  11. Combination of PI3K/Akt/mTOR inhibitors and PDT in endothelial and tumor cells

    NASA Astrophysics Data System (ADS)

    Fateye, Babasola; Chen, Bin

    2011-02-01

    The PI3/Akt/mTOR kinase signaling pathway is a major signaling pathway in eukaryotic cells, and dysregulation of this signaling pathway has been implicated in tumorigenesis and malignancy in several cancers including prostate cancer. We assessed the effects of combination PI3K pathway inhibition on the efficacy of PDT in human prostate tumor cell line (PC3) and SV40-transformed mouse endothelial cell line (SVEC-40). Combination of PDT and BEZ 235 (BEZ), a pan-PI3/ mTOR kinase inhibitor additively enhanced efficacy of sub-lethal PDT in both cell lines. The combination of the pan-PI3/ mTOR kinase inhibitor LY294002 (LY) with PDT also enhanced efficacy of PDT in PC3 in an additive manner but synergistically in SVEC. In order to determine the mechanism of enhancement of efficacy, we assessed apoptosis and autophagy following PDT. PDT-mediated apoptosis was enhanced in endothelial cells, by both BEZ and LY rapidly after treatment. Compared to SVEC, PC3 cells are apoptosis-deficient and apoptosis was not significantly enhanced by either LY or BEZ. However, lethal PDT of PC3 cells induced a delayed autophagic response which may be enhanced by combination, depending on PI3K inhibitor and dose.

  12. Pediatric and adult glioblastoma radiosensitization induced by PI3K/mTOR inhibition causes early metabolic alterations detected by nuclear magnetic resonance spectroscopy.

    PubMed

    Agliano, Alice; Balarajah, Geetha; Ciobota, Daniela M; Sidhu, Jasmin; Clarke, Paul A; Jones, Chris; Workman, Paul; Leach, Martin O; Al-Saffar, Nada M S

    2017-07-18

    Poor outcome for patients with glioblastomas is often associated with radioresistance. PI3K/mTOR pathway deregulation has been correlated with radioresistance; therefore, PI3K/mTOR inhibition could render tumors radiosensitive. In this study, we show that NVP-BEZ235, a dual PI3K/mTOR inhibitor, potentiates the effects of irradiation in both adult and pediatric glioblastoma cell lines, resulting in early metabolic changes detected by nuclear magnetic resonance (NMR) spectroscopy. NVP-BEZ235 radiosensitises cells to X ray exposure, inducing cell death through the inhibition of CDC25A and the activation of p21cip1(CDKN1A). Lactate and phosphocholine levels, increased with radiation, are decreased after NVP-BEZ235 and combination treatment, suggesting that inhibiting the PI3K/mTOR pathway reverses radiation induced metabolic changes. Importantly, NVP-BEZ235 potentiates the effects of irradiation in a xenograft model of adult glioblastoma, where we observed a decrease in lactate and phosphocholine levels after seven days of combination treatment. Although tumor size was not affected due to the short length of the treatment, a significant increase in CASP3 mRNA was observed in the combination group. Taken together, our data suggest that NMR metabolites could be used as biomarkers to detect an early response to combination therapy with PI3K/mTOR inhibitors and radiotherapy in adult and pediatric glioblastoma patients.

  13. A Reference Grammar of Bena

    ERIC Educational Resources Information Center

    Morrison, Michelle Elizabeth

    2011-01-01

    This dissertation is a grammar of Rena (ISO bez), a Bantu language spoken in southwestern Tanzania by approximately 600,000 people. Bena is largely undocumented, and though aspects of Bena grammar have been described, there is no usable, detailed treatment of the Bena language. Therefore the goal of this dissertation is provide the first detailed…

  14. Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention

    DOE PAGES

    Smallwood, Heather S.; Duan, Susu; Morfouace, Marie; ...

    2017-05-23

    Influenza is a worldwide health and financial burden posing a significant risk to the immune-compromised, obese, diabetic, elderly, and pediatric populations. We identified increases in glucose metabolism in the lungs of pediatric patients infected with respiratory pathogens. Using quantitative mass spectrometry, we found metabolic changes occurring after influenza infection in primary human respiratory cells and validated infection-associated increases in c-Myc, glycolysis, and glutaminolysis. We confirmed these findings with a metabolic drug screen that identified the PI3K/mTOR inhibitor BEZ235 as a regulator of infectious virus production. BEZ235 treatment ablated the transient induction of c-Myc, restored PI3K/mTOR pathway homeostasis measured by 4E-BP1more » and p85 phosphorylation, and reversed infection-induced changes in metabolism. Importantly, BEZ235 reduced infectious progeny but had no effect on the early stages of viral replication. BEZ235 significantly increased survival in mice, while reducing viral titer. We show metabolic reprogramming of host cells by influenza virus exposes targets for therapeutic intervention.« less

  15. Pediatric and adult glioblastoma radiosensitization induced by PI3K/mTOR inhibition causes early metabolic alterations detected by nuclear magnetic resonance spectroscopy

    PubMed Central

    Agliano, Alice; Balarajah, Geetha; Ciobota, Daniela M.; Sidhu, Jasmin; Clarke, Paul A.; Jones, Chris; Workman, Paul; Leach, Martin O.; Al-Saffar, Nada M.S.

    2017-01-01

    Poor outcome for patients with glioblastomas is often associated with radioresistance. PI3K/mTOR pathway deregulation has been correlated with radioresistance; therefore, PI3K/mTOR inhibition could render tumors radiosensitive. In this study, we show that NVP-BEZ235, a dual PI3K/mTOR inhibitor, potentiates the effects of irradiation in both adult and pediatric glioblastoma cell lines, resulting in early metabolic changes detected by nuclear magnetic resonance (NMR) spectroscopy. NVP-BEZ235 radiosensitises cells to X ray exposure, inducing cell death through the inhibition of CDC25A and the activation of p21cip1(CDKN1A). Lactate and phosphocholine levels, increased with radiation, are decreased after NVP-BEZ235 and combination treatment, suggesting that inhibiting the PI3K/mTOR pathway reverses radiation induced metabolic changes. Importantly, NVP-BEZ235 potentiates the effects of irradiation in a xenograft model of adult glioblastoma, where we observed a decrease in lactate and phosphocholine levels after seven days of combination treatment. Although tumor size was not affected due to the short length of the treatment, a significant increase in CASP3 mRNA was observed in the combination group. Taken together, our data suggest that NMR metabolites could be used as biomarkers to detect an early response to combination therapy with PI3K/mTOR inhibitors and radiotherapy in adult and pediatric glioblastoma patients. PMID:28624789

  16. Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention.

    PubMed

    Smallwood, Heather S; Duan, Susu; Morfouace, Marie; Rezinciuc, Svetlana; Shulkin, Barry L; Shelat, Anang; Zink, Erika E; Milasta, Sandra; Bajracharya, Resha; Oluwaseum, Ajayi J; Roussel, Martine F; Green, Douglas R; Pasa-Tolic, Ljiljana; Thomas, Paul G

    2017-05-23

    Influenza is a worldwide health and financial burden posing a significant risk to the immune-compromised, obese, diabetic, elderly, and pediatric populations. We identified increases in glucose metabolism in the lungs of pediatric patients infected with respiratory pathogens. Using quantitative mass spectrometry, we found metabolic changes occurring after influenza infection in primary human respiratory cells and validated infection-associated increases in c-Myc, glycolysis, and glutaminolysis. We confirmed these findings with a metabolic drug screen that identified the PI3K/mTOR inhibitor BEZ235 as a regulator of infectious virus production. BEZ235 treatment ablated the transient induction of c-Myc, restored PI3K/mTOR pathway homeostasis measured by 4E-BP1 and p85 phosphorylation, and reversed infection-induced changes in metabolism. Importantly, BEZ235 reduced infectious progeny but had no effect on the early stages of viral replication. BEZ235 significantly increased survival in mice, while reducing viral titer. We show metabolic reprogramming of host cells by influenza virus exposes targets for therapeutic intervention. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  17. A Reference Grammar of Bena

    ERIC Educational Resources Information Center

    Morrison, Michelle Elizabeth

    2011-01-01

    This dissertation is a grammar of Rena (ISO bez), a Bantu language spoken in southwestern Tanzania by approximately 600,000 people. Bena is largely undocumented, and though aspects of Bena grammar have been described, there is no usable, detailed treatment of the Bena language. Therefore the goal of this dissertation is provide the first detailed…

  18. PI3K/AKT/mTOR and sonic hedgehog pathways cooperate together to inhibit human pancreatic cancer stem cell characteristics and tumor growth.

    PubMed

    Sharma, Narinder; Nanta, Rajesh; Sharma, Jay; Gunewardena, Sumedha; Singh, Karan P; Shankar, Sharmila; Srivastava, Rakesh K

    2015-10-13

    Cancer stem cells (CSCs) play major roles in cancer initiation, progression, and metastasis. It is evident from growing reports that PI3K/Akt/mTOR and Sonic Hedgehog (Shh) signaling pathways are aberrantly reactivated in pancreatic CSCs. Here, we examined the efficacy of combining NVP-LDE-225 (PI3K/mTOR inhibitor) and NVP-BEZ-235 (Smoothened inhibitor) on pancreatic CSCs characteristics, microRNA regulatory network, and tumor growth. NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting pancreatic CSC's characteristics and tumor growth in mice by acting at the level of Gli. Combination of NVP-LDE-225 and NVP-BEZ-235 inhibited self-renewal capacity of CSCs by suppressing the expression of pluripotency maintaining factors Nanog, Oct-4, Sox-2 and c-Myc, and transcription of Gli. NVP-LDE-225 co-operated with NVP-BEZ-235 to inhibit Lin28/Let7a/Kras axis in pancreatic CSCs. Furthermore, a superior interaction of these drugs was observed on spheroid formation by pancreatic CSCs isolated from Pankras/p53 mice. The combination of these drugs also showed superior effects on the expression of proteins involved in cell proliferation, survival and apoptosis. In addition, NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting EMT through modulation of cadherin, vimentin and transcription factors Snail, Slug and Zeb1. In conclusion, these data suggest that the combined inhibition of PI3K/Akt/mTOR and Shh pathways may be beneficial for the treatment of pancreatic cancer.

  19. Activation of endoplasmic reticulum stress promotes autophagy and apoptosis and reverses chemoresistance of human small cell lung cancer cells by inhibiting the PI3K/AKT/mTOR signaling pathway

    PubMed Central

    Yu, Xin-Shuang; Du, Juan; Fan, Yu-Jun; Liu, Feng-Jun; Cao, Li-Li; Liang, Ning; Xu, De-Guo; Zhang, Jian-Dong

    2016-01-01

    Objective This study aims to investigate the effects of endoplasmic reticulum stress (ERS) on autophagy, apoptosis and chemoresistance of human small cell lung cancer (SCLC) cells via the PI3K/AKT/mTOR signaling pathway. Results The expressions of ERS-related proteins (PEAK, eIF2α and CHOP) up-regulated, autophagy-related proteins (LC3, LC3-II and Beclin1) and apoptosis-related proteins (Bax and procaspase-3) down-regulated in NCI-H446 and H69 cells after tunicamycin treatment for 24 h. Compared with the blank group, the tunicamycin, BEZ235 and tunicamycin + BEZ235 groups exhibited decreased expressions of p-PI3K, p-AKT and p-mTOR, and increased expressions of autophagy-related proteins (LC3, LC3-II and Beclin1) and apoptosis proteins (Bax and procaspase-3), and the most obvious changes were observed in the tunicamycin + BEZ235 group. Materials and Methods CCK-8 assay was applied to select the best cell line from five SCLC cell lines (NCI-H446, H69, H526, H146 and H209). Finally, NCI-H446 and H69 cells were selected for further experiments. NCI-H446/CDDP and H69/CDDP were selected and divided into the blank group, tunicamycin (an ESR inducer) group, BEZ235 (inhibitors of PI3K/AKT/mTOR pathway) group and tunicamycin + BEZ235 group. Cell apoptosis was detected by flow cytometry. Autophagy was observed by fluorescence microscopy and flow cytometry. Western blotting was used to detect the expressions of ERS-related proteins, autophagy-related proteins, apoptosis-related proteins and PI3K/AKT/mTOR pathway-related proteins. Conclusions Our findings provide evidence that the activation of ERS could promote autophagy and apoptosis and reverse chemoresistance of human SCLC cells by inhibiting the PI3K/AKT/mTOR pathway. PMID:27765907

  20. PI3K/mTOR INHIBITION MARKEDLY POTENTIATES HDAC INHIBITOR ACTIVITY IN NHL CELLS THROUGH BIM- and MCL-1-DEPENDENT MECHANISMS IN VITRO AND IN VIVO

    PubMed Central

    Rahmani, Mohamed; Aust, Mandy Mayo; Benson, Elisa C; Wallace, LaShanale; Friedberg, Jonathan; Grant, Steven

    2014-01-01

    Purpose To explore the efficacy and define mechanisms of action of co-administration of the PI3K/mTOR inhibitor BEZ235 and pan-HDAC inhibitor panobinostat in DLBCL cells. Experimental Design Various DLBCL cells were exposed to panobinostat and BEZ235 alone or together after which apoptosis and signaling/survival pathway perturbations were monitored by flow cytometry and Western blot analysis. Genetic strategies defined the functional significance of such changes, and xenograft mouse models were used to assess tumor growth and animal survival. Results Panobinostat and BEZ235 interacted synergistically in ABC-, GC-, and double-hit DLBCL cells, and MCL cells, but not normal CD34+ cells. Synergism was associated with pronounced AKT dephosphorylation, GSK3 dephosphorylation/activation, Mcl-1 downregulation, Bim up-regulation and increased Bcl-2/Bcl-xL binding, diminished Bax/Bak binding to Bcl-2/Bcl-xL/Mcl-1, increased γH2A.X phosphorylation and histone H3/H4 acetylation, and abrogation of p21CIP1 induction. BEZ235/panobinostat lethality was not susceptible to stromal/microenvironmental forms of resistance. Genetic strategies confirmed significant functional roles for AKT inactivation, Mcl-1 down-regulation, Bim up-regulation, and Bax/Bak in synergism. Finally, co-administration of BEZ235 with panobinostat in immunocompromised mice bearing SU-DHL4-derived tumors significantly reduced tumor growth in association with similar signaling changes observed in vitro, and increased animal survival compared to single agents. Conclusions BEZ235/panobinostat exhibits potent anti-DLBCL activity, including in poor-prognosis ABC- and double-hit sub-types, but not in normal CD34+ cells. Synergism is most likely multi-factorial, involving AKT inactivation/GSK3 activation, Bim up-regulation, Mcl-1 down-regulation, enhanced DNA damage, and is operative in vivo. Combined PI3K/mTOR and HDAC inhibition warrants further attention in DLBCL. PMID:25070836

  1. Design and performance tests of a distributed power-driven wheel loader

    NASA Astrophysics Data System (ADS)

    Jin, Xiaolin; Shi, Laide; Bian, Yongming

    2010-03-01

    An improved ZLM15B distributed power-driven wheel loader was designed, whose travel and brake system was accomplished by two permanent magnet synchronous motorized-wheels instead of traditional mechanical components, and whose hydraulic systems such as the working device system and steering system were both actuated by an induction motor. All above systems were flexibly coupled with 3-phase 380VAC electric power with which the diesel engine power is replaced. On the level cement road, traveling, braking, traction and steering tests were carried out separately under non-load and heavy-load conditions. Data show that machine speed is 5 km/h around and travel efficiency of motorized-wheels is above 95%; that machine braking deceleration is between 0.5 and 0.64 m/s2 but efficiency of motorized-wheels is less than 10%; that maximum machine traction is above 2t while efficiency of motorized-wheels is more than 90% and that adaptive differential steering can be smoothly achieved by motorized-wheels.

  2. Design and performance tests of a distributed power-driven wheel loader

    NASA Astrophysics Data System (ADS)

    Jin, Xiaolin; Shi, Laide; Bian, Yongming

    2009-12-01

    An improved ZLM15B distributed power-driven wheel loader was designed, whose travel and brake system was accomplished by two permanent magnet synchronous motorized-wheels instead of traditional mechanical components, and whose hydraulic systems such as the working device system and steering system were both actuated by an induction motor. All above systems were flexibly coupled with 3-phase 380VAC electric power with which the diesel engine power is replaced. On the level cement road, traveling, braking, traction and steering tests were carried out separately under non-load and heavy-load conditions. Data show that machine speed is 5 km/h around and travel efficiency of motorized-wheels is above 95%; that machine braking deceleration is between 0.5 and 0.64 m/s2 but efficiency of motorized-wheels is less than 10%; that maximum machine traction is above 2t while efficiency of motorized-wheels is more than 90% and that adaptive differential steering can be smoothly achieved by motorized-wheels.

  3. MDM2 antagonists synergize with PI3K/mTOR inhibition in well-differentiated/dedifferentiated liposarcomas

    PubMed Central

    Laroche, Audrey; Chaire, Vanessa; Algeo, Marie-Paule; Karanian, Marie; Fourneaux, Benjamin; Italiano, Antoine

    2017-01-01

    Background Well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS) are characterized by a consistent amplification of the MDM2 gene. The PI3K/AKT/mTOR pathway has been suggested to play also an important role in their tumorigenesis. Our goal was to determine whether combined MDM2 and PI3K/AKT/mTOR targeting is associated with higher anti-tumor activity than single agent alone in preclinical models of WDLPS/DDLPS. Methods WDLPS/DDLPS cells were exposed to RG7388 (MDM2 antagonist) and BEZ235 (PI3K/mTOR dual inhibitor) after which apoptosis and signaling/survival pathway perturbations were monitored by flow cytometry and Western blot analysis. Xenograft mouse models were used to assess tumor growth and animal survival. Western blotting, histopathology, and tumor volume evolution were used for the assessment of treatment efficacy. Results The PI3K/AKT/mTOR was upregulated in up to 81% of the human WDLPS/DDLPS samples analysed. Treatment with RG7388 and BEZ235 resulted in a greater tumor activity than either drug alone with a significant difference in terms of cell viability after 72h of treatment with RG-73888 alone, BEZ235 alone and a combination of both agents. Consistent with these observations, we found a significant increase in apoptosis with the combination versus the single agent treatment alone. We then analysed the in vivo antitumor activity of RG7388 and BEZ235 in a xenograft model of DDLPS. The combination regimen significantly reduced tumor growth rate in comparison with single agent alone. Conclusions Our results represent the first in vivo evidence of synergy between MDM2 and PI3K/AKT/mTOR antagonists and represent a strong rationale to evaluate the therapeutic potential of such a combination in WDLPS/DDLPS.

  4. MDM2 antagonists synergize with PI3K/mTOR inhibition in well-differentiated/dedifferentiated liposarcomas.

    PubMed

    Laroche, Audrey; Chaire, Vanessa; Algeo, Marie-Paule; Karanian, Marie; Fourneaux, Benjamin; Italiano, Antoine

    2017-08-15

    Well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS) are characterized by a consistent amplification of the MDM2 gene. The PI3K/AKT/mTOR pathway has been suggested to play also an important role in their tumorigenesis. Our goal was to determine whether combined MDM2 and PI3K/AKT/mTOR targeting is associated with higher anti-tumor activity than single agent alone in preclinical models of WDLPS/DDLPS. WDLPS/DDLPS cells were exposed to RG7388 (MDM2 antagonist) and BEZ235 (PI3K/mTOR dual inhibitor) after which apoptosis and signaling/survival pathway perturbations were monitored by flow cytometry and Western blot analysis. Xenograft mouse models were used to assess tumor growth and animal survival. Western blotting, histopathology, and tumor volume evolution were used for the assessment of treatment efficacy. The PI3K/AKT/mTOR was upregulated in up to 81% of the human WDLPS/DDLPS samples analysed. Treatment with RG7388 and BEZ235 resulted in a greater tumor activity than either drug alone with a significant difference in terms of cell viability after 72h of treatment with RG-73888 alone, BEZ235 alone and a combination of both agents. Consistent with these observations, we found a significant increase in apoptosis with the combination versus the single agent treatment alone. We then analysed the in vivo antitumor activity of RG7388 and BEZ235 in a xenograft model of DDLPS. The combination regimen significantly reduced tumor growth rate in comparison with single agent alone. Our results represent the first in vivo evidence of synergy between MDM2 and PI3K/AKT/mTOR antagonists and represent a strong rationale to evaluate the therapeutic potential of such a combination in WDLPS/DDLPS.

  5. Dual inhibition of the PI3K/AKT/mTOR pathway suppresses the growth of leiomyosarcomas but leads to ERK activation through mTORC2: biological and clinical implications

    PubMed Central

    Fourneaux, Benjamin; Chaire, Vanessa; Lucchesi, Carlo; Karanian, Marie; Pineau, Raphael; Laroche-Clary, Audrey; Italiano, Antoine

    2017-01-01

    The PI3K/AKT/mTOR pathway plays a crucial role in the development of leiomyosarcomas (LMSs). In this study, we tested the efficacy of dual PI3K/mTOR (BEZ235), PI3K (BKM120) and mTOR (everolimus) inhibitors in three human LMS cell lines. In vitro and in vivo studies using LMS cell lines showed that BEZ235 has a significantly higher anti-tumor effect than either BKM120 or everolimus, resulting in a greater reduction in tumor growth and more pronounced inhibitory effects on mitotic activity and PI3K/AKT/mTOR signaling. Strikingly, BEZ235 but neither BKM120 nor everolimus markedly enhanced the ERK pathway. This effect was reproduced by the combination of BKM120 and everolimus, suggesting the involvement of mTORC2 via a PI3K-independent mechanism. Silencing of RICTOR in LMS cells confirmed the role of mTORC2 in the regulation of ERK activity. Combined treatment with BEZ235 and GSK1120212, a potent MEK inhibitor, resulted in synergistic growth inhibition and apoptosis induction in vitro and in vivo. These findings document for the first time that dual PI3K/mTOR inhibition in leiomyosarcomas suppress a negative feedback loop mediated by mTORC2, leading to enhanced ERK pathway activity. Thus, combining a dual PI3K/mTOR inhibitor with MEK inhibitors may be a relevant approach to increase anti-tumor activity and prevent drug resistance in patients with LMS. PMID:28002802

  6. Dual inhibition of the PI3K/AKT/mTOR pathway suppresses the growth of leiomyosarcomas but leads to ERK activation through mTORC2: biological and clinical implications.

    PubMed

    Fourneaux, Benjamin; Chaire, Vanessa; Lucchesi, Carlo; Karanian, Marie; Pineau, Raphael; Laroche-Clary, Audrey; Italiano, Antoine

    2017-01-31

    The PI3K/AKT/mTOR pathway plays a crucial role in the development of leiomyosarcomas (LMSs). In this study, we tested the efficacy of dual PI3K/mTOR (BEZ235), PI3K (BKM120) and mTOR (everolimus) inhibitors in three human LMS cell lines. In vitro and in vivo studies using LMS cell lines showed that BEZ235 has a significantly higher anti-tumor effect than either BKM120 or everolimus, resulting in a greater reduction in tumor growth and more pronounced inhibitory effects on mitotic activity and PI3K/AKT/mTOR signaling. Strikingly, BEZ235 but neither BKM120 nor everolimus markedly enhanced the ERK pathway. This effect was reproduced by the combination of BKM120 and everolimus, suggesting the involvement of mTORC2 via a PI3K-independent mechanism. Silencing of RICTOR in LMS cells confirmed the role of mTORC2 in the regulation of ERK activity. Combined treatment with BEZ235 and GSK1120212, a potent MEK inhibitor, resulted in synergistic growth inhibition and apoptosis induction in vitro and in vivo. These findings document for the first time that dual PI3K/mTOR inhibition in leiomyosarcomas suppress a negative feedback loop mediated by mTORC2, leading to enhanced ERK pathway activity. Thus, combining a dual PI3K/mTOR inhibitor with MEK inhibitors may be a relevant approach to increase anti-tumor activity and prevent drug resistance in patients with LMS.

  7. Kamera-basierte Erkennung von Geschwindigkeitsbeschränkungen auf deutschen Straen

    NASA Astrophysics Data System (ADS)

    Nienhüser, Dennis; Ziegenmeyer, Marco; Gumpp, Thomas; Scholl, Kay-Ulrich; Zöllner, J. Marius; Dillmann, Rüdiger

    An Fahrerassistenzsysteme im industriellen Einsatz werden hohe Anforderungen bezüglich Zuverlässigkeit und Robustheit gestellt. In dieser Arbeit wird die Kombination robuster Verfahren wie der Hough-Transformation und Support-Vektor-Maschinen zu einem Gesamtsystem zur Erkennung von Geschwindigkeitsbeschränkungen beschrieben. Es setzt eine Farbvideokamera als Sensorik ein. Die Evaluation auf Testdaten bestätigt durch die ermittelte hohe Korrektklassifikationsrate bei gleichzeitig geringer Zahl Fehlalarme die Zuverlässigkeit des Systems.

  8. Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma

    PubMed Central

    Chen, Ming-Huang; Chiang, Kun-Chun; Cheng, Chi-Tung; Huang, Shih-Chiang; Chen, Yeng-Yang; Chen, Tsung-Wen; Yeh, Ta-Sen; Jan, Yi-Yin; Wang, Hsi-Ming; Weng, Jiang-Jie; Chang, Peter Mu-Hsin; Liu, Chun-Yu; Li, Chung-Pin; Chao, Yee; Chen, Ming-Han; Huang, Chi-Ying F.; Yeh, Chun-Nan

    2014-01-01

    The PI3K/Akt/mTOR pathway is overactivated and heat shock protein (HSP) 90 is overexpressed in common cancers. We hypothesized that targeting both pathways can kill intrahepatic cholangiocarcinoma (CCA) cells. HSP90 and PTEN protein expression was evaluated by immunohistochemical staining of samples from 78 patients with intrahepatic CCA. CCA cell lines and a thioacetamide (TAA)-induced CCA animal model were treated with NVP-AUY922 (an HSP90 inhibitor) and NVP-BEZ235 (a PI3K/mTOR inhibitor) alone or in combination. Both HSP90 overexpression and loss of PTEN were poor prognostic factors in patients with intrahepatic CCA. The combination of the HSP90 inhibitor NVP-AUY922 and the PI3K/mTOR inhibitor NVP-BEZ235 was synergistic in inducing cell death in CCA cells. A combination of NVP-AUY922 and NVP-BEZ235 caused tumor regression in CCA rat animal model. This combination not only inhibited the PI3K/Akt/mTOR pathway but also induced ROS, which may exacerbate the vicious cycle of ER stress. Our data suggest simultaneous targeting of the PI3K/mTOR and HSP pathways for CCA treatment. PMID:24796583

  9. Co-targeting the PI3K/mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms

    PubMed Central

    Bartalucci, Niccolò; Tozzi, Lorenzo; Bogani, Costanza; Martinelli, Serena; Rotunno, Giada; Villeval, Jean-Luc; Vannucchi, Alessandro M

    2013-01-01

    Aberrant JAK2 signalling plays a central role in myeloproliferative neoplasms (MPN). JAK2 inhibitors have proven to be clinically efficacious, however, they are not mutation-specific and competent enough to suppress neoplastic clonal haematopoiesis. We hypothesized that, by simultaneously targeting multiple activated signalling pathways, MPN could be more effectively treated. To this end we investigated the efficacy of BEZ235, a dual PI3K/mTOR inhibitor, alone and in combination with the JAK1/JAK2 inhibitor ruxolitinib, in different preclinical models of MPN. Single-agent BEZ235 inhibited the proliferation and induced cell cycle arrest and apoptosis of mouse and human JAK2V617F mutated cell lines at concentrations significantly lower than those required to inhibit the wild-type counterpart, and preferentially prevented colony formation from JAK2V617F knock-in mice and patients' progenitor cells compared with normal ones. Co-treatment of BEZ235 and ruxolitinib produced significant synergism in all these in-vitro models. Co-treatment was also more effective than single drugs in reducing the extent of disease and prolonging survival of immunodeficient mice injected with JAK2V617F-mutated Ba/F3-EPOR cells and in reducing spleen size, decreasing reticulocyte count and improving spleen histopathology in conditional JAK2V617F knock-in mice. In conclusion, combined inhibition of PI3K/mTOR and JAK2 signalling may represent a novel therapeutic strategy in MPN. PMID:24237791

  10. Efficacy of Phosphatidylinositol-3 Kinase Inhibitors in a Primary Mouse Model of Undifferentiated Pleomorphic Sarcoma

    PubMed Central

    Kim, Suzy; Dodd, Rebecca D.; Mito, Jeffrey K.; Ma, Yan; Kim, Yongbaek; Riedel, Richard F.; Kirsch, David G.

    2012-01-01

    Recent advances in sarcoma genomics have identified novel mutations in the PI3K pathway in human sarcomas. Here, we use a mouse model of primary soft-tissue sarcoma for preclinical testing of doxorubicin and inhibitors of the PI3K pathway: BKM120 (PI3K inhibitor) and BEZ235 (a dual PI3K/mTOR inhibitor). Doxorubicin-treated tumors (n = 15) showed a partial response rate of 6.6%, just as the majority of human sarcomas do not respond to doxorubicin. Treatment with BKM120 elicited a partial response in 50% of tumors (n = 10), which was also seen in combination with doxorubicin (n = 10). Additionally, BKM120 treatment produced a robust delay in tumor growth kinetics. BEZ235-treated tumors (n = 9) showed a complete response rate of 11.1%. Combining BEZ235 with doxorubicin (n = 10) increased the complete response rate to 50% (P = 0.035). These studies demonstrate that PI3K pathway inhibition is a viable and attractive target for soft-tissue sarcomas. PMID:22619567

  11. mTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids.

    PubMed

    Gagliano, Teresa; Bellio, Mariaenrica; Gentilin, Erica; Molè, Daniela; Tagliati, Federico; Schiavon, Marco; Cavallesco, Narciso Giorgio; Andriolo, Luigi Gaetano; Ambrosio, Maria Rosaria; Rea, Federico; Degli Uberti, Ettore; Zatelli, Maria Chiara

    2013-08-01

    Bronchial carcinoids (BCs) are rare neuroendocrine tumors that are still orphans of medical treatment. Human BC primary cultures may display resistance to everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), in terms of cell viability reduction. Our aim was to assess whether the novel dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor NVP-BEZ235 is effective in everolimus-resistant human BC tissues and cell lines. In addition, we searched for possible markers of the efficacy of mTOR inhibitors that may help in identifying the patients who may benefit from treatment with mTOR inhibitors, sparing them from ineffective therapy. We found that NVP-BEZ235 is twice as potent as everolimus in reducing cell viability and activating apoptosis in human BC tissues that display sensitivity to mTOR inhibitors, but is not effective in everolimus-resistant BC tissues and cell lines that bypass cyclin D1 downregulation and escape G0/G1 blockade. Rebound AKT activation was not observed in response to treatment with either mTOR inhibitor in the 'resistant' BC cells. In addition to total mTOR levels, putative markers of the sensitivity of BCs to mTOR inhibitors are represented by AKT, p70S6K (RPS6KB2), and ERK1/2 (MAPK3/1) protein levels. Finally, we validated these markers in an independent BC group. These data indicate that the dual PI3K/mTOR inhibitor NVP-BEZ235 is more potent than everolimus in reducing the proliferation of human BC cells. 'Resistant' cells display lower levels of mTOR, p70S6K, AKT, and ERK1/2, indicating that these proteins may be useful as predictive markers of resistance to mTOR and PI3K/mTOR inhibitors in human BCs.

  12. Combined blockade of signalling pathways shows marked anti-tumour potential in phaeochromocytoma cell lines

    PubMed Central

    Nölting, Svenja; Garcia, Edwin; Alusi, Ghassan; Giubellino, Alessio; Pacak, Karel; Korbonits, Márta; Grossman, Ashley B

    2016-01-01

    Currently, there is no completely effective therapy available for metastatic phaeochromocytomas (PCCs) and paragangliomas. In this study, we explore new molecular targeted therapies for these tumours, using one more benign (mouse phaeochromocytoma cell (MPC)) and one more malignant (mouse tumour tissue (MTT)) mouse PCC cell line –both generated from heterozygous neurofibromin 1 knockout mice. Several PCC-promoting gene mutations have been associated with aberrant activation of PI3K/AKT, mTORC1 and RAS/RAF/ERK signalling. We therefore investigated different agents that interfere specifically with these pathways, including antagonism of the IGF1 receptor by NVP-AEW541. We found that NVP-AEW541 significantly reduced MPC and MTT cell viability at relatively high doses but led to a compensatory up-regulation of ERK and mTORC1 signalling at suboptimal doses while PI3K/AKT inhibition remained stable. We subsequently investigated the effect of the dual PI3K/mTORC1/2 inhibitor NVP-BEZ235, which led to a significant decrease of MPC and MTT cell viability at doses down to 50 nM but again increased ERK signalling. Accordingly, we next examined the combination of NVP-BEZ235 with the established agent lovastatin, as this has been described to inhibit ERK signalling. Lovastatin alone significantly reduced MPC and MTT cell viability at therapeutically relevant doses and inhibited both ERK and AKT signalling, but increased mTORC1/p70S6K signalling. Combination treatment with NVP-BEZ235 and lovastatin showed a significant additive effect in MPC and MTT cells and resulted in inhibition of both AKT and mTORC1/p70S6K signalling without ERK up-regulation. Simultaneous inhibition of PI3K/AKT, mTORC1/2 and ERK signalling suggests a novel therapeutic approach for malignant PCCs. PMID:22715163

  13. Unfälle mit Zweiradfahrzeugen

    NASA Astrophysics Data System (ADS)

    Tschirschwitz, Christian

    Auf einer außerörtlichen Bundesstraße kam es in einem Baustellenbereich zum frontalen Anprall eines Pkw Ford Fiesta an die rechte Flanke eines Fahrrads, welches durch einen Fußgänger von links nach rechts, bezüglich der Fahrtrichtung des Pkw, geschoben wurde. Das Fahrrad und der Fußgänger wurden auf den Vorbau des Pkw aufgeladen und etwa 15m weit geworfen. Der Fußgänger verstarb noch an der Unfallstelle.

  14. Komplexität der Geographie

    NASA Astrophysics Data System (ADS)

    Diekert, Volker; Hertrampf, Ulrich

    Das allgemein als Prototyp eines PSPACE-vollständigen Spiels gesehene Geographiespiel wird bezüglich seiner Komplexität genauer untersucht. Das Interesse der theoretischen Informatik an diesem Spiel wurde sehr durch die Darstellung in dem Lehrbuch von Papadimitriou [Pap94] gefördert. Allerdings bestimmt dieses Lehrbuch nicht die Komplexität des Standardspiels sondern verwendet eine Verallgemeinerung. Die Aussage in dem Lehrbuch bleibt damit etwas unbefriedigend und hinter den Möglichkeiten. Wir zeigen hier, dass die komplexitätstheoretische Charakterisierung schon für die Standardvariante des Spiels gilt.

  15. Deciphering Combinations of PI3K/AKT/mTOR Pathway Drugs Augmenting Anti-Angiogenic Efficacy In Vivo

    PubMed Central

    Sasore, Temitope; Kennedy, Breandán

    2014-01-01

    Ocular neovascularization is a common pathology associated with human eye diseases e.g. age-related macular degeneration and proliferative diabetic retinopathy. Blindness represents one of the most feared disabilities and remains a major burden to health-care systems. Current approaches to treat ocular neovascularisation include laser photocoagulation, photodynamic therapy and anti-VEGF therapies: Ranibizumab (Lucentis) and Aflibercept (Eylea). However, high clinical costs, frequent intraocular injections, and increased risk of infections are challenges related with these standards of care. Thus, there is a clinical need to develop more effective drugs that overcome these challenges. Here, we focus on an alternative approach by quantifying the in vivo anti-angiogenic efficacy of combinations of phosphatidylinositol-3-kinase (PI3K) pathway inhibitors. The PI3K/AKT/mTOR pathway is a complex signalling pathway involved in crucial cellular functions such as cell proliferation, migration and angiogenesis. RT-PCR confirms the expression of PI3K target genes (pik3ca, pik3r1, mtor and akt1) in zebrafish trunks from 6 hours post fertilisation (hpf) and in eyes from 2 days post fertilisation (dpf). Using both the zebrafish intersegmental vessel and hyaloid vessel assays to measure the in vivo anti-angiogenic efficacy of PI3K/Akt/mTOR pathway inhibitors, we identified 5 µM combinations of i) NVP-BEZ235 (dual PI3K-mTOR inhibitor) + PI-103 (dual PI3K-mTOR inhibitor); or ii) LY-294002 (pan-PI3K inhibitor) + NVP-BEZ235; or iii) NVP-BEZ235 + rapamycin (mTOR inhibitor); or iv) LY-294002 + rapamycin as the most anti-angiogenic. Treatment of developing larvae from 2–5 dpf with 5 µM NVP-BEZ235 plus PI-103 resulted in an essentially intact ocular morphology and visual behaviour, whereas other combinations severely disrupted the developing retinal morphology and visual function. In human ARPE19 retinal pigment epithelium cells, however, no significant difference in cell number was

  16. Evaluation of in vitro effects of various targeted drugs on plasma cells and putative neoplastic stem cells in patients with multiple myeloma

    PubMed Central

    Blatt, Katharina; Herrmann, Harald; Stefanzl, Gabriele; Sperr, Wolfgang R.; Valent, Peter

    2016-01-01

    Multiple myeloma (MM) is a malignancy characterized by monoclonal paraproteinemia and tissue plasmocytosis. In advanced MM cytopenia and osteopathy may occur. Although several effective treatment strategies have been developed in recent years, there is still a need to identify new drug targets and to develop more effective therapies for patients with advanced MM. We examined the effects of 15 targeted drugs on growth and survival of primary MM cells and 5 MM cell lines (MM.1S, NCI-H929, OPM-2, RPMI-8226, U-266). The PI3-kinase blocker BEZ235, the pan-BCL-2 inhibitor obatoclax, the Hsp90-targeting drug 17AAG, and the Polo-like kinase-1 inhibitor BI2536, were found to exert major growth-inhibitory effects in all 5 MM cell lines tested. Moreover, these drugs suppressed the in vitro proliferation of primary bone marrow-derived MM cells and induced apoptosis at pharmacologic drug concentrations. Apoptosis-inducing effects were not only seen in the bulk of MM cells but also in MM stem cell-containing CD138−/CD20+/CD27+ memory B-cell fractions. Synergistic growth-inhibitory effects were observed in MM cell lines using various drug combinations, including 17AAG+BI2536 in MM.1S, OPM-2, RPMI-8226, and U-266 cells, 17AAG+BEZ235 in MM.1S, OPM-2, RPMI-8226, and U-266 cells, 17AAG+obatoclax in MM.1S, NCI-H929, OPM-2, and RPMI-8226 cells, BI2536+BEZ235 in MM.1S, NCI-H929, OPM-2, and RPMI-8226 cells, BI2536+obatoclax in MM.1S, OPM-2 and RPMI-8226 cells, and BEZ235+obatoclax in MM.1S and RPMI-8226 cells. Together, our data show that various targeted drugs induce profound and often synergistic anti-neoplastic effects in MM cells which may have clinical implications and may contribute to the development of novel treatment strategies in advanced MM. PMID:27582537

  17. Unfälle mit Zweiradfahrzeugen

    NASA Astrophysics Data System (ADS)

    Tschirschwitz, Christian

    Auf einer außerörtlichen Bundesstraße kam es in einem Baustellenbereich zum frontalen Anprall eines Pkw Ford Fiesta an die rechte Flanke eines Fahrrads, welches durch einen Fußgänger von links nach rechts, bezüglich der Fahrtrichtung des Pkw, geschoben wurde. Das Fahrrad und der Fußgänger wurden auf den Vorbau des Pkw aufgeladen und etwa 15m weit geworfen. Der Fußgänger verstarb noch an der Unfallstelle.

  18. Methodisches Vorgehen zur integralen Auslegung von Produkt und Montage

    NASA Astrophysics Data System (ADS)

    Meyer, André; Grauer, Matthias; Rittner, Martin; Zeltner, Stefan; März, Martin; Egelkraut, Sven; Birkner, Klaus; Braun, Steven

    Die Produktlebenszyklen werden durch den steigenden Wettbewerbsdruck stetig kürzer. Dies veranlasst Unternehmen, Produktinnovationen in immer geringeren Zeitabständen auf den Markt zu bringen und Produktentwicklungszeiten zu verkürzen. Zusätzlich wirken sich erhöhte Anforderungen bezüglich Produktzuverlässigkeit und -lebensdauer erschwerend aus. Um dieser Herausforderung zu begegnen ist eine enge Zusammenarbeit zwischen Entwicklung, Konstruktion, Fertigungsplanung und Prozessentwicklung unabdingbar, denn nur durch eine optimale Abstimmung von Konstruktion und Fertigungsprozess lassen sich die hohen Qualitätsanforderungen erfüllen.

  19. Different metabolic responses to PI3K inhibition in NSCLC cells harboring wild-type and G12C mutant KRAS

    PubMed Central

    Marabese, Mirko; Broggini, Massimo; Lupi, Monica; Pastorelli, Roberta

    2016-01-01

    KRAS mutations in non-small-cell lung cancer (NSCLC) patients are considered a negative predictive factor and indicate poor response to anticancer treatments. KRAS mutations lead to activation of the PI3K/akt/mTOR pathway, whose inhibition remains a challenging clinical target. Since the PI3K/akt/mTOR pathway and KRAS oncogene mutations all have roles in cancer cell metabolism, we investigated whether the activity of PI3K/akt/mTOR inhibitors (BEZ235 and BKM120) in cells harboring different KRAS status is related to their metabolic effect. Isogenic NSCLC cell clones expressing wild-type (WT) and mutated (G12C) KRAS were used to determine the response to BEZ235 and BKM120. Metabolomics analysis indicated the impairment of glutamine in KRAS-G12C and serine metabolism in KRAS-WT, after pharmacological blockade of the PI3K signaling, although the net effect on cell growth, cell cycle distribution and caspase activation was similar. PI3K inhibitors caused autophagy in KRAS-WT, but not in KRAS-G12C, where there was a striking decrease in ammonia production, probably a consequence of glutamine metabolism impairment. These findings lay the grounds for more effective therapeutic combinations possibly distinguishing wild-type and mutated KRAS cancer cells in NSCLC, exploiting their different metabolic responses to PI3K/akt/mTOR inhibitors. PMID:27283493

  20. Prognosis of probability of BRCA1 and BRCA2 mutations carriage in women with compromised family history of breast and/or ovarian cancer.

    PubMed

    Rybchenko, L A; Bychkova, A M; Skyban, G V; Klymenko, S V

    2013-01-01

    Obtjazhenist' simejnogo anamnezu shhodo raku molochnoi' zalozy ta/abo raku jajechnykiv mozhe svidchyty pro nosijstvo mutacii' v BRCA1 ta BRCA2 genah. Meta: ocinyty ta porivnjaty mozhlyvosti Manchesters'koi' bal'noi' systemy, algorytmu Penn II ta Myriad na indyvidual'nomu rivni vidriznjaty pacijentiv z mutacijeju BRCA1/2 ta osib bez mutantnyh alelej sered ukrai'ns'kyh zhinok z rannim rozvytkom raku molochnoi' zalozy ta/abo obtjazhenym simejnym anamnezom shhodo raku molochnoi' zalozy ta/abo raku jajechnykiv. Material ta metody doslidzhennja. Materialom doslidzhennja sluguvaly rezul'taty genealogichnogo, molekuljarno-genetychnogo ta kliniko-morfologichnogo obstezhennja 44 osib, hvoryh na rak molochnoi' zalozy, z rannim rozvytkom zahvorjuvannja abo z obtjazhenym simejnym anamnezom shhodo onkologichnoi' patologii' molochnoi' zalozy ta/abo jajechnykiv. Vyznachennja najbil'sh imovirnyh nosii'v mutacij BRCA1 i BRCA2 sered obstezhenyh zhinok provodyly za dopomogoju tr'oh vyshhezgadanyh algorytmiv. Rezul'taty ta vysnovky. Manchesters'ka bal'na systema maje krashhu zdatnist' na indyvidual'nomu rivni vidriznjaty pacijentiv z mutacijeju ta osib bez mutantnyh alelej. Ploshha pid kryvoju Manchesters'koi' bal'noi' systemy skladaje 0,84, Penn II – 0,66, Myriad – 0,68.

  1. MCL-1-independent mechanisms of synergy between dual PI3K/mTOR and BCL-2 inhibition in diffuse large B cell lymphoma

    PubMed Central

    Lee, J. Scott; Tang, Sarah S.; Ortiz, Veronica; Vo, Thanh-Trang; Fruman, David A.

    2015-01-01

    The PI3K/AKT/mTOR axis promotes survival and is a frequently mutated pathway in cancer. Yet, inhibitors targeting this pathway are insufficient to induce cancer cell death as single agents in some contexts, including diffuse large B cell lymphoma (DLBCL). In these situations, combinations with inhibitors targeting BCL-2 survival proteins (ABT-199 and ABT-263) may hold potential. Indeed, studies have demonstrated marked synergy in contexts where PI3K/mTOR inhibitors suppress expression of the pro-survival protein, MCL-1. In this study, we use BH3 profiling to confirm that BCL-2 and BCL-XL support survival following PI3K pathway inhibition, and that the dual PI3K/mTOR inhibitor BEZ235 strongly synergizes with BCL-2 antagonists in DLBCL. However, we identify an alternative mechanism of synergy between PI3K/mTOR and BCL-2 inhibitors, independent of MCL-1 down-regulation. Instead, we show that suppression of AKT activation by BEZ235 can induce the mitochondrial accumulation of pro-apoptotic BAD and BIM, and that expression of a constitutively active form of AKT prevents sensitization to BCL-2 antagonism. Thus, our work identifies an additional mechanism of synergy between PI3K pathway inhibitors and BCL-2 antagonists that strengthens the rationale for testing this combination in DLBCL. PMID:26460954

  2. Oncogenic features of the bone morphogenic protein 7 (BMP7) in pheochromocytoma

    PubMed Central

    Leinhäuser, Ines; Richter, Andrea; Lee, Misu; Höfig, Ines; Anastasov, Nataša; Fend, Falko; Ercolino, Tonino; Mannelli, Massimo; Gimenez-Roqueplo, Anne-Paule; Robledo, Mercedes; de Krijger, Ronald; Beuschlein, Felix; Atkinson, Michael J.; Pellegata, Natalia S.

    2015-01-01

    BMP7 is a growth factor playing pro- or anti-oncogenic roles in cancer in a cell type-dependent manner. We previously reported that the BMP7 gene is overexpressed in pheochromocytomas (PCCs) developing in MENX-affected rats and human patients. Here, analyzing a large cohort of PCC patients, we found that 72% of cases showed elevated levels of the BMP7 protein. To elucidate the role of BMP7 in PCC, we modulated its levels in PCC cell lines (overexpression in PC12, knockdown in MPC and MTT cells) and conducted functional assays. Active BMP signaling promoted cell proliferation, migration, and invasion, and sustained survival of MENX rat primary PCC cells. In PCC, BMP7 signals through the PI3K/AKT/mTOR pathway and causes integrin β1 up-regulation. Silencing integrin β1 in PC12 cells suppressed BMP7-mediated oncogenic features. Treatment of MTT cells with DMH1, a novel BMP antagonist, suppressed proliferation and migration. To verify the clinical applicability of our findings, we evaluated a dual PI3K/mTOR inhibitor (NVP-BEZ235) in MENX-affected rats in vivo. PCCs treated with NVP-BEZ235 had decreased proliferation and integrin β1 levels, and higher apoptosis. Altogether, BMP7 activates pro-oncogenic pathways in PCC. Downstream effectors of BMP7-mediated signaling may represent novel targets for treating progressive/inoperable PCC, still orphan of effective therapy. PMID:26337467

  3. On the history of plasma treatment and comparison of microbiostatic efficacy of a historical high-frequency plasma device with two modern devices.

    PubMed

    Napp, Judith; Daeschlein, Georg; Napp, Matthias; von Podewils, Sebastian; Gümbel, Denis; Spitzmueller, Romy; Fornaciari, Paolo; Hinz, Peter; Jünger, Michael

    2015-01-01

    Hintergrund: Kaltes Atmosphärendruckplasma (CAP) hat durch seine mannigfaltigen bioaktiven Eigenschaften ein neues medizinisches Feld definiert: die Plasmamedizin. Allerdings wurde vor etwa 100 Jahren CAP in verwandter Form in der Hochfrequenztherapie genutzt. Zielsetzung dieser Studie war eine Übersicht über die historischen Plasmabehandlungen zu gewinnen und Daten bezüglich der antimikrobiellen Wirkung eines historischen Hochfrequenzapparats zu gewinnen.Methode: Erstens wurde historische Literatur bezüglich CAP-Behandlungen ausgewertet, da aus dem heutigen Schrifttum keine Angaben gewonnen werden konnten. Zweitens wurde die Empfindlichkeit von fünf verschiedenen bakteriellen Wundisolaten auf Agar gegenüber einer historischen Plasmaquelle (violet wand [VW]) und zwei modernen Geräten (atmospheric pressure plasma jet [APPJ] und Dielectric Barrier Discharge [DBD]) ermittelt. Die erzielten Hemmhöfe wurde verglichen. Ergebnisse: Die seinerzeit populärsten elektromedizinischen Anwendungen erzeugten durch Glaselektroden sogenannte Effluvien, die mit modernem CAP verwandt sind. Alle drei untersuchten Plasmaquellen zeigten eine vollständige Eradikation aller behandelter Isolate im plasmabehandelten Bereich. Die historische Plasmaquelle (VW) war dabei ähnlich wirksam wie die modernen Plasmaquellen. Schlussfolgerung: In begrenztem Umfang kann retrograd ein Wirksamkeitsnachweis der historischen Plasmabehandlungen abgeleitet werden, insbesondere bei der Behandlung infektiöser Erkrankungen. Die zugrunde liegende Technologie könnte für die Entwicklung moderner Nachfolgegeräte genutzt werden.

  4. [Quality of involuntary hospital administration in Switzerland].

    PubMed

    Jäger, Matthias; Ospelt, Isabelle; Kawohl, Wolfram; Theodoridou, Anastasia; Rössler, Wulf; Hoff, Paul

    2014-05-21

    Fragestellung: Diese Studie hat zum Ziel, die vor Einführung des neuen Kindes- und Erwachsenenschutzrechts per Januar 2013 bestehende Praxis der Fürsorgerischen Freiheitsentziehung (FFE) anhand formaler und inhaltlicher Kriterien der Zuweisungsschreiben zu untersuchen. Hinweise auf Unterschiede zwischen Zuweisern mit verschiedenen professionellen Hintergründen sollen überprüft und die eingewiesenen Personen charakterisiert werden. Methode: Retrospektive Auswertung der Zuweisungsformulare und der Krankenakten sämtlicher per FFE in die Psychiatrische Universitätsklinik Zürich eingetretenen Patienten in einem Zeitraum von sechs Monaten (n=489). Resultate: Es bestehen erhebliche Mängel bezüglich formaler und insbesondere inhaltlicher Qualitätskriterien. Psychiatrische Fachärzte erstellen die Zeugnisse mit der höchsten Qualität, gefolgt von Notärzten sowie Spitälern und Hausärzten. Die Patienten dieser Zuweisergruppen unterscheiden sich bezüglich soziodemographischer und klinischer Variablen. Schlussfolgerungen: Die formale und insbesondere inhaltliche Qualität der Zwangseinweisungen ist angesichts der schwerwiegenden ethischen und juristischen Konsequenzen für die betroffene Person verbesserungsbedürftig. Die Auswirkungen der neuen Gesetzgebung auf die Qualität der Zuweisungen sollten überprüft werden, sodass etwaige Defizite in der Anwendung freiheitsbeschränkender Massnahmen in der Aus- und Weiterbildungspraxis adressiert werden können.

  5. Quantitative (31)P HR-MAS MR spectroscopy for detection of response to PI3K/mTOR inhibition in breast cancer xenografts.

    PubMed

    Esmaeili, Morteza; Bathen, Tone F; Engebråten, Olav; Mælandsmo, Gunhild M; Gribbestad, Ingrid S; Moestue, Siver A

    2014-06-01

    Phospholipid metabolites are of importance in cancer studies, and have been suggested as candidate metabolic biomarkers for response to targeted anticancer drugs. The purpose of this study was to develop a phosphorus ((31) P) high resolution magic angle spinning magnetic resonance spectroscopy protocol for quantification of phosphorylated metabolites in intact cancer tissue. (31) P spectra were acquired on a 14.1 T spectrometer with a triplet (1) H/(13) C/(31) P MAS probe. Quantification of metabolites was performed using the PULCON principle. Basal-like and luminal-like breast cancer xenografts were treated with the dual PI3K/mTOR inhibitor BEZ235, and the impact of treatment on the concentration of phosphocholine, glycerophosphocholine, phosphoethanolamine and glycerophosphoethanolamine was evaluated. In basal-like xenografts, BEZ235 treatment induced a significant decrease in phosphoethanolamine (-25.6%, P = 0.01) whilst phosphocholine (16.5%, P = 0.02) and glycerophosphocholine (37.3%, P < 0.001) were significantly increased. The metabolic changes could partially be explained by increased levels of phospholipase A2 group 4A (PLA2G4A). (31) P high resolution magic angle spinning magnetic resonance spectroscopy is a useful method for quantitative assessment of metabolic responses to PI3K inhibition. Using the PULCON principle for quantification, the levels of phosphocholine, glycerophosphocholine, phosphoethanolamine, and glycerophosphoethanolamine could be evaluated with high precision and accuracy. Copyright © 2013 Wiley Periodicals, Inc.

  6. Inhibition of constitutively activated phosphoinositide 3-kinase/AKT pathway enhances antitumor activity of chemotherapeutic agents in breast cancer susceptibility gene 1-defective breast cancer cells.

    PubMed

    Yi, Yong Weon; Kang, Hyo Jin; Kim, Hee Jeong; Hwang, Jae Seok; Wang, Antai; Bae, Insoo

    2013-09-01

    Loss or decrease of wild type BRCA1 function, by either mutation or reduced expression, has a role in hereditary and sporadic human breast and ovarian cancers. We report here that the PI3K/AKT pathway is constitutively active in BRCA1-defective human breast cancer cells. Levels of phospho-AKT are sustained even after serum starvation in breast cancer cells carrying deleterious BRCA1 mutations. Knockdown of BRCA1 in MCF7 cells increases the amount of phospho-AKT and sensitizes cells to small molecule protein kinase inhibitors (PKIs) targeting the PI3K/AKT pathway. Restoration of wild type BRCA1 inhibits the activated PI3K/AKT pathway and de-sensitizes cells to PKIs targeting this pathway in BRCA1 mutant breast cancer cells, regardless of PTEN mutations. In addition, clinical PI3K/mTOR inhibitors, PI-103, and BEZ235, showed anti-proliferative effects on BRCA1 mutant breast cancer cell lines and synergism in combination with chemotherapeutic drugs, cisplatin, doxorubicin, topotecan, and gemcitabine. BEZ235 synergizes with the anti-proliferative effects of gemcitabine by enhancing caspase-3/7 activity. Our results suggest that the PI3K/AKT pathway can be an important signaling pathway for the survival of BRCA1-defective breast cancer cells and pharmacological inhibition of this pathway is a plausible treatment for a subset of breast cancers.

  7. Bezafibrate and medroxyprogesterone acetate target resting and CD40L-stimulated primary marginal zone lymphoma and show promise in indolent B-cell non-Hodgkin lymphomas.

    PubMed

    Hayden, Rachel E; Kussaibati, Racha; Cronin, Laura M; Pratt, Guy; Roberts, Claudia; Drayson, Mark T; Bunce, Christopher M

    2015-04-01

    B cell non-Hodgkin lymphomas (B-NHLs) are the most common adult hematological cancers and many remain incurable. Development of chemotherapy regimens is confounded by the prevalence of B-NHL in older, frailer patients and the chemo-protective tumor microenvironment. Although biological therapies such as rituximab have significantly improved outcomes and selective kinase inhibitors are showing promise, the rate of new drug discovery remains disappointing, the treatments expensive and long-term benefits uncertain. An alternative strategy is redeployment of available, inexpensive and non-toxic drugs. Here, we demonstrate the antiproliferative and mitochondrial superoxide (MSO) driven pro-apoptotic activities of bezafibrate (BEZ) and medroxyprogesterone acetate (MPA) against B-NHL cells, with a bias toward MZL, in the presence and absence of the microenvironmental signal CD40L. Our study is the first to confirm the presence of CD40L within the lymph node of B-NHL and its capacity to drive B-NHL proliferation. These findings implicate BEZ + MPA as a potential therapeutic strategy in B-NHL.

  8. Active kinase profiling, genetic and pharmacological data define mTOR as an important common target in triple-negative breast cancer.

    PubMed

    Montero, J C; Esparís-Ogando, A; Re-Louhau, M F; Seoane, S; Abad, M; Calero, R; Ocaña, A; Pandiella, A

    2014-01-09

    Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer. Despite response to chemotherapy, relapses are frequent and resistance to available treatments is often seen in the metastatic setting. Therefore, identification of new therapeutic targets is required. With this aim, we have profiled the activation status of 44 receptor tyrosine kinases (RTKs) and their major signaling pathways in patient-derived TNBC tumors. Frequent co-activation of several RTKs as well as the extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and mammalian target of rapamycin (mTOR) routes was found. Pharmacologic targeting of the activated kinases indicated that agents that attack the mTOR route are more potent and efficient antitumoral treatments than agents targeting RTKs. mTOR signals through two multiprotein complexes, mTORC1 and mTORC2. We used a genetic approach to explore the contribution of each of the two mTOR branches to the regulation of cell number of TNBC cells. RNA interference experiments indicated that mTORC1 predominated over mTORC2 in the control of TNBC cell proliferation. Moreover, RNA interference of mTOR had a superior antiproliferative action than separately acting on mTORC1 or mTORC2. To analyze the relevance of mTOR targeting in vivo, we used mice with TNBC. Treatment of these mice with BEZ235, a drug that targets mTOR, slowed tumor growth. Mechanistically, BEZ235 delayed cell cycle progression without affecting cell viability. Our results show that TNBCs are particularly sensitive to inhibition of the mTOR pathway, and indicate that mTOR targeting may be a more efficient anti-TNBC therapy than exclusively acting on the mTORC1 branch of the pathway. This is relevant as most mTOR inhibitors used in the clinic act on mTORC1. Collectively with the fact that BEZ235 synergized with drugs commonly used in the treatment of TNBC, our data support the clinical development of agents that act on mTOR as a therapy for this disease.

  9. Inhibition of PI3K/mTOR overcomes nilotinib resistance in BCR-ABL1 positive leukemia cells through translational down-regulation of MDM2.

    PubMed

    Ding, Jie; Romani, Julia; Zaborski, Margarete; MacLeod, Roderick A F; Nagel, Stefan; Drexler, Hans G; Quentmeier, Hilmar

    2013-01-01

    Chronic myeloid leukemia (CML) is a cytogenetic disorder resulting from formation of the Philadelphia chromosome (Ph), that is, the t(9;22) chromosomal translocation and the formation of the BCR-ABL1 fusion protein. Tyrosine kinase inhibitors (TKI), such as imatinib and nilotinib, have emerged as leading compounds with which to treat CML. t(9;22) is not restricted to CML, 20-30% of acute lymphoblastic leukemia (ALL) cases also carry the Ph. However, TKIs are not as effective in the treatment of Ph+ ALL as in CML. In this study, the Ph+ cell lines JURL-MK2 and SUP-B15 were used to investigate TKI resistance mechanisms and the sensitization of Ph+ tumor cells to TKI treatment. The annexin V/PI (propidium iodide) assay revealed that nilotinib induced apoptosis in JURL-MK2 cells, but not in SUP-B15 cells. Since there was no mutation in the tyrosine kinase domain of BCR-ABL1 in cell line SUP-B15, the cells were not generally unresponsive to TKI, as evidenced by dephosphorylation of the BCR-ABL1 downstream targets, Crk-like protein (CrkL) and Grb-associated binder-2 (GAB2). Resistance to apoptosis after nilotinib treatment was accompanied by the constitutive and nilotinib unresponsive activation of the phosphoinositide 3-kinase (PI3K) pathway. Treatment of SUP-B15 cells with the dual PI3K/mammalian target of rapamycin (mTOR) inhibitor BEZ235 alone induced apoptosis in a low percentage of cells, while combining nilotinib and BEZ235 led to a synergistic effect. The main role of PI3K/mTOR inhibitor BEZ235 and the reason for apoptosis in the nilotinib-resistant cells was the block of the translational machinery, leading to the rapid downregulation of the anti-apoptotic protein MDM2 (human homolog of the murine double minute-2). These findings highlight MDM2 as a potential therapeutic target to increase TKI-mediated apoptosis and imply that the combination of PI3K/mTOR inhibitor and TKI might form a novel strategy to combat TKI-resistant BCR-ABL1 positive leukemia.

  10. Inhibition of PI3K/mTOR Overcomes Nilotinib Resistance in BCR-ABL1 Positive Leukemia Cells through Translational Down-Regulation of MDM2

    PubMed Central

    Ding, Jie; Romani, Julia; Zaborski, Margarete; MacLeod, Roderick A. F.; Nagel, Stefan; Drexler, Hans G.; Quentmeier, Hilmar

    2013-01-01

    Chronic myeloid leukemia (CML) is a cytogenetic disorder resulting from formation of the Philadelphia chromosome (Ph), that is, the t(9;22) chromosomal translocation and the formation of the BCR-ABL1 fusion protein. Tyrosine kinase inhibitors (TKI), such as imatinib and nilotinib, have emerged as leading compounds with which to treat CML. t(9;22) is not restricted to CML, 20-30% of acute lymphoblastic leukemia (ALL) cases also carry the Ph. However, TKIs are not as effective in the treatment of Ph+ ALL as in CML. In this study, the Ph+ cell lines JURL-MK2 and SUP-B15 were used to investigate TKI resistance mechanisms and the sensitization of Ph+ tumor cells to TKI treatment. The annexin V/PI (propidium iodide) assay revealed that nilotinib induced apoptosis in JURL-MK2 cells, but not in SUP-B15 cells. Since there was no mutation in the tyrosine kinase domain of BCR-ABL1 in cell line SUP-B15, the cells were not generally unresponsive to TKI, as evidenced by dephosphorylation of the BCR-ABL1 downstream targets, Crk-like protein (CrkL) and Grb-associated binder-2 (GAB2). Resistance to apoptosis after nilotinib treatment was accompanied by the constitutive and nilotinib unresponsive activation of the phosphoinositide 3-kinase (PI3K) pathway. Treatment of SUP-B15 cells with the dual PI3K/mammalian target of rapamycin (mTOR) inhibitor BEZ235 alone induced apoptosis in a low percentage of cells, while combining nilotinib and BEZ235 led to a synergistic effect. The main role of PI3K/mTOR inhibitor BEZ235 and the reason for apoptosis in the nilotinib-resistant cells was the block of the translational machinery, leading to the rapid downregulation of the anti-apoptotic protein MDM2 (human homolog of the murine double minute-2). These findings highlight MDM2 as a potential therapeutic target to increase TKI-mediated apoptosis and imply that the combination of PI3K/mTOR inhibitor and TKI might form a novel strategy to combat TKI-resistant BCR-ABL1 positive leukemia. PMID

  11. Effects of temperature on biological and biochemical indicators of the life-history strategy of bullhead Cottus gobio.

    PubMed

    Reyjol, Y; Léna, J-P; Hervant, F; Pont, D

    2009-10-01

    The biological and biochemical effects of temperature on life-history strategy of female bullhead Cottus gobio were investigated. Fish from two populations (Bez Basin, south-east France) experiencing contrasted thermal environments (i.e. more or less stable) were reared during 4 months at three distinct temperatures (7, 9 or 12 degrees C). Both somatic (soma fresh mass and muscle triglyceride content) and reproductive (gonad fresh mass, fecundity, mean diameter of eggs and gonad triglyceride content) indicators were examined. Mixed models indicated that an increasing temperature had significant negative effects on all life-history indicators except for soma fresh mass. Differences in life-history strategy with regard to muscle and gonad triglyceride contents, however, suggest that populations experiencing more variable thermal environments may be better adapted than others to cope with an increasing temperature. These findings may have important implications for C. gobio populations, within the context of climate warming.

  12. [MBA - The Physician of Tomorrow?

    PubMed

    Bork, U; Welsch, T; Weitz, J

    2015-12-01

    In den letzten zehn Jahren hat sich das deutsche Gesundheitssystem zunehmend gewandelt. Kliniken stehen unter deutlichem ökonomischen Druck und betriebswirtschaftliches Wissen wird auch für Mediziner immer wichtiger, auch um mit der Klinikverwaltung optimal im Sinne der Patienten zusammenarbeiten zu können. Medizin und Ökonomie stehen hierbei nicht im Widerspruch zueinander. Durch effizientere Leitung einer Abteilung lassen sich häufig Ressourcen einsparen, Prozessabläufe besser gestalten und auch für den Patienten vorteilhafte Ergebnisse bezüglich Service und medizinischer Qualität erzielen.In den letzten Jahren hat das Angebot an ökonomischen und betriebswirtschaftlichen Zusatzstudiengängen und Weiterbildungsangeboten für Mediziner stetig zugenommen und wird im Folgenden beleuchtet.

  13. Functional exploration of colorectal cancer genomes using Drosophila

    PubMed Central

    Bangi, Erdem; Murgia, Claudio; Teague, Alexander G.S.; Sansom, Owen J.; Cagan, Ross L.

    2016-01-01

    The multigenic nature of human tumours presents a fundamental challenge for cancer drug discovery. Here we use Drosophila to generate 32 multigenic models of colon cancer using patient data from The Cancer Genome Atlas. These models recapitulate key features of human cancer, often as emergent properties of multigenic combinations. Multigenic models such as ras p53 pten apc exhibit emergent resistance to a panel of cancer-relevant drugs. Exploring one drug in detail, we identify a mechanism of resistance for the PI3K pathway inhibitor BEZ235. We use this data to identify a combinatorial therapy that circumvents this resistance through a two-step process of emergent pathway dependence and sensitivity we term ‘induced dependence'. This approach is effective in cultured human tumour cells, xenografts and mouse models of colorectal cancer. These data demonstrate how multigenic animal models that reference cancer genomes can provide an effective approach for developing novel targeted therapies. PMID:27897178

  14. Straightforward synthesis of a novel ring-fused pyrazole-lactam and in vitro cytotoxic activity on cancer cell lines.

    PubMed

    Bertuzzi, G; Locatelli, E; Colecchia, D; Calandro, P; Bonini, B F; Chandanshive, J Z; Mazzanti, A; Zani, P; Chiariello, M; Comes Franchini, M

    2016-07-19

    In this paper a straightforward synthesis of a novel pyrazole derivative is reported. Prominent feature of this synthetic process is a 1,3-Dipolar Cycloaddition of a suitable nitrile imine with an activated α,β-unsaturated lactam to afford directly and regioselectively the corresponding ring-fused pyrazole. Having obtained the central core of the synthetic target, a double stepwise functionalization with a "side chain" characterized by a terminal cyclic aliphatic amine was carried out. This molecular structure was designed to interact strongly with typical biological residues, and indeed it showed potent anticancer capability: in vitro cytotoxicity test on five different cancer cell lines showed interesting IC50 values in the range of 15-60 μM for exposure time of 24-72 h, thus resulting comparable with commercially available and nowadays therapeutically exploited anticancer compounds, such as 5-FU and NVP-BEZ235.

  15. Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors

    PubMed Central

    Vandamme, Timon; Beyens, Matthias; de Beeck, Ken Op; Dogan, Fadime; van Koetsveld, Peter M; Pauwels, Patrick; Mortier, Geert; Vangestel, Christel; de Herder, Wouter; Van Camp, Guy; Peeters, Marc; Hofland, Leo J

    2016-01-01

    Background: The mTOR-inhibitor everolimus improves progression-free survival in advanced pancreatic neuroendocrine tumours (PNETs). However, adaptive resistance to mTOR inhibition is described. Methods: QGP-1 and BON-1, two human PNET cell lines, were cultured with increasing concentrations of everolimus up to 22 weeks to reach a dose of 1 μM everolimus, respectively, 1000-fold and 250-fold initial IC50. Using total DNA content as a measure of cell number, growth inhibitory dose–response curves of everolimus were determined at the end of resistance induction and over time after everolimus withdrawal. Response to ATP-competitive mTOR inhibitors OSI-027 and AZD2014, and PI3K-mTOR inhibitor NVP-BEZ235 was studied. Gene expression of 10 PI3K-Akt-mTOR pathway-related genes was evaluated using quantitative real-time PCR (RT–qPCR). Results: Long-term everolimus-treated BON-1/R and QGP-1/R showed a significant reduction in everolimus sensitivity. During a drug holiday, gradual return of everolimus sensitivity in BON-1/R and QGP-1/R led to complete reversal of resistance after 10–12 weeks. Treatment with AZD2014, OSI-027 and NVP-BEZ235 had an inhibitory effect on cell proliferation in both sensitive and resistant cell lines. Gene expression in BON-1/R revealed downregulation of MTOR, RICTOR, RAPTOR, AKT and HIF1A, whereas 4EBP1 was upregulated. In QGP-1/R, a downregulation of HIF1A and an upregulation of ERK2 were observed. Conclusions: Long-term everolimus resistance was induced in two human PNET cell lines. Novel PI3K-AKT-mTOR pathway-targeting drugs can overcome everolimus resistance. Differential gene expression profiles suggest different mechanisms of everolimus resistance in BON-1 and QGP-1. PMID:26978006

  16. [Caregivers' needs concerning mobility support of a family member with terminal cancer - a narrative review].

    PubMed

    Gattinger, Heidrun; Siegl, Eva; Senn, Beate; Hantikainen, Virpi

    2014-06-01

    Hintergrund: Die häusliche Pflege krebskranker Menschen wird häufig von Angehörigen übernommen. Die letzte Lebensphase geht in der Regel mit Einschränkungen der Bewegungsfähigkeit einher. Ziel: Ziel dieser narrativen Literaturübersicht ist es, die Bedürfnisse pflegender Angehöriger bezüglich Mobilitätsunterstützung und -förderung bei der alltäglichen Pflege des an Krebs erkrankten Familienmitgliedes am Lebensende zu erfassen. Methode: Die Literatursuche erfolgte in den Datenbanken Cochrane, PubMed, PsychINFO, ERIC und CINAHL. Eingeschlossen wurden englisch- und deutschsprachige Studien, die Bedürfnisse betreffend der Mobilitätsunterstützung und -förderung der Angehörigen hinsichtlich der häuslichen Pflege krebskranker Menschen untersuchten. Zwei Autorinnen beurteilten die methodische Qualität der eingeschlossenen Studien. Ergebnisse: Insgesamt wurden elf Studien mit unterschiedlichen Studiendesigns eingeschlossen. Die Ergebnisse zeigen, dass das Bedürfnis nach Information, Anleitung und Unterstützung betreffend Mobilität in zwei Bereichen besteht: i) Tätigkeiten des alltäglichen Lebens inklusive Körperpflege und ii) Einsatz von Hilfsmitteln inklusive Transport. Schlussfolgerung: Die Literaturanalyse zeigt, dass Bedürfnisse pflegender Angehöriger zu pflegerischen Skills bezüglich der Mobilitätsunterstützung und -förderung unzureichend und unsystematisch beschrieben sind. Zukünftige Studien sind notwendig, in denen diese Bedürfnisse systematisch untersucht werden, um darauf aufbauend gut definierte Interventionen für die Vermittlung pflegerischer Skills zu entwickeln.

  17. Co-targeting Deoxyribonucleic Acid–Dependent Protein Kinase and Poly(Adenosine Diphosphate-Ribose) Polymerase-1 Promotes Accelerated Senescence of Irradiated Cancer Cells

    SciTech Connect

    Azad, Arun; Bukczynska, Patricia; Jackson, Susan; Haput, Ygal; Cullinane, Carleen; McArthur, Grant A.; Solomon, Benjamin

    2014-02-01

    Purpose: To examine the effects of combined blockade of DNA-dependent protein kinase (DNA-PK) and poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1) on accelerated senescence in irradiated H460 and A549 non-small cell lung cancer cells. Methods and Materials: The effects of KU5788 and AG014699 (inhibitors of DNA-PK and PARP-1, respectively) on clonogenic survival, DNA double-strand breaks (DSBs), apoptosis, mitotic catastrophe, and accelerated senescence in irradiated cells were examined in vitro. For in vivo experiments, H460 xenografts established in athymic nude mice were treated with BEZ235 (a DNA-PK, ATM, and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor) and AG014699 to determine effects on proliferation, DNA DSBs, and accelerated senescence after radiation. Results: Compared with either inhibitor alone, combination treatment with KU57788 and AG014699 reduced postradiation clonogenic survival and significantly increased persistence of Gamma-H2AX (γH2AX) foci in irradiated H460 and A549 cells. Notably, these effects coincided with the induction of accelerated senescence in irradiated cells as reflected by positive β-galactosidase staining, G2-M cell-cycle arrest, enlarged and flattened cellular morphology, increased p21 expression, and senescence-associated cytokine secretion. In irradiated H460 xenografts, concurrent therapy with BEZ235 and AG014699 resulted in sustained Gamma-H2AX (γH2AX) staining and prominent β-galactosidase activity. Conclusion: Combined DNA-PK and PARP-1 blockade increased tumor cell radiosensitivity and enhanced the prosenescent properties of ionizing radiation in vitro and in vivo. These data provide a rationale for further preclinical and clinical testing of this therapeutic combination.

  18. Dual PI3K/mTOR Inhibition in Colorectal Cancers with APC and PIK3CA Mutations.

    PubMed

    Foley, Tyler M; Payne, Susan N; Pasch, Cheri A; Yueh, Alex E; Van De Hey, Dana R; Korkos, Demetra P; Clipson, Linda; Maher, Molly E; Matkowskyj, Kristina A; Newton, Michael A; Deming, Dustin A

    2017-02-09

    Therapeutic targeting of the PI3K pathway is an active area of research in multiple cancer types, including breast and endometrial cancers. This pathway is commonly altered in cancer and plays an integral role in numerous vital cellular functions. Mutations in the PIK3CA gene, resulting in a constitutively active form of PI3K, often occur in colorectal cancer, though the population of patients who would benefit from targeting this pathway has yet to be identified. In human colorectal cancers, PIK3CA mutations most commonly occur concomitantly with loss of adenomatous polyposis coli (APC). Here, treatment strategies are investigated that target the PI3K pathway in colon cancers with mutations in APC and PIK3CA Colorectal cancer spheroids with Apc and Pik3ca mutations were generated and characterized confirming that these cultures represent the tumors from which they were derived. Pan and alpha isomer-specific PI3K inhibitors did not induce a significant treatment response, whereas the dual PI3K/mTOR inhibitors BEZ235 and LY3023414 induced a dramatic treatment response through decreased cellular proliferation and increased differentiation. The significant treatment responses were confirmed in mice with Apc and Pik3ca-mutant colon cancers as measured using endoscopy with a reduction in median lumen occlusion of 53% with BEZ235 and a 24% reduction with LY3023414 compared with an increase of 53% in controls (P < 0.001 and P = 0.03, respectively). This response was also confirmed with (18)F-FDG microPET/CT imaging.Implications: Spheroid models and transgenic mice suggest that dual PI3K/mTOR inhibition is a potential treatment strategy for APC and PIK3CA-mutant colorectal cancers. Thus, further clinical studies of dual PI3K/mTOR inhibitors are warranted in colorectal cancers with these mutations. Mol Cancer Res; 15(3); 1-11. ©2016 AACR.

  19. PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways.

    PubMed

    Chang, L; Graham, P H; Hao, J; Ni, J; Bucci, J; Cozzi, P J; Kearsley, J H; Li, Y

    2014-10-02

    The PI3K/Akt/mTOR pathway has a central role in cancer metastasis and radiotherapy. To develop effective therapeutics to improve radiosensitivity, understanding the possible pathways of radioresistance involved and the effects of a combination of the PI3K/Akt/mTOR inhibitors with radiotherapy on prostate cancer (CaP) radioresistant cells is needed. We found that compared with parent CaP cells, CaP-radioresistant cells demonstrated G0/G1 and S phase arrest, activation of cell cycle check point, autophagy and DNA repair pathway proteins, and inactivation of apoptotic proteins. We also demonstrated that compared with combination of single PI3K or mTOR inhibitors (BKM120 or Rapamycin) and radiation, low-dose of dual PI3K/mTOR inhibitors (BEZ235 or PI103) combined with radiation greatly improved treatment efficacy by repressing colony formation, inducing more apoptosis, leading to the arrest of the G2/M phase, increased double-strand break levels and less inactivation of cell cycle check point, autophagy and non-homologous end joining (NHEJ)/homologous recombination (HR) repair pathway proteins in CaP-radioresistant cells. This study describes the possible pathways associated with CaP radioresistance and demonstrates the putative mechanisms of the radiosensitization effect in CaP-resistant cells in the combination treatment. The findings from this study suggest that the combination of dual PI3K/Akt/mTOR inhibitors (BEZ235 or PI103) with radiotherapy is a promising modality for the treatment of CaP to overcome radioresistance.

  20. Activity guided isolation and modification of juglone from Juglans regia as potent cytotoxic agent against lung cancer cell lines.

    PubMed

    Zhang, Xue-Bang; Zou, Chang-Lin; Duan, Yu-Xia; Wu, Fang; Li, Gang

    2015-11-03

    Juglans regia has been found to exhibit significant anticancer activity against various human cancer cell lines. This study was undertaken to isolate the active chemical constituent (Juglone) and to investigate its cytotoxic activity along with its various analogs against different human cancer cell lines. Isolation of juglone, a napthoquinone, from the chloroform extract of the root part of Juglans regia was executed by flash chromatography using silica gel as stationary phase. The isolated Juglone was used as starting material for the further synthesis of a novel series of triazolyl analogs using click chemistry approach to investigate their cytotoxic potential against different human cancer cell lines using 3-(4,5-Dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) assay. The different extracts of Juglans regia and the isolated compound (juglone) exhibited satisfactory cytotoxic activity against a panel of eight different human cancer cell lines namely, prostate colon (Colo-205 and HCT-116), breast (T47D), prostate (PC-3 and DU-145), skin (A-431) and lung (NCI-H322 and A549). Interestingly, all the synthesised analogs displayed enhanced and selective cytotoxic activity against lung cancer cell lines only. Of the synthesized derivatives, 15a and 16a displayed the best activity with IC50 of 4.72 and 4.67 μM against A549 cells. Both these derivatives exhibited superior potency to BEZ-235 against both the lung cancer cell lines. So far as the structural aspects are concerned, electron withdrawing substituents at the ortho position of R moiety of the triazolyl analogs seem to be essential for attaining better activity. The present study demonstrates the selective and enhanced cytotoxic activity of the triazolyl analogs of juglone against NCI-H322 and A549 human lung cancer cell lines. Some derivatives exhibited superior potency to BEZ-235, a commercially available anticancer agent.

  1. RPPA-based protein profiling reveals eIF4G overexpression and 4E-BP1 serine 65 phosphorylation as molecular events that correspond with a pro-survival phenotype in chronic lymphocytic leukemia

    PubMed Central

    Shull, Austin Y.; Noonepalle, Satish K.; Awan, Farrukh T.; Liu, Jimei; Pei, Lirong; Bollag, Roni J.; Salman, Huda; Ding, Zhiyong; Shi, Huidong

    2015-01-01

    Chronic lymphocytic leukemia (CLL), the most common adult leukemia, remains incurable despite advancements in treatment regimens over the past decade. Several expression profile studies have been pursued to better understand CLL pathogenesis. However, these large-scale studies only provide information at the transcriptional level. To better comprehend the differential protein changes that take place in CLL, we performed a reverse-phase protein array (RPPA) analysis using 167 different antibodies on B-cell lysates from 18 CLL patients and 6 normal donors. From our analysis, we discovered an enrichment of protein alterations involved with mRNA translation, specifically upregulation of the translation initiator eIF4G and phosphorylation of the cap-dependent translation inhibitor 4E-BP1 at serine 65. Interestingly, 4E-BP1 phosphorylation occurred independently of AKT phosphorylation, suggesting a disconnect between PI3K/AKT pathway activation and 4E-BP1 phosphorylation. Based on these results, we treated primary CLL samples with NVP-BEZ235, a PI3K/mTOR dual inhibitor, and compared its apoptotic-inducing potential against the BTK inhibitor Ibrutinib and the PI3Kδ inhibitor Idelalisib. We demonstrated that treatment with NVP-BEZ235 caused greater apoptosis, greater apoptotic cleavage of eIF4G, and greater dephosphorylation of 4E-BP1 in primary CLL cells. Taken together, these results highlight the potential dependence of eIF4G overexpression and 4E-BP1 phosphorylation in CLL survival. PMID:25999352

  2. Identification of CD25 as STAT5-Dependent Growth-Regulator of Leukemic Stem Cells in Ph+ CML

    PubMed Central

    Sadovnik, Irina; Hoelbl-Kovacic, Andrea; Herrmann, Harald; Eisenwort, Gregor; Warsch, Wolfgang; Hoermann, Gregor; Greiner, Georg; Blatt, Katharina; Peter, Barbara; Stefanzl, Gabriele; Berger, Daniela; Bilban, Martin; Herndlhofer, Susanne; Sill, Heinz; Sperr, Wolfgang R.; Streubel, Berthold; Mannhalter, Christine; Holyoake, Tessa L.; Sexl, Veronika; Valent, Peter

    2015-01-01

    Purpose In chronic myeloid leukemia (CML), leukemic stem cells (LSCs) represent a critical target of therapy. However, little is known about markers and targets expressed by LSCs. The aim of this project was to identify novel interesting markers of CML LSCs. Experimental Design CML LSCs were examined by flow cytometry, qPCR, and various bioassays. In addition, we examined the multipotent CD25+ CML cell line KU812. Results In contrast to normal hematopoietic stem cells, CD34+/CD38− CML LSCs expressed the interleukin-2 receptor alpha chain, IL-2RA (CD25). STAT5 was found to induce expression of CD25 in Lin−/Sca-1+/Kit+ stem cells in C57Bl/6 mice. Correspondingly, shRNA-induced STAT5-depletion resulted in decreased CD25 expression in KU812 cells. Moreover, the BCR/ABL1 inhibitors nilotinib and ponatinib were found to decrease STAT5 activity and CD25 expression in KU812 cells and primary CML LSCs. A CD25-targeting shRNA was found to augment proliferation of KU812 cells in vitro and their engraftment in vivo in NOD/SCID-IL-2Rγ−/− mice. In drug-screening experiments, the PI3-Kinase/mTOR blocker BEZ235 promoted the expression of STAT5 and CD25 in CML cells. Finally, we found that BEZ235 produces synergistic anti-neoplastic effects on CML cells when applied in combination with nilotinib or ponatinib. Conclusion CD25 is a novel STAT5-dependent marker of CML LSCs and may be useful for LSC detection and LSC isolation in clinical practice and basic science. Moreover, CD25 serves as a growth-regulator of CML LSCs, which may have biological and clinical implications and may pave the way for the development of new more effective LSC-eradicating treatment strategies in CML. PMID:26607600

  3. Mismatch of arterial and central venous blood gas analysis during haemorrhage.

    PubMed

    Theusinger, Oliver M; Thyes, Caroline; Frascarolo, Philippe; Schramm, Sebastian; Seifert, Burkhardt; Spahn, Donat R

    2010-10-01

    Arterial base excess and lactate levels are key parameters in the assessment of critically ill patients. The use of venous blood gas analysis may be of clinical interest when no arterial blood is available initially. Twenty-four pigs underwent progressive normovolaemic haemodilution and subsequent progressive haemorrhage until the death of the animal. Base excess and lactate levels were determined from arterial and central venous blood after each step. In addition, base excess was calculated by the Van Slyke equation modified by Zander (BE(z)). Continuous variables were summarized as mean +/- SD and represent all measurements (n = 195). Base excess according to National Committee for Clinical Laboratory Standards for arterial blood was 2.27 +/- 4.12 versus 2.48 +/- 4.33 mmol(-l) for central venous blood (P = 0.099) with a strong correlation (r(2) = 0.960, P < 0.001). Standard deviation of the differences between these parameters (SD-DIFBE) did not increase (P = 0.355) during haemorrhage as compared with haemodilution. Arterial lactate was 2.66 +/- 3.23 versus 2.71 +/- 2.80 mmol(-l) in central venous blood (P = 0.330) with a strong correlation (r(2) = 0.983, P < 0.001). SD-DIFLAC increased (P < 0.001) during haemorrhage. BE(z) for central venous blood was 2.22 +/- 4.62 mmol(-l) (P = 0.006 versus arterial base excess according to National Committee for Clinical Laboratory Standards) with strong correlation (r(2) = 0.942, P < 0.001). SD-DIFBE(z)/base excess increased (P < 0.024) during haemorrhage. Central venous blood gas analysis is a good predictor for base excess and lactate in arterial blood in steady-state conditions. However, the variation between arterial and central venous lactate increases during haemorrhage. The modification of the Van Slyke equation by Zander did not improve the agreement between central venous and arterial base excess.

  4. A Polyphenol-Enriched Fraction of Rose Oil Distillation Wastewater Inhibits Cell Proliferation, Migration and TNF-α-Induced VEGF Secretion in Human Immortalized Keratinocytes.

    PubMed

    Wedler, Jonas; Rusanov, Krasimir; Atanassov, Ivan; Butterweck, Veronika

    2016-07-01

    Water steam distillation of rose flowers separates the essential oil from the polyphenol-containing rose oil distillation wastewater. Recently, a strategy was developed to separate rose oil distillation wastewater into a polyphenol depleted water fraction and a polyphenol-enriched fraction [RF20-(SP-207)]. The objective of the present study was to investigate RF20-(SP-207) and fraction F(IV), augmented in quercetin and ellagic acid, for possible antiproliferative effects in immortalized human keratinocytes (HaCaT) since rose petals are known to contain compounds with potential antiproliferative activity.RF20-(SP-207) revealed dose-dependent antiproliferative activity (IC50 of 9.78 µg/mL). In a nontoxic concentration of 10 µg/mL, this effect was stronger than that of the two positive controls LY294002 (10 µM, PI3 K-inhibitor, 30 % inhibition) and NVP-BEZ235 (100 nM, dual PI3 K/mTOR inhibitor, 30 % inhibition) and clearly exceeded the antiproliferative action of quercetin (50 µM, 25 % inhibition) and ellagic acid (1 µM, 15 % inhibition). Time-lapse microscopy detected a significant impairment of cell migration of RF20-(SP-207) and F(IV). At concentrations of 10 µg/mL of both, extract and fraction, cell migration was strongly suppressed (51 % and 28 % gap closure, respectively, compared to 95 % gap closure 24 hours after control treatment). The suppression of cell migration was comparable to the positive controls LY294002, NVP-BEZ235, and quercetin. Furthermore, basal and TNF-α-stimulated VEGF-secretion was significantly reduced by RF20-(SP-207) and F(IV) at 10 µg/mL (44 % vs. untreated control).In conclusion, RF20-(SP-207) showed promising antiproliferative and antimigratory effects and could be developed as a supportive, therapy against hyperproliferation-involved skin diseases.

  5. Development and Characterization of Bladder Cancer Patient-Derived Xenografts for Molecularly Guided Targeted Therapy

    PubMed Central

    Lin, Tzu-yin; Davis, Ryan R.; Keck, James; Ghosh, Paramita M.; Gill, Parkash; Airhart, Susan; Bult, Carol; Gandara, David R.; Liu, Edison; de Vere White, Ralph W.

    2015-01-01

    Background The overarching goal of this project is to establish a patient-derived bladder cancer xenograft (PDX) platform, annotated with deep sequencing and patient clinical information, to accelerate the development of new treatment options for bladder cancer patients. Herein, we describe the creation, initial characterization and use of the platform for this purpose. Methods and Findings Twenty-two PDXs with annotated clinical information were established from uncultured unselected clinical bladder cancer specimens in immunodeficient NSG mice. The morphological fidelity was maintained in PDXs. Whole exome sequencing revealed that PDXs and parental patient cancers shared 92–97% of genetic aberrations, including multiple druggable targets. For drug repurposing, an EGFR/HER2 dual inhibitor lapatinib was effective in PDX BL0440 (progression-free survival or PFS of 25.4 days versus 18.4 days in the control, p = 0.007), but not in PDX BL0269 (12 days versus 13 days in the control, p = 0.16) although both expressed HER2. To screen for the most effective MTT, we evaluated three drugs (lapatinib, ponatinib, and BEZ235) matched with aberrations in PDX BL0269; but only a PIK3CA inhibitor BEZ235 was effective (p<0.0001). To study the mechanisms of secondary resistance, a fibroblast growth factor receptor 3 inhibitor BGJ398 prolonged PFS of PDX BL0293 from 9.5 days of the control to 18.5 days (p<0.0001), and serial biopsies revealed that the MAPK/ERK and PIK3CA-AKT pathways were activated upon resistance. Inhibition of these pathways significantly prolonged PFS from 12 day of the control to 22 days (p = 0.001). To screen for effective chemotherapeutic drugs, four of the first six PDXs were sensitive to the cisplatin/gemcitabine combination, and chemoresistance to one drug could be overcome by the other drug. Conclusion The PDX models described here show good correlation with the patient at the genomic level and known patient response to treatment. This supports further

  6. Multi-Scale Genomic, Transcriptomic and Proteomic Analysis of Colorectal Cancer Cell Lines to Identify Novel Biomarkers

    PubMed Central

    Briffa, Romina; Um, Inhwa; Faratian, Dana; Zhou, Ying; Turnbull, Arran K.; Langdon, Simon P.; Harrison, David J.

    2015-01-01

    Selecting colorectal cancer (CRC) patients likely to respond to therapy remains a clinical challenge. The objectives of this study were to establish which genes were differentially expressed with respect to treatment sensitivity and relate this to copy number in a panel of 15 CRC cell lines. Copy number variations of the identified genes were assessed in a cohort of CRCs. IC50’s were measured for 5-fluorouracil, oxaliplatin, and BEZ-235, a PI3K/mTOR inhibitor. Cell lines were profiled using array comparative genomic hybridisation, Illumina gene expression analysis, reverse phase protein arrays, and targeted sequencing of KRAS hotspot mutations. Frequent gains were observed at 2p, 3q, 5p, 7p, 7q, 8q, 12p, 13q, 14q, and 17q and losses at 2q, 3p, 5q, 8p, 9p, 9q, 14q, 18q, and 20p. Frequently gained regions contained EGFR, PIK3CA, MYC, SMO, TRIB1, FZD1, and BRCA2, while frequently lost regions contained FHIT and MACROD2. TRIB1 was selected for further study. Gene enrichment analysis showed that differentially expressed genes with respect to treatment response were involved in Wnt signalling, EGF receptor signalling, apoptosis, cell cycle, and angiogenesis. Stepwise integration of copy number and gene expression data yielded 47 candidate genes that were significantly correlated. PDCD6 was differentially expressed in all three treatment responses. Tissue microarrays were constructed for a cohort of 118 CRC patients and TRIB1 and MYC amplifications were measured using fluorescence in situ hybridisation. TRIB1 and MYC were amplified in 14.5% and 7.4% of the cohort, respectively, and these amplifications were significantly correlated (p≤0.0001). TRIB1 protein expression in the patient cohort was significantly correlated with pERK, Akt, and Caspase 3 expression. In conclusion, a set of candidate predictive biomarkers for 5-fluorouracil, oxaliplatin, and BEZ235 are described that warrant further study. Amplification of the putative oncogene TRIB1 has been described for

  7. Untersuchung von asynchronen Timing-Strategien für digitale Subthreshold-Schaltungen

    NASA Astrophysics Data System (ADS)

    Lotze, N.; Ortmanns, M.; Manoli, Y.

    2008-05-01

    Eine der großen Herausforderungen beim Betrieb von Schaltungen bei extrem niedrigen Versorgungsspannungen ist die starke Zunahme des Einflusses zufälliger Prozessvariationen auf die Verzögerungszeiten der Gatter. Dies erfordert sehr hohe Sicherheitsmargen im Timing der Schaltungen, was zu einer deutlichen Verringerung der Geschwindigkeit und einem Anstieg der Energie pro Operation führt. Asynchrone Schaltungstechniken, die durch ihre Kodierung das Ende einer Operation detektieren können, sind daher bei dieser Anwendung eine interessante Alternative. In dieser Veröffentlichung werden die notwendigen Sicherheitsmargen in Delay-Line basierten Subthreshold-Schaltungen diskutiert und mögliche asynchrone Dual-Rail Entwurfsmethoden vorgestellt. Transistor-Level Simulationsergebnisse für einen einfachen, in den diskutierten Techniken realisierten Zähler werden vorgestellt, um die Funktionsfähigkeit dieser Techniken im Subthreshold-Bereich zu demonstrieren. Multiplizier mit unterschiedlicher Wortbreite dienen als Beispiel für eine komplexere Schaltung, welche bezüglich Geschwindigkeit, Energiebedarf und Flächenaufwand mit einer entsprechenden Standard-Realisierung verglichen wird, was abschließend eine Aussage darüber zulässt, wann die untersuchten Techniken gewinnbringend eingesetzt werden können.

  8. Sevoflurane Postconditioning Protects Rat Hearts against Ischemia-Reperfusion Injury via the Activation of PI3K/AKT/mTOR Signaling

    PubMed Central

    Zhang, Jing; Wang, Chen; Yu, Shuchun; Luo, Zhenzhong; Chen, Yong; Liu, Qin; Hua, Fuzhou; Xu, Guohai; Yu, Peng

    2014-01-01

    Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway plays a key role in myocardial ischemia-reperfusion (I/R) injury. Mammalian target of rapamycin (mTOR), a downstream target of PI3K/AKT signaling, is necessary and sufficient to protect the heart from I/R injury. Inhaled anesthetic sevoflurane is widely used in cardiac surgeries because its induction and recovery are faster and smoother than other inhaled anesthetics. Sevoflurane proved capable of inducing postconditioning effects in the myocardium. However, the underlying molecular mechanisms for sevoflurane-induced postconditioning (SPC) were largely unclear. In the present study, we demonstrated that SPC protects myocardium from I/R injury with narrowed cardiac infarct focus, increased ATP content, and decreased cardiomyocyte apoptosis, which are mainly due to the activation of PI3K/AKT/mTOR signaling and the protection of mitochondrial energy metabolism. Application of dactolisib (BEZ235), a PI3K/mTOR dual inhibitor, abolishes the up-regulation of pho-AKT, pho-GSK, pho-mTOR, and pho-p70s6k induced by SPC, hence abrogating the anti-apoptotic effect of sevoflurane and reducing SPC-mediated protection of heart from I/R injury. As such, this study proved that PI3K/AKT/mTOR pathway plays an important role in SPC induced cardiac protection against I/R injury. PMID:25471136

  9. Effect of kinase inhibitors on the therapeutic properties of monoclonal antibodies

    PubMed Central

    Duong, Minh Ngoc; Matera, Eva-Laure; Mathé, Doriane; Evesque, Anne; Valsesia-Wittmann, Sandrine; Clémenceau, Béatrice; Dumontet, Charles

    2015-01-01

    Targeted therapies of malignancies currently consist of therapeutic monoclonal antibodies and small molecule kinase inhibitors. The combination of these novel agents raises the issue of potential antagonisms. We evaluated the potential effect of 4 kinase inhibitors, including the Bruton tyrosine kinase inhibitor ibrutinib, and 3 PI3K inhibitors idelalisib, NVP-BEZ235 and LY294002, on the effects of the 3 monoclonal antibodies, rituximab and obinutuzumab (directed against CD20) and trastuzumab (directed against HER2). We found that ibrutinib potently inhibits antibody-dependent cell-mediated cytotoxicity exerted by all antibodies, with a 50% inhibitory concentration of 0.2 microM for trastuzumab, 0.5 microM for rituximab and 2 microM for obinutuzumab, suggesting a lesser effect in combination with obinutuzumab than with rituximab. The 4 kinase inhibitors were found to inhibit phagocytosis by fresh human neutrophils, as well as antibody-dependent cellular phagocytosis induced by the 3 antibodies. Conversely co-administration of ibrutinib with rituximab, obinutuzumab or trastuzumab did not demonstrate any inhibitory effect of ibrutinib in vivo in murine xenograft models. In conclusion, some kinase inhibitors, in particular, ibrutinib, are likely to exert inhibitory effects on innate immune cells. However, these effects do not compromise the antitumor activity of monoclonal antibodies in vivo in the models that were evaluated. PMID:25523586

  10. Comparative Analysis of Radiosensitizers for K-RAS Mutant Rectal Cancers

    PubMed Central

    Kim, Stephen Y.; Hong, Theodore S.; Haigis, Kevin M.

    2013-01-01

    Approximately 40% of rectal cancers harbor activating K-RAS mutations, and these mutations are associated with poor clinical response to chemoradiotherapy. We aimed to identify small molecule inhibitors (SMIs) that synergize with ionizing radiation (IR) (“radiosensitizers”) that could be incorporated into current treatment strategies for locally advanced rectal cancers (LARCs) expressing mutant K-RAS. We first optimized a high-throughput assay for measuring individual and combined effects of SMIs and IR that produces similar results to the gold standard colony formation assay. Using this screening platform and K-RAS mutant rectal cancer cell lines, we tested SMIs targeting diverse signaling pathways for radiosensitizing activity and then evaluated our top hits in follow-up experiments. The two most potent radiosensitizers were the Chk1/2 inhibitor AZD7762 and the PI3K/mTOR inhibitor BEZ235. The chemotherapeutic agent 5-fluorouracil (5-FU), which is used to treat LARC, synergized with AZD7762 and enhanced radiosensitization by AZD7762. This study is the first to compare different SMIs in combination with IR for the treatment of K-RAS mutant rectal cancer, and our findings suggest that Chk1/2 inhibitors should be evaluated in new clinical trials for LARC. PMID:24349411

  11. Ultra Low Power Bandgap Strom- und Spannungsquellen in CMOS-Technologie für integrierte drahtlose Systeme

    NASA Astrophysics Data System (ADS)

    Fedtschenko, T.; Kokozinski, R.; Kolnsberg, S.

    2006-09-01

    In modernen drahtlosen Systemen sind niedriger Stromverbrauch und das Betreiben bei niedriger Spannung (Low Voltage Operation) von entscheidender Bedeutung. Dabei ist für viele elektronische Anwendungen eine genaue Spannungs- bzw. Stromreferenz notwendig. Aus diesem Grund werden an eine Referenzquelle hohe Anforderungen bezüglich ihrer Temperatur- und Langzeitstabilität gestellt, was gleichzeitig schwierig mit den "Low-Power" Anforderungen zu vereinbaren ist. Besonders für die auf passiven Transpondern basierenden RFID-Systeme, bei denen die Energieversorgung der Schaltung aus dem Hochfrequenzträgersignal gewonnen wird, stellt die Erzeugung einer genauen Spannungsreferenz ein Problem dar. Vor allem die Spannungsstabilität und die Unabhängigkeit von Temperatur- und Prozessschwankungen bereiten große Schwierigkeiten. In diesem Artikel wird das Design einer CMOS Bandgap Strom- und Spannungsreferenz, realisiert in einer 0,25 μm CMOS-Prozess-Technologie, mit 2,5 V Versorgungsspannung vorgestellt. Die entwickelte Schaltung hat eine Stromaufnahme von 50 μA bei einer Genauigkeit von 1% im Temperaturbereich von -40°C bis 125°C. Ein Testchip wurde in die Fertigung eingespeist. Ausgehend von einem Überblick über bekannte Realisierungen von Bandgap-Schaltungen wird die Besonderheit der neu entwickelten Low-Power Schaltung vergleichend gegenübergestellt.

  12. CCR7 regulates Twist to induce the epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma.

    PubMed

    Li, Kexin; Xu, Baofeng; Xu, Guangying; Liu, Rui

    2016-01-01

    As reported, the CC chemokine receptor 7 (CCR7) trigger a series of signaling cascades in the epithelial-mesenchymal transition (EMT) of some malignancies. Meanwhile, Twist promotes EMT in pancreatic ductal adenocarcinoma (PDAC) progression. Here, effects of Twist on CCR7-induced EMT in the PDAC were investigated in detail. The immunohistochemistry was used to detect the expression of Twist, and then, in vitro assays were applied. The expression rate of Twist was 72.0 % in PDAC samples and closely correlated with tumor-node-metastasis (TNM) stage and invasion. When PDAC cell line PANC1 was subjected to CCL19 stimulation, the expression of p-ERK, p-AKT, Twist, N-cadherin, MMP9, and α-smooth muscle actin (α-SMA) was induced, while the GSK1120212, BEZ235, and MK2206 prohibited the increase of Twist and EMT biomarkers. For another thing, the si-Twist treatment attenuated CCL19-stimulated EMT occurrence, migration, and invasion phenotypes of PANC1 cells. In conclusion, CCR7 pathway up-regulates Twist expression via ERK and PI3K/AKT signaling to manage the EMT of PDAC. Our work allows for clinical gene or protein-targeted regimen of PDAC patients in the near future.

  13. Effects of inhibiting PI3K-Akt-mTOR pathway on lipid metabolism homeostasis in goose primary hepatocytes.

    PubMed

    Liu, D D; Han, C C; Wan, H F; He, F; Xu, H Y; Wei, S H; Du, X H; Xu, F

    2016-08-01

    Phosphatidylinositol-3 kinases (PI3K)-Protein kinase B (Akt)-mammalian target of rapamycin (mTOR) pathway plays an important role in the synthesis and secretion of triacylglycerol. However, the mechanism of PI3K-Akt-mTOR pathway in regulating lipid metabolism of goose liver was poorly understood. The purpose of this study was to determine how PI3K-Akt-mTOR pathway regulating lipid metabolic homeostasis in goose hepatocytes. Goose primary hepatocytes were treated with different PI3K-Akt-mTOR signal inhibitors (LY294002, rapamycin and NVP-BEZ235) for 24 h. The results showed that these inhibitors evidently inhibited PI3K-Akt-mTOR downstream signaling. Meanwhile, these PI3K-Akt-mTOR inhibitors reduced intracellular lipid accumulation, decreased the mRNA expression and protein content of genes involved in the de novo fatty acid synthesis, while increased the transcriptional and protein level of key factors involved in fatty acid oxidation and very low density lipoprotein (VLDL) assembly and secretion. These findings suggested that the reduction of lipids accumulation induced-by inhibiting PI3K-Akt-mTOR pathway was closely linked to the decrease of lipogenesis, the increase of fatty acids oxidation, and the increase of VLDL assembly and secretion in goose hepatocytes.

  14. Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors

    PubMed Central

    Echeverry, N; Ziltener, G; Barbone, D; Weder, W; Stahel, R A; Broaddus, V C; Felley-Bosco, E

    2015-01-01

    Malignant pleural mesothelioma (MPM) originates in most of the cases from chronic inflammation of the mesothelium due to exposure to asbestos fibers. Given the limited effect of chemotherapy, a big effort is being made to find new treatment options. The PI3K/mTOR pathway was reported to be upregulated in MPM. We tested the cell growth inhibition properties of two dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 on 19 MPM cell lines. We could identify resistant and sensitive lines; however, there was no correlation to the downregulation of PI3K/mTOR activity markers. As a result of mTOR inhibition, both drugs efficiently induced long-term autophagy but not cell death. Autophagy blockade by chloroquine in combination with the dual PI3K/mTOR inhibitors significantly induced caspase-independent cell death involving RIP1 in the sensitive cell line SPC212. Cell death in the resistant cell line Mero-82 was less pronounced, and it was not induced via RIP1-dependent mechanism, suggesting the involvement of RIP1 downstream effectors. Cell death induction was confirmed in 3D systems. Based on these results, we identify autophagy as one of the main mechanisms of cell death resistance against dual PI3K/mTOR inhibitors in MPM. As PI3K/mTOR inhibitors are under investigation in clinical trials, these results may help interpreting their outcome and suggest ways for intervention. PMID:25950487

  15. Investigation of the anti-glioma activity of Oviductus ranae protein hydrolysate.

    PubMed

    Sui, Xin; Li, Xiao-Hua; Duan, Ming-Hua; Jia, Ai-Ling; Wang, Ye; Liu, Da; Li, Yi-Ping; Qiu, Zhi-Dong

    2016-07-01

    Oviductus Ranae is the dry oviducts of Rana temporaria chensinensis, and it has been reported to have a range of biological activities. This study aimed to investigate the effects of Oviductus Ranae protein hydrolysate (ORPH) on human glioma C6 cell proliferation and apoptosis in vitro and in vivo. Following in vitro treatment, cell viability and colony formation assays showed that ORPH inhibited C6 cell proliferation. In addition, the results of western blotting also demonstrated that ORPH effectively regulated the expression of the apoptosis related proteins, cleaved caspase-3, Bax and Bcl-2, DNA staining and flow cytometry analysis demonstrated that ORPH significantly promoted apoptosis in this cell line, a finding that was confirmed in vivo using terminal deoxynucleotidyl transferase dUTP nick end labeling. Further investigation demonstrated that ORPH increased apoptosis by modulating the release of inflammatory cytokines and the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway; this was demonstrated using a PI3K/AKT inhibitor (NVP-BEZ235). In summary, the present study suggested that ORPH promoted apoptosis and inhibited glioma cell proliferation by influencing the PI3K/AKT signaling pathway. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  16. Autophagy and Akt promote survival in glioma.

    PubMed

    Fan, Qi-Wen; Weiss, William A

    2011-05-01

    Signaling through phosphatidylinositol 3-kinase (PtdIns3K)-Akt-mTOR is frequently activated in cancers including glioblastoma multiforme (GBM), where this kinase network regulates survival. It is thus surprising that inhibitors of these pathways induce minimal cell death in glioma. We showed that the dual PtdIns3K-mTOR inhibitor PI-103 induces autophagy in therapy-resistant, PTEN-mutant glioma, with blockade of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) contributing independently to autophagy. Inhibition of autophagosome maturation synergizes with PI-103 to induce apoptosis through the Bax-dependent intrinsic mitochondrial pathway, indicating that PI-103 induces autophagy as a survival pathway in this setting. Not all inhibitors of PtdIns3K-Akt-mTOR signaling synergize with inhibitors of autophagy. The allosteric mTORC1 inhibitor rapamycin fails to induce apoptosis in conjunction with blockade of autophagy, due to feedback-activation of Akt. Apoptosis in the setting of rapamycin therapy requires concurrent inhibition of both autophagy and of PtdIns3K-Akt. Moreover, the clinical PtdIns3K-mTOR inhibitor NVP-BEZ235 cooperates with the clinical lysosomotropic autophagy inhibitor chloroquine to induce apoptosis in PTEN-mutant glioma xenografts in vivo, offering a therapeutic approach translatable to patients.

  17. Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors.

    PubMed

    Echeverry, N; Ziltener, G; Barbone, D; Weder, W; Stahel, R A; Broaddus, V C; Felley-Bosco, E

    2015-05-07

    Malignant pleural mesothelioma (MPM) originates in most of the cases from chronic inflammation of the mesothelium due to exposure to asbestos fibers. Given the limited effect of chemotherapy, a big effort is being made to find new treatment options. The PI3K/mTOR pathway was reported to be upregulated in MPM. We tested the cell growth inhibition properties of two dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 on 19 MPM cell lines. We could identify resistant and sensitive lines; however, there was no correlation to the downregulation of PI3K/mTOR activity markers. As a result of mTOR inhibition, both drugs efficiently induced long-term autophagy but not cell death. Autophagy blockade by chloroquine in combination with the dual PI3K/mTOR inhibitors significantly induced caspase-independent cell death involving RIP1 in the sensitive cell line SPC212. Cell death in the resistant cell line Mero-82 was less pronounced, and it was not induced via RIP1-dependent mechanism, suggesting the involvement of RIP1 downstream effectors. Cell death induction was confirmed in 3D systems. Based on these results, we identify autophagy as one of the main mechanisms of cell death resistance against dual PI3K/mTOR inhibitors in MPM. As PI3K/mTOR inhibitors are under investigation in clinical trials, these results may help interpreting their outcome and suggest ways for intervention.

  18. Interfering with Resistance to Smoothened Antagonists by Inhibition of the PI3K Pathway in Medulloblastoma

    PubMed Central

    Buonamici, Silvia; Williams, Juliet; Morrissey, Michael; Wang, Anlai; Guo, Ribo; Vattay, Anthony; Hsiao, Kathy; Yuan, Jing; Green, John; Ospina, Beatrice; Yu, Qunyan; Ostrom, Lance; Fordjour, Paul; Anderson, Dustin L.; Monahan, John E.; Kelleher, Joseph F.; Peukert, Stefan; Pan, Shifeng; Wu, Xu; Maira, Sauveur-Michel; Garcia-Echeverria, Carlos; Briggs, Kimberly J.; Watkins, D. Neil; Yao, Yung-mae; Lengauer, Christoph; Warmuth, Markus; Sellers, William R.; Dorsch, Marion

    2012-01-01

    Mutations in Hedgehog (Hh) pathway genes, leading to constitutive activation of Smoothened (Smo), occur in medulloblastoma. Antagonists of Smo induce tumor regression in mouse models of medulloblastoma and hold great promise for treating this disease. However, acquired resistance has emerged as a challenge to targeted therapeutics and may limit their anti-cancer efficacy. Here, we describe novel mechanisms of acquired resistance to Smo antagonists in medulloblastoma. NVP-LDE225, a potent and selective Smo antagonist, inhibits Hh signaling and induces tumor regressions in allograft models of medulloblastoma that are driven by mutations of Patched (Ptch), a tumor suppressor in the Hh pathway. However, evidence of resistance was observed during the course of treatment. Molecular analysis of resistant tumors revealed distinct resistance mechanisms. Chromosomal amplification of Gli2, a downstream effector of Hh signaling, or more rarely point mutations in Smo led to reactivated Hh signaling and restored tumor growth. Unexpectedly, analysis of pathway gene-expression signatures selectively deregulated in resistant tumors identified increased phosphoinositide 3-kinase (PI3K) signaling as another potential resistance mechanism. Probing the functional relevance of increased PI3K signaling, we demonstrated that the combination of NVP-LDE225 with the PI3K class I inhibitor NVP-BKM120 or the dual PI3K/mTOR inhibitor NVP-BEZ235 markedly delayed the development of resistance. Our findings have important clinical implications for future treatment strategies in medulloblastoma. PMID:20881279

  19. Dual-Blocking of PI3K and mTOR Improves Chemotherapeutic Effects on SW620 Human Colorectal Cancer Stem Cells by Inducing Differentiation

    PubMed Central

    Kim, Buyun

    2016-01-01

    Cancer stem cells (CSCs) have tumor initiation, self-renewal, metastasis and chemo-resistance properties in various tumors including colorectal cancer. Targeting of CSCs may be essential to prevent relapse of tumors after chemotherapy. Phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signals are central regulators of cell growth, proliferation, differentiation, and apoptosis. These pathways are related to colorectal tumorigenesis. This study focused on PI3K and mTOR pathways by inhibition which initiate differentiation of SW620 derived CSCs and investigated its effect on tumor progression. By using rapamycin, LY294002, and NVP-BEZ235, respectively, PI3K and mTOR signals were blocked independently or dually in colorectal CSCs. Colorectal CSCs gained their differentiation property and lost their stemness properties most significantly in dual-blocked CSCs. After treated with anti-cancer drug (paclitaxel) on the differentiated CSCs cell viability, self-renewal ability and differentiation status were analyzed. As a result dual-blocking group has most enhanced sensitivity for anti-cancer drug. Xenograft tumorigenesis assay by using immunodeficiency mice also shows that dual-inhibited group more effectively increased drug sensitivity and suppressed tumor growth compared to single-inhibited groups. Therefore it could have potent anti-cancer effects that dual-blocking of PI3K and mTOR induces differentiation and improves chemotherapeutic effects on SW620 human colorectal CSCs. PMID:26955235

  20. The PI3K/Akt pathway contributes to arenavirus budding.

    PubMed

    Urata, Shuzo; Ngo, Nhi; de la Torre, Juan Carlos

    2012-04-01

    Several arenaviruses, chiefly Lassa virus (LASV), cause hemorrhagic fever (HF) disease in humans and pose a significant public health concern in regions where they are endemic. On the other hand, evidence indicates that the globally distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway participates in many cellular processes, including cell survival and differentiation, and also has been shown to play important roles in different steps of the life cycles of a variety of viruses. Here we report that the inhibition of the PI3K/Akt pathway inhibited budding and to a lesser extent RNA synthesis, but not cell entry, of LCMV. Accordingly, BEZ-235, a PI3K inhibitor currently in cancer clinical trials, inhibited LCMV multiplication in cultured cells. These findings, together with those previously reported for Junin virus (JUNV), indicate that targeting the PI3K/Akt pathway could represent a novel antiviral strategy to combat human-pathogenic arenaviruses.

  1. Role of radiosensitivity and radioresistance genetic markers in hematological and cardiovascular disease in persons exposed after the Chornobyl accident.

    PubMed

    Minchenko, J M; Dyagil, I S; Dmytrenko, O O; Dmytrenko, I V; Shlaykhtychenko, T Y; Gavrylenko, T I; Biliy, D O; Khomenko, V I; Bebeshko, V G

    2013-01-01

    Meta roboty poljagala u vyvchenni vnesku imunogenetychnoi' komponenty v formuvannja postradiacijnyh efektiv u viddalenomu periodi pislja oprominennja na rivni imunnogo reaguvannja organizmu ljudyny, jak prognostychnogo kryteriju ocinky ryzyku realizacii' radiacijno-asocijovanoi' somatychnoi' patologii'. Ob’jektom doslidzhennja buly rekonvalescenty gostroi' promenevoi' hvoroby (GPH) I stupenja tjazhkosti i 88 pacijentiv z analogichnym radiacijnym anamnezom, ale z nepidtverdzhenym diagnozom GPH, 73 pacijenty, jaki majut' status uchasnykiv likvidacii' naslidkiv Chornobyl's'koi' katastrofy (ULNChK) z hronichnoju ishemichnoju hvoroboju sercja (HIHS), 65 pacijentiv – ULNChK bez HIHS, 120 neoprominenyh pacijentiv z HIHS. Pacijenty z onkogematologichnoju patologijeju – 256 osib. 500 praktychno zdorovyh osib – populjacijnyj kontrol'. Rezul'taty. Na osnovi vyvchennja spektru imunologichnyh, gematologichnyh ta molekuljarno-genetychnyh porushen' u spivvidnoshenni z imunogenetychnymy chynnykamy vyznacheni markery ryzyku realizacii' genetychnoi' shyl'nosti do onkogematologichnoi' ta sercevo-sudynnoi' patologii' u zaznachenyh kontyngentiv. Vysnovky. Otrymani dani svidchat' pro te, shho odnym iz mehanizmiv formuvannja radiacijno-asocijovanoi' mul'tyfaktorial'noi' patologii', je realizacija HLA-genetychnoi' shyl'nosti do zahvorjuvannja, jak na rivni rozladiv u gemopoezi ta imunopoezi, tak i na rivni zahvorjuvannja v cilomu, a nosijstvo v feno/genotypi markeriv radiochutlyvosti pidvyshhuje ryzyk realizacii' patologichnogo procesu v umovah oprominennja.

  2. Student evaluation of problem-based learning in a dental orthodontic curriculum--a pilot study.

    PubMed

    Ratzmann, Anja; Wiesmann, U; Proff, P; Kordaß, Bernd; Gedrange, T

    2013-01-01

    Ziel: In der vorliegenden Fragebogenstudie wurde die studentische Rezeption des problemorientierten Lernens (POL) im Curriculum der Kieferorthopädie hinsichtlich Akzeptanz, Sinn/Motivation, Wissen/Verstehen und tutorieller Unterstützung) untersucht. Methode: Es erfolgte eine Gegenüberstellung zweier verschiedener didaktischer Methoden (POL, Kurzreferate) bei der Durchführung des kieferorthopädischen Diagnostikkurses in einem randomisierten Zwei-Gruppen-Plan über zwei Semester, in dem die Reihenfolge der Methoden variiert wurde. Ergebnisse: Es konnten keine Unterschiede zwischen den Gruppen bezüglich ihrer Einschätzungen und Prüfungsleistungen gefunden werden. Es zeigt sich, dass die Akzeptanz des POL hauptsächlich mit der individuellen Motivation zum POL zusammenhängt. Je höher die Motivation, desto positiver die Einstellung. Die Studierenden können mit der Methode effektiver und konstruktiver arbeiten, wenn sie selbst motiviert sind bzw. für sich einen Sinn in POL erkennen. Schlussfolgerung: Unter Berücksichtigung des Literaturstudiums und der vorliegenden Ergebnisse ist das POL grundsätzlich als Lehrmethode in die zahnmedizinische Ausbildung integrierbar. Die Motivation der Studierenden stellt einen entscheidenden Faktor für den Lernerfolg dar.

  3. Mixed convection from an isothermal vertical flat plate moving in parallel or reversely to a free stream

    NASA Astrophysics Data System (ADS)

    Lin, H.-T.; Hoh, H.-L.

    Mixed convection heat transfer from a vertically moving plate to a flowing free stream is investigated. The plate moves either in parallel or reversely to the free stream; and the buoyancy force accelerates or retards the flow. An universal formulation can be obtained from which similarity and nonsimilarity equations for six limiting cases of forced, natural, and mixed convection can be readily reduced. Accurate finite-difference solutions and comprehensive correlations of heat transfer rate for 0.01<=Pr<=10000 are presented over the entire domains of mixed convection and relative velocity. Zusammenfassung Die Untersuchung bezieht sich auf den Wärmeübergang bei Mischkonvektion an einer vertikalen Platte, die parallel zu einem Freistrom (gleich- oder gegensinnig) bewegt wird, wobei die Auftriebskraft fördernd oder hemmend auf die Strömung wirkt. Es läßt sich eine universelle Formulierung finden, aus der unmittelbar Ähnlichkeits- und Nichtähnlichkeitsgleichungen für sechs Grenzfälle bezüglich erzwungener, freier und gemischter Konvektion hergeleitet werden können. Genaue Finitdifferenzen-Lösungen und umfangreiche Berechnungsformeln für den gesamten Bereich der Mischkonvektion und der Relativgeschwindigkeit werden angegeben, wobei die Prandtl-Zahlen von 0,01 bis 10000 variieren.

  4. Berechnung von Nichtlinearitätsparametern von RF MOS Mischern mittels Volterra-Reihen

    NASA Astrophysics Data System (ADS)

    Susic, A.; Darrat, A. H.; Mathis, W.

    2011-07-01

    Die Nichtlinearität einer Mischerschaltung bezüglich des Informationssignals führt zu unerwünschten Spektralanteilen am Ausgang des Mischers. Da nicht alle Spektralanteile kritisch sind, müssen bei einer Nichtlinearitätsanalyse nur bestimmte Spektralanteile ermittelt werden. In dieser Arbeit wird ein Verfahren zur Bestimmung der Spektralanteile der Zustandsgrößen im Mischer mit Hilfe der Volterra-Reihe gezeigt. Das Verfahren basiert auf die Methode der nichtlinearen Stromquellen. Es wird sowohl auf nicht-schaltende als auch schaltende Mischer angewendet. Hierbei wird der erste als ein zeitinvariantes System mit zwei Eingängen und der zweite als ein periodisch zeitvariantes System mit einem Eingang modelliert. Das Verfahren wird in dem Computeralgebraprogramm MAPLE für den einfach balancierten MOS Mischer implementiert. Es ermöglicht die Herleitung von semi-symbolischen Ausdrücken für die Spektralanteile in Abhängigkeit von den Entwurfsparametern. Die numerischen Ergebnisse des Verfahrens werden gegenüber Simulationen mit SpectreRF verglichen.

  5. Prä- und perioperative Aspekte der Versorgung dermatochirurgischer Patienten.

    PubMed

    Müller, Cornelia S L; Hubner, Wakiko; Thieme-Ruffing, Sigrid; Pföhler, Claudia; Vogt, Thomas; Volk, Thomas; Gärtner, Barbara C; Bialas, Patric

    2017-02-01

    Die Dermatochirurgie nimmt hinsichtlich vieler Punkte eine Sonderstellung unter den operativen Fächern ein. Hierzu gehört in erster Linie die Tatsache, dass bis auf wenige Ausnahmen fast alle Eingriffe traditionell in Lokal- bzw. Regionalanästhesie und oft auch in räumlich-infrastruktureller Trennung von den großen Zentral-Operationssälen stattfinden können. Die peri- und postoperative Überwachung obliegt dabei dem dermatochirurgischen Operationsteam. Das sui generis kleinere OP-Team hat somit eine ganze Reihe perioperativer Notwendigkeiten zu beachten, um die sich in den "großen" chirurgischen Fächern eine Vielzahl verschiedener beteiligter Fachgruppen gemeinsam kümmern. Hierzu gehören neben Hygieneaspekten, Kenntnissen in der Überwachung der Patienten sowie dem Aspekt der surgical site infections auch Fragen zur postoperativen Schmerztherapie sowie detailliertes pharmakologisches Wissen über die zur Anwendung kommenden Lokalanästhetika und das Handling der damit assoziierten toxischen und allergischen Reaktionen. Eine interdisziplinäre Zusammenarbeit und Verantwortung für den Patienten ist notwendig und erfordert die Erarbeitung und Umsetzung qualitätsorientierter und evidenzbasierter Handlungsanweisungen, die im dermatochirurgischen OP-Setting meist weit über das eigentliche Fach hinausgehen. Ziel dieses Weiterbildungsartikels soll die komprimierte Darstellung der genannten fachübergreifenden Standpunkte bezüglich der wichtigsten perioperativen Aspekte sein. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  6. Synthesis and biological evaluation of novel 3-O-tethered triazoles of diosgenin as potent antiproliferative agents.

    PubMed

    Masood-Ur-Rahman; Mohammad, Younis; Fazili, Khalid Majid; Bhat, Khursheed Ahmad; Ara, Tabassum

    2017-02-01

    Diosgenin, a promising anticancer steroidal sapogenin, was isolated from Dioscorea deltoidea. Keeping its stereochemistry rich architecture intact, a scheme for the synthesis of novel diosgenin analogues was designed using Cu (I)-catalysed alkyne-azide cycloaddition in order to study their structure-activity relationship. Both diosgenin and its analogues exhibited interesting anti-proliferative effect against four human cancer cell lines viz. HBL-100 (breast), A549 (lung), HT-29 (colon) and HCT-116 (colon) using [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide] (MTT) assay. Among the synthesized analogues, Dgn-1 bearing a simple phenyl R moiety attached via triazole to the parent molecule was identified as the most potent analogue against A549 cancer cell line having IC50 of 5.54μM, better than the positive control (BEZ-235). Dgn-2 and Dgn-5 bearing o-nitrophenyl and o-cyanophenyl R moieties respectively, displayed impressive anti-proliferative activity against all the tested human cancer cell lines with IC50 values ranging from 5.77 to 9.44μM. The structure-activity relationship (SAR) revealed that the analogues with simple phenyl R moiety or electron withdrawing ortho substituted R moieties seem to have beneficial impact on the anti-proliferative activity.

  7. Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors

    PubMed Central

    Vaughan, Lynsey; Clarke, Paul A.; Barker, Karen; Chanthery, Yvan; Gustafson, Clay W.; Tucker, Elizabeth; Renshaw, Jane; Raynaud, Florence; Li, Xiaodun; Burke, Rosemary; Jamin, Yann; Robinson, Simon P.; Pearson, Andrew; Maira, Michel; Weiss, William A.; Workman, Paul; Chesler, Louis

    2016-01-01

    MYC oncoproteins deliver a potent oncogenic stimulus in several human cancers, making them major targets for drug development, but efforts to deliver clinically practical therapeutics have not yet been realized. In childhood cancer, aberrant expression of MYC and MYCN genes delineates a group of aggressive tumours responsible for a major proportion of pediatric cancer deaths. We designed a chemical-genetic screen that identifies compounds capable of enhancing proteasomal elimination of MYCN oncoprotein. We isolated several classes of compound that selectively kill MYCN expressing cells and we focus on inhibitors of PI3K/mTOR pathway in this study. We show that PI3K/mTOR inhibitors selectively killed MYCN-expressing neuroblastoma tumor cells, and induced significant apoptosis of transgenic MYCN-driven neuroblastoma tumors concomitant with elimination of MYCN protein in vivo. Mechanistically, the ability of these compounds to degrade MYCN requires complete blockade of mTOR but not PI3 kinase activity and we highlight NVP-BEZ235 as a PI3K/mTOR inhibitor with an ideal activity profile. These data establish that MYCN expression is a marker indicative of likely clinical sensitivity to mTOR inhibition, and provide a rationale for the selection of clinical candidate MYCN-destabilizers likely to be useful for the treatment of MYCN-driven cancers. PMID:27438153

  8. NASA's Best-Observed X-Class Flare of All Time

    NASA Image and Video Library

    2017-09-27

    A combination of many (but not all) of the datasets which observed this flare. -- On March 29, 2014 the sun released an X-class flare. It was observed by NASA's Interface Region Imaging Spectrograph, or IRIS; NASA's Solar Dynamics Observatory, or SDO; NASA's Reuven Ramaty High Energy Solar Spectroscopic Imager, or RHESSI; the Japanese Aerospace Exploration Agency's Hinode; and the National Solar Observatory's Dunn Solar Telescope located at Sacramento Peak in New Mexico. To have a record of such an intense flare from so many observatories is unprecedented. Such research can help scientists better understand what catalyst sets off these large explosions on the sun. Perhaps we may even some day be able to predict their onset and forewarn of the radio blackouts solar flares can cause near Earth - blackouts that can interfere with airplane, ship and military communications. Read more: 1.usa.gov/1kMDQbO Join our Google+ Hangout on May 8 at 2:30pm EST: go.nasa.gov/1mwbBEZ Credit: NASA Goddard NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram

  9. NASA's Best-Observed X-Class Flare of All Time

    NASA Image and Video Library

    2017-09-27

    On March 29, 2014 the sun released an X-class flare. It was observed by NASA's Interface Region Imaging Spectrograph, or IRIS; NASA's Solar Dynamics Observatory, or SDO; NASA's Reuven Ramaty High Energy Solar Spectroscopic Imager, or RHESSI; the Japanese Aerospace Exploration Agency's Hinode; and the National Solar Observatory's Dunn Solar Telescope located at Sacramento Peak in New Mexico. To have a record of such an intense flare from so many observatories is unprecedented. Such research can help scientists better understand what catalyst sets off these large explosions on the sun. Perhaps we may even some day be able to predict their onset and forewarn of the radio blackouts solar flares can cause near Earth - blackouts that can interfere with airplane, ship and military communications. Read more: 1.usa.gov/1kMDQbO Join our Google+ Hangout on May 8 at 2:30pm EST: go.nasa.gov/1mwbBEZ Credit: NASA Goddard NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram

  10. NASA's Best-Observed X-Class Flare of All Time

    NASA Image and Video Library

    2017-09-27

    Zoom in on the flare in ultraviolet (SDO/AIA), X-rays (Hinode) and gamma-rays (RHESSI) -- On March 29, 2014 the sun released an X-class flare. It was observed by NASA's Interface Region Imaging Spectrograph, or IRIS; NASA's Solar Dynamics Observatory, or SDO; NASA's Reuven Ramaty High Energy Solar Spectroscopic Imager, or RHESSI; the Japanese Aerospace Exploration Agency's Hinode; and the National Solar Observatory's Dunn Solar Telescope located at Sacramento Peak in New Mexico. To have a record of such an intense flare from so many observatories is unprecedented. Such research can help scientists better understand what catalyst sets off these large explosions on the sun. Perhaps we may even some day be able to predict their onset and forewarn of the radio blackouts solar flares can cause near Earth - blackouts that can interfere with airplane, ship and military communications. Read more: 1.usa.gov/1kMDQbO Join our Google+ Hangout on May 8 at 2:30pm EST: go.nasa.gov/1mwbBEZ Credit: NASA Goddard NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram

  11. Effect of kinase inhibitors on the therapeutic properties of monoclonal antibodies.

    PubMed

    Duong, Minh Ngoc; Matera, Eva-Laure; Mathé, Doriane; Evesque, Anne; Valsesia-Wittmann, Sandrine; Clémenceau, Béatrice; Dumontet, Charles

    2015-01-01

    Targeted therapies of malignancies currently consist of therapeutic monoclonal antibodies and small molecule kinase inhibitors. The combination of these novel agents raises the issue of potential antagonisms. We evaluated the potential effect of 4 kinase inhibitors, including the Bruton tyrosine kinase inhibitor ibrutinib, and 3 PI3K inhibitors idelalisib, NVP-BEZ235 and LY294002, on the effects of the 3 monoclonal antibodies, rituximab and obinutuzumab (directed against CD20) and trastuzumab (directed against HER2). We found that ibrutinib potently inhibits antibody-dependent cell-mediated cytotoxicity exerted by all antibodies, with a 50% inhibitory concentration of 0.2 microM for trastuzumab, 0.5 microM for rituximab and 2 microM for obinutuzumab, suggesting a lesser effect in combination with obinutuzumab than with rituximab. The 4 kinase inhibitors were found to inhibit phagocytosis by fresh human neutrophils, as well as antibody-dependent cellular phagocytosis induced by the 3 antibodies. Conversely co-administration of ibrutinib with rituximab, obinutuzumab or trastuzumab did not demonstrate any inhibitory effect of ibrutinib in vivo in murine xenograft models. In conclusion, some kinase inhibitors, in particular, ibrutinib, are likely to exert inhibitory effects on innate immune cells. However, these effects do not compromise the antitumor activity of monoclonal antibodies in vivo in the models that were evaluated.

  12. Silencing of epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) via siRNA-induced cell death in glioblastoma.

    PubMed

    Serban, Florentina; Daianu, Oana; Tataranu, Ligia Gabriela; Artene, Stefan-Alexandru; Emami, Ghazaleh; Georgescu, Ada Maria; Alexandru, Oana; Purcaru, Stefana Oana; Tache, Daniela Elise; Danciulescu, Maria Mihaela; Sfredel, Veronica; Dricu, Anica

    2017-01-01

    The failure of therapies targeting tumor angiogenesis may be caused by anti-angiogenic resistance mechanisms induced by VEGF and non-VEGF pathways alterations. Anti-angiogenic therapy failure is also attributed to immune system, acting by tumor-associated macrophages that release pro-angiogenic factors and a consequent increase of blood vessels. Recently, in a study by Rheal et al., a new angiogenic receptor, epidermal growth factor, latrophilin, and 7 trans-membrane domain-containing protein 1 on chromosome 1(ELTD1) has been identified as a promising glioma biomarker. In this study we aim to analyse whether this receptor may be used as a target molecule in glioblastoma therapy. Our results showed that small interfering RNA silencing ELTD1 caused cytotoxicity in glioblastoma cells. We also found that PDGFR, VEGFR, and their common PI3K/mTOR intracellular pathway inactivation-induced cytotoxicity in glioblastoma cells. Further, we found high percent of cytotoxicity in a low passage glioblastoma cell line after BEZ235 (a dual inhibitor of PI3K/mTOR pathway) treatment at nanomolar concentrations, compared to AG1433 (a PDGFR inhibitor) and SU1498 (a VEGFR inhibitor) that were only cytotoxic at micromolar ranges. In the future, these could prove as attractive therapeutic targets in single therapy or coupled with classic therapeutic approaches such as chemotherapy of radiotherapy.

  13. Genetic Evidence for Male and Female Dispersal in Wild Lemur catta.

    PubMed

    Parga, Joyce A; Sauther, Michelle L; Cuozzo, Frank P; Youssouf Jacky, Ibrahim Antho; Gould, Lisa; Sussman, Robert W; Lawler, Richard R; Pastorini, Jennifer

    2015-01-01

    Lemur catta has traditionally been considered a species with male-biased dispersal; however, occasional female dispersal occurs. Using molecular data, we evaluated dispersal patterns in 2 L. catta populations in southwestern Madagascar: Tsimanampesotse National Park (TNP) and Bezà Mahafaly Special Reserve (BMSR). We also investigated the genetic differentiation between the populations and dispersal partner relatedness. Results showed minor genetic differentiation between the populations (ϴ(ST) = 0.039), which may indicate gene flow historically occurring in this region, made possible by the presence of L. catta groups between the sites. Different patterns of sex-biased dispersal were found between the sites using corrected assignment indices: male-biased dispersal in TNP, and a lack of sex-biased dispersal in BMSR. Observational evidence of female dispersal in BMSR supports these results and may imply intense female resource competition in and around BMSR, because small groups of 2-3 females have been observed dispersing within BMSR and entering the reserve from outside. These dispersing groups largely consisted of mothers transferring with daughters, although we have an aunt-niece pair transferring together. Genetic data suggest that males also transfer with relatives. Our data demonstrate that dispersal partners consist of same-sexed kin for L. catta males and females, highlighting the importance of kin selection.

  14. Host age, social group, and habitat type influence the gut microbiota of wild ring-tailed lemurs (Lemur catta).

    PubMed

    Bennett, Genevieve; Malone, Matthew; Sauther, Michelle L; Cuozzo, Frank P; White, Bryan; Nelson, Karen E; Stumpf, Rebecca M; Knight, Rob; Leigh, Steven R; Amato, Katherine R

    2016-08-01

    The gut microbiota contributes to host health by maintaining homeostasis, increasing digestive efficiency, and facilitating the development of the immune system. The composition of the gut microbiota can change dramatically within and between individuals of a species as a result of diet, age, or habitat. Therefore, understanding the factors determining gut microbiota diversity and composition can contribute to our knowledge of host ecology as well as to conservation efforts. Here we use high-throughput sequencing to describe variation in the gut microbiota of the endangered ring-tailed lemur (Lemur catta) at the Bezà Mahafaly Special Reserve (BMSR) in southwestern Madagascar. Specifically, we measured the diversity and composition of the gut microbiota in relation to social group, age, sex, tooth wear and loss, and habitat disturbance. While we found no significant variation in the diversity of the ring-tailed lemur gut microbiota in response to any variable tested, the taxonomic composition of the gut microbiota was influenced by social group, age, and habitat disturbance. However, effect sizes were small and appear to be driven by the presence or absence of relatively low abundance taxa. These results suggest that habitat disturbance may not impact the lemur gut microbiota as strongly as it impacts the gut microbiota of other primate species, highlighting the importance of distinct host ecological and physiological factors on host-gut microbe relationships. Am. J. Primatol. 78:883-892, 2016. © 2016 Wiley Periodicals, Inc.

  15. Antipredator Vocalization Usage in the Male Ring-Tailed Lemur (Lemur catta).

    PubMed

    Bolt, Laura M; Sauther, Michelle L; Cuozzo, Frank P; Youssouf Jacky, Ibrahim Antho

    2015-01-01

    The ring-tailed lemur (Lemur catta) is a group-living strepsirrhine primate endemic to Madagascar that faces considerable predation pressure from aerial and terrestrial predators. This species engages in mobbing and vigilance behavior in response to predators, and has referential alarm vocalizations. Because L. catta is female dominant, less is known about the alarm calls of males. We tested 3 hypotheses for male antipredator vocalization behavior on L. catta at the Bezà Mahafaly Special Reserve in Madagascar: the predator confusion, group maintenance, and predation risk allocation hypotheses. We found support for 2 hypotheses. When a male L. catta made an antipredator call, other group members vocalized in response. Dominant males did not make alarm calls at higher rates than subordinate males. Predators were more abundant on the western side of Parcel 1, but an even greater number of antipredator vocalizations occurred in this area than predator abundance warranted. We show that male L. catta consistently participated in group-level antipredator vocalization usage in high-risk locations. Although female L. catta are known to hold the primary role in group defense, male L. catta are also key participants in group-wide behaviors that may confuse or drive away predators.

  16. Ecological risk aversion and juvenile ring-tailed lemur feeding and foraging.

    PubMed

    O'Mara, M Teague

    2015-01-01

    The extended primate juvenile period has been linked to interactions between feeding ecology and sociality. However, accumulating field data on juvenile primates suggest variation in the linkages between foraging efficiency, group foraging and social behaviour. In many non-human primates, juvenile ability (strength, coordination and motor skills) does not limit foraging success. If predicted limitations in feeding are not found in juvenile monkeys, it is possible that the gregarious strepsirrhines may show foraging patterns similar to those implicated in the evolution of a life history where long juvenile periods are advantageous. To test these behavioural predictions, I present a mixed longitudinal sample of observations on feeding and foraging behaviour from ring-tailed lemurs (Lemur catta) at the Bezà Mahafaly Special Reserve, Madagascar. Like several platyrrhine species, close proximity during foraging, low feeding efficiency and low dietary diversity are not typical of ring-tailed lemurs. The lack of ecological trade-offs in these species may indicate stronger common roles of sociality and social complexity in structuring the elongation of the primate juvenile period.

  17. PI3K/AKT signaling modulates transcriptional expression of EWS/FLI1 through specificity protein 1

    PubMed Central

    Giorgi, Chiara; Boro, Aleksandar; Rechfeld, Florian; Lopez-Garcia, Laura A.; Gierisch, Maria E.; Schäfer, Beat W.; Niggli, Felix K.

    2015-01-01

    Ewing sarcoma (ES) is the second most frequent bone cancer in childhood and is characterized by the presence of the balanced translocation t(11;22)(q24;q12) in more than 85% of cases, generating a dysregulated transcription factor EWS/FLI1. This fusion protein is an essential oncogenic component of ES development which is necessary for tumor cell maintenance and represents an attractive therapeutic target. To search for modulators of EWS/FLI1 activity we screened a library of 153 targeted compounds and identified inhibitors of the PI3K pathway to directly modulate EWS/FLI1 transcription. Surprisingly, treatment of four different ES cell lines with BEZ235 resulted in down regulation of EWS/FLI1 mRNA and protein by ∼50% with subsequent modulation of target gene expression. Analysis of the EWS/FLI1 promoter region (−2239/+67) using various deletion constructs identified two 14bp minimal elements as being important for EWS/FLI1 transcription. We identified SP1 as modulator of EWS/FLI1 gene expression and demonstrated direct binding to one of these regions in the EWS/FLI1 promoter by EMSA and ChIP experiments. These results provide the first insights on the transcriptional regulation of EWS/FLI1, an area that has not been investigated so far, and offer an additional molecular explanation for the known sensitivity of ES cell lines to PI3K inhibition. PMID:26336820

  18. Binding of a coordinatively unsaturated mercury(II) thiolate compound by carboxylate anions.

    PubMed

    Tang, Xiao-Yan; Zheng, Ai-Xia; Shang, Hai; Yuan, Rong-Xin; Li, Hong-Xi; Ren, Zhi-Gang; Lang, Jian-Ping

    2011-01-17

    Reactions of [Hg(Tab)2](PF6)2 (TabH = 4-(trimethylammonio)benzenethiol) (1) with acetic acid (HAc), propanoic acid (HPro), salicylic acid (HSal), benzoic acid (HBez), malonic acid (H2Mal), oxalic acid (H2Oxa), adipic acid (H2Adi), or methylimindiacetic acid (H2Meida) in the presence of Et3N gave rise to a family of mercury(II)-thiolate-carboxylate compounds, [Hg(Tab)2(Ac)](PF6) · 0.5H2O (2 · 0.5H2O), [Hg(Tab)2(Pro)](PF6) (3), [Hg(Tab)2(Sal)](PF6) · MeOH (4 · MeOH), [Hg(Tab)2(Sal)](Sal) · MeOH (5 · MeOH), [Hg(Tab)2(Bez)](PF6) · H2O (6 · H2O), [Hg(Tab)2(HMal)](Mal)0.5 H2O (7 · H2O), [{Hg(Tab)2}2(μ-Oxa)](PF6)2 H2O (8·2H2O), [{Hg(Tab)2}2(μ-Adi)](PF6)2 (9), [Hg(μ-Tab)(μ-Adi)]2n (10), and [Hg(Tab)2(Meida)] · 2.5H2O (11 · 2.5H2O). These compounds were characterized by elemental analysis, IR spectra, UV-vis spectra, (1)H NMR, and single-crystal X-ray crystallography. Each mercury(II) atom in [Hg(Tab)2](2+) dication of 2-7 is further coordinated by two oxygen atoms from one Ac(-), Pro(-), Sal(-), Bez(-), Mal(2-) or HMal(-) anion, forming a unique seesaw-shaped coordination geometry. In 8 or 9, two [Hg(Tab)2](2+) dications are connected by one bridging oxalate or adipate dianion to generate a dimeric structure with each mercury(II) center adopting a seesaw-shaped geometry. In 10, a pair of octahedrally coordinated mercury(II) atoms are bridged by two sulfur atoms of two Tab ligands to form a [Hg(μ-Tab)2Hg](4+) fragment, which is further connected to its equivalent ones via four adipate dianions, thereby forming a rare two-dimensional network. In 11, the mercury(II) atom in the [Hg(Tab)2](2+) dication is coordinated by one nitrogen and two oxygen atoms from one Meida(2-) dianion to have a rare square pyramidal geometry. The formation of 2-11 from 1 may be applicable to mimicking the interactions of the mercury(II) sites of Hg-MerR and Hg-MT with various amino acids encountered in nature.

  19. PI3K/AKT/mTOR pathway plays a major pathogenetic role in glycogen accumulation and tumor development in renal distal tubules of rats and men.

    PubMed

    Ribback, Silvia; Cigliano, Antonio; Kroeger, Nils; Pilo, Maria G; Terracciano, Luigi; Burchardt, Martin; Bannasch, Peter; Calvisi, Diego F; Dombrowski, Frank

    2015-05-30

    Activation of the PI3K/AKT/mTOR pathway is a crucial molecular event in human clear cell renal cell carcinoma (ccRCC), and is also upregulated in diabetic nephropathy. In diabetic rats metabolic changes affect the renal distal tubular epithelium and lead to glycogen-storing Armanni-Ebstein lesions (AEL), precursor lesions of RCC in the diabetes induced nephrocarcinogenesis model. These lesions resemble human sporadic clear cell tubules (CCT) and tumor cells of human ccRCC.Human sporadic CCT were examined in a collection of 324 nephrectomy specimen, in terms of morphologic, metabolic and molecular alterations, and compared to preneoplastic CCT and RCC developed in the rat following streptozotocin-induced diabetes or N-Nitrosomorpholine administration. Diabetic and non-diabetic rats were subjected to the dual PI3K/mTOR inhibitor, NVP/BEZ235.Human sporadic CCT could be detected in 17.3% of kidney specimens. Human and rat renal CCT display a strong induction of the PI3K/AKT/mTOR pathway and related metabolic alterations. Proteins involved in glycolysis and de novo lipogenesis were upregulated. In in vivo experiments, dual inhibition of PI3K and mTOR resulted in a reduction of proliferation of rat diabetes related CCT and increased autophagic activity.The present data indicate that human sporadic CCT exhibit a pattern of morphologic and metabolic alterations similar to preneoplastic lesions in the rat model. Activation of the PI3K/AKT/mTOR pathway in glycogenotic tubuli is a remarkable molecular event and suggests a preneoplastic character of these lesions also in humans.

  20. Vernachlässigte klinische Merkmale der follikulotropen Mycosis fungoides: eine große klinische Fallserie.

    PubMed

    Baykal, Can; Atci, Tugba; Ozturk Sari, Sule; Polat Ekinci, Algun; Buyukbabani, Nesimi

    2017-03-01

    Als seltene Form der Mycosis fungoides (MF), ist die follikulotrope MF (FMF) durch ein breites Spektrum klinischer Symptome gekennzeichnet. Dazu gehören, neben den vorherrschenden follikulären Läsionen, auch viele atypische Manifestationen. Das Ziel der vorliegenden Studie war eine klinische Bewertung von FMF-Patienten, unter besonderer Berücksichtigung von vernachlässigten dermatologischen Merkmalen. Insgesamt wurden 27 FMF-Patienten aus dem 572 Patienten umfassenden MF-Register unserer Abteilung retrospektiv bezüglich ihrer Demographie sowie der klinischen Merkmale, Behandlungsformen, Nachsorge und Therapieergebnisse bewertet. Neben den bekannten klinischen Symptomen der FMF fanden wir Lichen-spinulosus-artige Läsionen mit begleitender Hypopigmentierung (n = 3) und Alopezie (n = 2), infiltrierte/erhabene, erythematöse Plaques im Gesicht, die zunächst als Lupus tumidus angesehen wurden (n = 2), pseudotumorale Läsionen, die klinisch eine MF im Tumorstadium vortäuschten (n = 1), dauerhafte Exkoriationen (n = 1), erythematöse, Rosazea-artige Papeln im Gesicht (n = 1) sowie kuppelförmige, asymptomatische, mit Muzin gefüllte (in der Histologie) Papeln/Knoten (n = 2), die andere krankheitsbedingte Läsionen überlagerten. Es kamen mehrere Therapieansätze mit unterschiedlichem Ergebnis zur Anwendung. Acht (29,6 %) Patienten hatten FMF im Spätstadium. Das Bewusstsein für vernachlässigte klinische Symptome kann wesentlich dazu beitragen, verspätete Diagnosen dieser aggressiven MF-Variante zu verringern. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  1. Krankheitsverlauf, medizinische Versorgung und Lebensqualität von Patienten mit kongenitalen melanozytären Nävi - Auswertung des deutschsprachigen KMN-Registers.

    PubMed

    Elisabeth Wramp, Maria; Langenbruch, Anna; Augustin, Matthias; Zillikens, Detlef; Krengel, Sven

    2017-02-01

    Kongenitale melanozytäre Nävi (KMN) bedeuten für Patienten und Familien eine psychologische Belastung und bergen zudem medizinische Risiken. Das 2005 gegründete deutschsprachige KMN-Register wurde nun einer Zwischenauswertung bezüglich des Krankheitsverlaufes, der medizinischen Versorgung und der Lebensqualität unterzogen. 100 Patienten, die sich in den Jahren 2005 bis 2012 mit einem Erstmeldebogen registriert hatten, wurde im Rahmen einer prospektiven Kohortenstudie Anfang 2013 ein Folgemeldebogen zugesandt. Außerdem wurden mithilfe standardisierter Fragebögen Daten zu Lebensqualität (dermatology life quality index, DLQI) und Stigmatisierungserfahrungen (perceived stigmatization questionnaire, PSQ; social comfort questionnaire, SCQ) erhoben. 83 % der Patienten oder deren Eltern antworteten (Altersdurchschnitt 11,2 Jahre, Median 6 Jahre; mittleres Follow-up 4,4 Jahre). Im Gesamtkollektiv wurden vier Melanome diagnostiziert, davon zwei zerebrale Melanome im Kindesalter, ein kutanes Melanom im Erwachsenenalter und eines, das sich als proliferierender Knoten erwies. Bei vier Kindern wurde eine neurokutane Melanozytose festgestellt, drei davon mit neurologischer Symptomatik. Chirurgisch behandelt wurden 88 % (73/83). Achtundsiebzig Prozent der Befragten berichteten eine geringe oder keine Beeinträchtigung der Lebensqualität. Die wahrgenommene Stigmatisierung beziehungsweise Beeinträchtigung des sozialen Wohlbefindens war generell ebenfalls gering. Die Ergebnisse geben einen Überblick über die Situation von Patienten mit KMN in Deutschland, Österreich und der Schweiz. Ein Melanom entwickelte sich in 3 %, eine ZNS-Beteiligung bestand in 4 % der Fälle. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  2. NASA's Best-Observed X-Class Flare of All Time

    NASA Image and Video Library

    2017-09-27

    IBIS can focus in on different wavelengths of light, and so reveal different layers at different heights in the sun's lower atmosphere, the chromosphere. This image shows a region slightly higher than the former one. Credit: Lucia Kleint (BAER Institute), Paul Higgins (Trinity College Dublin, Ireland) -- On March 29, 2014 the sun released an X-class flare. It was observed by NASA's Interface Region Imaging Spectrograph, or IRIS; NASA's Solar Dynamics Observatory, or SDO; NASA's Reuven Ramaty High Energy Solar Spectroscopic Imager, or RHESSI; the Japanese Aerospace Exploration Agency's Hinode; and the National Solar Observatory's Dunn Solar Telescope located at Sacramento Peak in New Mexico. To have a record of such an intense flare from so many observatories is unprecedented. Such research can help scientists better understand what catalyst sets off these large explosions on the sun. Perhaps we may even some day be able to predict their onset and forewarn of the radio blackouts solar flares can cause near Earth - blackouts that can interfere with airplane, ship and military communications. Read more: 1.usa.gov/1kMDQbO Join our Google+ Hangout on May 8 at 2:30pm EST: go.nasa.gov/1mwbBEZ Credit: NASA Goddard NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram

  3. NASA's Best-Observed X-Class Flare of All Time

    NASA Image and Video Library

    2017-09-27

    This combined image shows the March 29, 2014, X-class flare as seen through the eyes of different observatories. SDO is on the bottom/left, which helps show the position of the flare on the sun. The darker orange square is IRIS data. The red rectangular inset is from Sacramento Peak. The violet spots show the flare's footpoints from RHESSI. -- On March 29, 2014 the sun released an X-class flare. It was observed by NASA's Interface Region Imaging Spectrograph, or IRIS; NASA's Solar Dynamics Observatory, or SDO; NASA's Reuven Ramaty High Energy Solar Spectroscopic Imager, or RHESSI; the Japanese Aerospace Exploration Agency's Hinode; and the National Solar Observatory's Dunn Solar Telescope located at Sacramento Peak in New Mexico. To have a record of such an intense flare from so many observatories is unprecedented. Such research can help scientists better understand what catalyst sets off these large explosions on the sun. Perhaps we may even some day be able to predict their onset and forewarn of the radio blackouts solar flares can cause near Earth - blackouts that can interfere with airplane, ship and military communications. Read more: 1.usa.gov/1kMDQbO Join our Google+ Hangout on May 8 at 2:30pm EST: go.nasa.gov/1mwbBEZ Credit: NASA Goddard NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram

  4. NASA's Best-Observed X-Class Flare of All Time

    NASA Image and Video Library

    2017-09-27

    Like almost all solar observatories, NASA's IRIS can provide images of different layers of the sun's atmosphere, which together create a whole picture of what's happening. This image shows light at a wavelength of 1400 Angstrom, which highlights material some 650 miles above the sun's surface. The vertical line in the middle shows the slit for IRIS's spectrograph, which can separate light into its many wavelengths to provide even more information about the temperature and velocity of material during a flare. Credit: NASA/IRIS/Goddard Space Flight Center -- On March 29, 2014 the sun released an X-class flare. It was observed by NASA's Interface Region Imaging Spectrograph, or IRIS; NASA's Solar Dynamics Observatory, or SDO; NASA's Reuven Ramaty High Energy Solar Spectroscopic Imager, or RHESSI; the Japanese Aerospace Exploration Agency's Hinode; and the National Solar Observatory's Dunn Solar Telescope located at Sacramento Peak in New Mexico. To have a record of such an intense flare from so many observatories is unprecedented. Such research can help scientists better understand what catalyst sets off these large explosions on the sun. Perhaps we may even some day be able to predict their onset and forewarn of the radio blackouts solar flares can cause near Earth - blackouts that can interfere with airplane, ship and military communications. Read more: 1.usa.gov/1kMDQbO Join our Google+ Hangout on May 8 at 2:30pm EST: go.nasa.gov/1mwbBEZ Credit: NASA Goddard NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram

  5. Secretin Receptor Promotes the Proliferation of Endocrine Tumor Cells Via the PI3K/AKT Pathway

    PubMed Central

    Lee, Misu; Waser, Beatrice; Reubi, Jean-Claude

    2012-01-01

    The secretin receptor (SR), a G protein-coupled receptor, mediates the effects of the gastrointestinal hormone secretin on digestion and water homeostasis. Recently, high SR expression has been observed in pancreatic ductal adenocarcinomas, cholangiocellular carcinomas, gastrinomas, and bronchopulmonary carcinoid tumors. Receptor overexpression associates with enhanced secretin-mediated signaling, but whether this molecule plays an independent role in tumorigenesis is currently unknown. We recently discovered that pheochromocytomas developing in rats affected by the MENX (multiple endocrine neoplasia-like) syndrome express at very high-level Sctr, encoding SR. We here report that SR are also highly abundant on the membranes of rat adrenal and extraadrenal pheochromocytoma, starting from early stages of tumor development, and are functional. PC12 cells, the best characterized in vitro pheochromocytoma model, also express Sctr at high level. Thus, we used them as model to study the role of SR in neoplastic transformation. Small interfering RNA-mediated knockdown of Sctr decreases PC12 cells proliferation and increases p27 levels. The proproliferative effect of SR in PC12 cells is mediated, in part, by the phosphatidylinositol 3 kinase (PI3K)/serine-threonine protein kinase (AKT) pathway. Transfection of Sctr in Y1 adrenocortical carcinoma cells, expressing low endogenous levels of Sctr, stimulates cell proliferation also, in part, via the PI3K/AKT signaling cascade. Because of the link between SR and PI3K/AKT signaling, tumor cells expressing high levels of the receptor (MENX-associated primary pheochromocytoma and NCI-H727 human bronchopulmonary carcinoid cells) respond well and in a SR-dependent manner to PI3K inhibitors, such as NVP-BEZ235. The association between SR levels and response to PI3K inhibition might open new avenues for the treatment of tumors overexpressing this receptor. PMID:22692904

  6. NCYM, a Cis-Antisense Gene of MYCN, Encodes a De Novo Evolved Protein That Inhibits GSK3β Resulting in the Stabilization of MYCN in Human Neuroblastomas

    PubMed Central

    Suenaga, Yusuke; Islam, S. M. Rafiqul; Alagu, Jennifer; Kaneko, Yoshiki; Kato, Mamoru; Tanaka, Yukichi; Kawana, Hidetada; Hossain, Shamim; Matsumoto, Daisuke; Yamamoto, Mami; Shoji, Wataru; Itami, Makiko; Shibata, Tatsuhiro; Nakamura, Yohko; Ohira, Miki; Haraguchi, Seiki; Takatori, Atsushi; Nakagawara, Akira

    2014-01-01

    The rearrangement of pre-existing genes has long been thought of as the major mode of new gene generation. Recently, de novo gene birth from non-genic DNA was found to be an alternative mechanism to generate novel protein-coding genes. However, its functional role in human disease remains largely unknown. Here we show that NCYM, a cis-antisense gene of the MYCN oncogene, initially thought to be a large non-coding RNA, encodes a de novo evolved protein regulating the pathogenesis of human cancers, particularly neuroblastoma. The NCYM gene is evolutionally conserved only in the taxonomic group containing humans and chimpanzees. In primary human neuroblastomas, NCYM is 100% co-amplified and co-expressed with MYCN, and NCYM mRNA expression is associated with poor clinical outcome. MYCN directly transactivates both NCYM and MYCN mRNA, whereas NCYM stabilizes MYCN protein by inhibiting the activity of GSK3β, a kinase that promotes MYCN degradation. In contrast to MYCN transgenic mice, neuroblastomas in MYCN/NCYM double transgenic mice were frequently accompanied by distant metastases, behavior reminiscent of human neuroblastomas with MYCN amplification. The NCYM protein also interacts with GSK3β, thereby stabilizing the MYCN protein in the tumors of the MYCN/NCYM double transgenic mice. Thus, these results suggest that GSK3β inhibition by NCYM stabilizes the MYCN protein both in vitro and in vivo. Furthermore, the survival of MYCN transgenic mice bearing neuroblastoma was improved by treatment with NVP-BEZ235, a dual PI3K/mTOR inhibitor shown to destabilize MYCN via GSK3β activation. In contrast, tumors caused in MYCN/NCYM double transgenic mice showed chemo-resistance to the drug. Collectively, our results show that NCYM is the first de novo evolved protein known to act as an oncopromoting factor in human cancer, and suggest that de novo evolved proteins may functionally characterize human disease. PMID:24391509

  7. NI-1: a novel canine mastocytoma model for studying drug resistance and IgER-dependent mast cell activation

    PubMed Central

    Hadzijusufovic, E; Peter, B; Herrmann, H; Rülicke, T; Cerny-Reiterer, S; Schuch, K; Kenner, L; Thaiwong, T; Yuzbasiyan-Gurkan, V; Pickl, W F; Willmann, M; Valent, P

    2012-01-01

    Background Advanced mast cell (MC) disorders are characterized by uncontrolled growth of neoplastic MC in various organs, mediator-related symptoms, and a poor prognosis. Kit mutations supposedly contribute to abnormal growth and drug resistance in these patients. Methods We established a novel canine mastocytoma cell line, NI-1, from a patient suffering from MC leukemia. Results NI-1 cells were found to form mastocytoma lesions in NOD/SCID IL-2Rgammanull mice and to harbor several homozygous Kit mutations, including missense mutations at nucleotides 107(C→T) and 1187(A→G), a 12-bp duplication (nucleotide 1263), and a 12-bp deletion (nucleotide 1550). NI-1 cells expressed several MC differentiation antigens, including tryptase, Kit, and a functional IgE receptor. Compared to the C2 mastocytoma cell line harboring a Kit exon 11 mutation, NI-1 cells were found to be less responsive against the Kit tyrosine kinase inhibitors (TKI) masitinib and imatinib, but were even more sensitive against proliferation-inhibitory effects of the mammalian target of rapamycin (mTOR) blocker RAD001 and PI3-kinase/mTOR blocker NVP-BEZ235. The Kit-targeting multikinase inhibitors PKC412 and dasatinib were also found to override TKI resistance in NI-1 cells, and produced growth inhibition with reasonable IC50 values (<0.1 μM). Conclusion NI-1 may serve as a useful tool to investigate IgE-dependent reactions and mechanisms of abnormal growth and drug resistance in neoplastic MC in advanced mastocytosis. PMID:22583069

  8. PI3K-Akt signaling activates mTOR-mediated epileptogenesis in organotypic hippocampal culture model of posttraumatic epilepsy

    PubMed Central

    Berdichevsky, Yevgeny; Dryer, Alexandra M.; Saponjian, Yero; Mahoney, Mark M.; Pimentel, Corrin A.; Lucini, Corrina A.; Usenovic, Marija; Staley, Kevin J.

    2013-01-01

    mTOR is activated in epilepsy, but the mechanisms of mTOR activation in post-traumatic epileptogenesis are unknown. It is also not clear whether mTOR inhibition has an antiepileptogenic, or merely anti-convulsive effect. The rat hippocampal organotypic culture model of post-traumatic epilepsy was used to study the effects of long term (four weeks) inhibition of signaling pathways that interact with mTOR. Ictal activity was quantified by measurement of lactate production and electrical recordings, and cell death was quantified with LDH release measurements and Nissl-stained neuron counts. Lactate and LDH measurements were well-correlated with electrographic activity and neuron counts, respectively. Inhibition of PI3K and Akt prevented activation of mTOR, and was as effective as inhibition of mTOR in reducing ictal activity and cell death. A dual inhibitor of PI3K and mTOR, NVP-BEZ235, was also effective. Inhibition of mTOR with rapamycin reduced axon sprouting. Late start of rapamycin treatment was effective in reducing epileptic activity and cell death, while early termination of rapamycin treatment did not result in increased epileptic activity or cell death. The conclusions of the study are: (1), the organotypic hippocampal culture model of posttraumatic epilepsy comprises a rapid assay of antiepileptogenic and neuroprotective activities and, in this model (2), mTOR activation depends on PI3K-Akt signaling, and (3) transient inhibition of mTOR has sustained effects on epilepsy. PMID:23699517

  9. Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints

    PubMed Central

    Beeharry, Neil; Banina, Eugenia; Hittle, James; Skobeleva, Natalia; Khazak, Vladimir; Deacon, Sean; Andrake, Mark; Egleston, Brian L; Peterson, Jeffrey R; Astsaturov, Igor; Yen, Timothy J

    2014-01-01

    Inhibitors of the DNA damage checkpoint kinase, Chk1, are highly effective as chemo- and radio-sensitizers in preclinical studies but are not well-tolerated by patients. We exploited the promiscuous nature of kinase inhibitors to screen 9 clinically relevant kinase inhibitors for their ability to sensitize pancreatic cancer cells to a sub-lethal concentration of gemcitabine. Bosutinib, dovitinib, and BEZ-235 were identified as sensitizers that abrogated the DNA damage checkpoint. We further characterized bosutinib, an FDA-approved Src/Abl inhibitor approved for chronic myelogenous leukemia. Unbeknownst to us, we used an isomer (Bos-I) that was unknowingly synthesized and sold to the research community as “authentic” bosutinib. In vitro and cell-based assays showed that both the authentic bosutinib and Bos-I inhibited DNA damage checkpoint kinases Chk1 and Wee1, with Bos-I showing greater potency. Imaging data showed that Bos-I forced cells to override gemcitabine-induced DNA damage checkpoint arrest and destabilized stalled replication forks. These inhibitors enhanced sensitivity to the DNA damaging agents’ gemcitabine, cisplatin, and doxorubicin in pancreatic cancer cell lines. The in vivo efficacy of Bos-I was validated using cells derived directly from a pancreatic cancer patient’s tumor. Notably, the xenograft studies showed that the combination of gemcitabine and Bos-I was significantly more effective in suppressing tumor growth than either agent alone. Finally, we show that the gatekeeper residue in Wee1 dictates its sensitivity to the 2 compounds. Our strategy to screen clinically relevant kinase inhibitors for off-target effects on cell cycle checkpoints is a promising approach to re-purpose drugs as chemosensitizers. PMID:24955955

  10. Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints.

    PubMed

    Beeharry, Neil; Banina, Eugenia; Hittle, James; Skobeleva, Natalia; Khazak, Vladimir; Deacon, Sean; Andrake, Mark; Egleston, Brian L; Peterson, Jeffrey R; Astsaturov, Igor; Yen, Timothy J

    2014-01-01

    Inhibitors of the DNA damage checkpoint kinase, Chk1, are highly effective as chemo- and radio-sensitizers in preclinical studies but are not well-tolerated by patients. We exploited the promiscuous nature of kinase inhibitors to screen 9 clinically relevant kinase inhibitors for their ability to sensitize pancreatic cancer cells to a sub-lethal concentration of gemcitabine. Bosutinib, dovitinib, and BEZ-235 were identified as sensitizers that abrogated the DNA damage checkpoint. We further characterized bosutinib, an FDA-approved Src/Abl inhibitor approved for chronic myelogenous leukemia. Unbeknownst to us, we used an isomer (Bos-I) that was unknowingly synthesized and sold to the research community as "authentic" bosutinib. In vitro and cell-based assays showed that both the authentic bosutinib and Bos-I inhibited DNA damage checkpoint kinases Chk1 and Wee1, with Bos-I showing greater potency. Imaging data showed that Bos-I forced cells to override gemcitabine-induced DNA damage checkpoint arrest and destabilized stalled replication forks. These inhibitors enhanced sensitivity to the DNA damaging agents' gemcitabine, cisplatin, and doxorubicin in pancreatic cancer cell lines. The in vivo efficacy of Bos-I was validated using cells derived directly from a pancreatic cancer patient's tumor. Notably, the xenograft studies showed that the combination of gemcitabine and Bos-I was significantly more effective in suppressing tumor growth than either agent alone. Finally, we show that the gatekeeper residue in Wee1 dictates its sensitivity to the 2 compounds. Our strategy to screen clinically relevant kinase inhibitors for off-target effects on cell cycle checkpoints is a promising approach to re-purpose drugs as chemosensitizers.

  11. [The role of the family in childhood and adolescent binge eating - a systematic review].

    PubMed

    Tetzlaff, Anne; Hilbert, Anja

    2014-01-01

    Fragestellung: Während der Einfluss der Familie bei Anorexia Nervosa und Bulimia Nervosa im Kindes- und Jugendalter belegt ist und bereits in Übersichtsarbeiten zusammengefasst wurde, liegen derzeit wenige Befunde zum Zusammenhang zu Essanfällen ohne kompensatorische Verhaltensweisen vor. Ziel dieser systematischen Übersichtsarbeit ist es daher, familiäre Einflussfaktoren auf die Entstehung und Aufrechterhaltung von Essanfällen zu beschreiben. Methodik: Eine systematische Datenbanksuche für Studien zum Zusammenhang von familiären Faktoren und Essanfällen wurde durchgeführt. Ergebnisse: Die eingeschlossenen Studien zeigten einheitlich, dass eine unsichere Bindung des Kindes, eine geringere Familienfunktionalität und geringere emotionale Unterstützung mit Essanfällen querschnittlich assoziiert sind, elterliche Arbeitslosigkeit sowie elterliche Depressionen retrospektive Korrelate darstellen und weniger Familienmahlzeiten und häufige kritische Kommentare über Figur und Gewicht innerhalb der Familie variable Risikofaktoren für Essanfälle sind. Inkonsistente Befunde fanden sich hingegen bezüglich der Familienstrukturen, dem Vorliegen elterlicher Essstörungen und Diäthalten sowie dem Erkennen von Essanfällen beim eigenen Kind. Geschlechterunterschiede hinsichtlich familiärer Beziehungen und gewichtsbezogener Stigmatisierung wurden identifiziert. Schlussfolgerungen: Ebenso wie bei anderen Essstörungen im Kindes- und Jugendalter spielen familiäre Einflussfaktoren auch bei Essanfällen eine wichtige Rolle. Daher könnten eine Diagnostik familiärer Einflüsse und familientherapeutische Interventionen in der Behandlung von Essanfällen im Kindes- und Jugendalter hilfreich sein. Mithilfe von prospektiven Studiendesigns könnten die divergierenden Ergebnisse aufgeklärt werden.

  12. PI3K/Akt Signaling Pathway Activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in Hyperinsulinemic db/db Mice

    PubMed Central

    Nishida, Hidenori; Sohara, Eisei; Nomura, Naohiro; Chiga, Motoko; Alessi, Dario R; Rai, Tatemitsu; Sasaki, Sei; Uchida, Shinichi

    2013-01-01

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt-sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently-identified WNK kinase-OSR1/SPAK kinases-NCC transporter phosphorylation cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC phosphorylation is regulated by the PI3K/Akt signaling cascade in the kidney in response to hyperinsulinemia. A PI3K inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC phosphorylation. Another more specific PI3K inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC phosphorylation. These results indicate that the PI3K/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions such as the metabolic syndrome. PMID:22949526

  13. Phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice.

    PubMed

    Nishida, Hidenori; Sohara, Eisei; Nomura, Naohiro; Chiga, Motoko; Alessi, Dario R; Rai, Tatemitsu; Sasaki, Sei; Uchida, Shinichi

    2012-10-01

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently identified with-no-lysine kinase (WNK)-oxidative stress-responsive kinase 1 (OSR1)/STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NaCl cotransporter (NCC) phosphorylation cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC phosphorylation is regulated by the phosphatidylinositol 3-kinase/Akt signaling cascade in the kidney in response to hyperinsulinemia. A phosphatidylinositol 3-kinase inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC phosphorylation. Another more specific phosphatidylinositol 3-kinase inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC phosphorylation. These results indicate that the phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions, such as the metabolic syndrome.

  14. A novel nonparametric measure of explained variation for survival data with an easy graphical interpretation.

    PubMed

    Weiß, Verena; Schmidt, Matthias; Hellmich, Martin

    2015-01-01

    Einleitung: Das Bestimmtheitsmaß kann bei Überlebenszeitdaten nicht verwendet werden um mithilfe einer Maßzahl anzugeben, wie gut ein Modell zu den vorliegenden Daten passt. Daher wurden in den letzten Jahren mehrere Maße der Erklärten Variation für Überlebenszeitdaten vorgeschlagen.Methoden: Wir analysieren eines dieser Maße der Erklärten Variation bezüglich gewisser Minimierungseigenschaften und zeigen, dass diese für das Maß nicht erfüllt sind.Ergebnisse: In Analogie zu der Kleinste-Quadrate-Methode aus der linearen Regression entwickeln wir ein neues Maß für kategorielle Kovariaten, welches nur auf dem Kaplan-Meier-Schätzer basiert. Dadurch ist das neue Maß komplett nichtparametrisch und besitzt eine einfache grafische Interpretation. Für das neue Maß stehen verschiedene Gewichtungsmöglichkeiten zur Verfügung und ein statistischer Signifikanztest kann angewendet werden. Abschließend bestimmen wir das neue Maß sowie weitere Maße der Erklärten Variation für die Personen eines Datensatzes mit einem histopathologisch gesicherten papillären Schilddrüsenkarzinom.Schlussfolgerung: Wir schlagen ein neues Maß der Erklärten Variation mit einer eingängigen Herleitung sowie einer grafischen Interpretation vor, welches bei künftigen Auswertungen von Überlebenszeitdaten verwendet werden könnte.

  15. Paternity in wild ring‐tailed lemurs (Lemur catta): Implications for male mating strategies

    PubMed Central

    Sauther, Michelle L.; Cuozzo, Frank P.; Youssouf Jacky, Ibrahim Antho; Lawler, Richard R.; Sussman, Robert W.; Gould, Lisa; Pastorini, Jennifer

    2016-01-01

    1 In group‐living species with male dominance hierarchies where receptive periods of females do not overlap, high male reproductive skew would be predicted. However, the existence of female multiple mating and alternative male mating strategies can call into question single‐male monopolization of paternity in groups. Ring‐tailed lemurs (Lemur catta) are seasonally breeding primates that live in multi‐male, multi‐female groups. Although established groups show male dominance hierarchies, male dominance relationships can break down during mating periods. In addition, females are the dominant sex and mate with multiple males during estrus, including group residents, and extra‐group males—posing the question of whether there is high or low male paternity skew in groups. In this study, we analyzed paternity in a population of wild L. catta from the Bezà Mahafaly Special Reserve in southwestern Madagascar. Paternity was determined with 80–95% confidence for 39 offspring born to nine different groups. We calculated male reproductive skew indices for six groups, and our results showed a range of values corresponding to both high and low reproductive skew. Between 21% and 33% of offspring (3 of 14 or three of nine, counting paternity assignments at the 80% or 95% confidence levels, respectively) were sired by extra‐troop males. Males siring offspring within the same group during the same year appear to be unrelated. Our study provides evidence of varying male reproductive skew in different L. catta groups. A single male may monopolize paternity across one or more years, while in other groups, >1 male can sire offspring within the same group, even within a single year. Extra‐group mating is a viable strategy that can result in extra‐group paternity for L. catta males. PMID:27391113

  16. Paternity in wild ring-tailed lemurs (Lemur catta): Implications for male mating strategies.

    PubMed

    Parga, Joyce A; Sauther, Michelle L; Cuozzo, Frank P; Youssouf Jacky, Ibrahim Antho; Lawler, Richard R; Sussman, Robert W; Gould, Lisa; Pastorini, Jennifer

    2016-12-01

    In group-living species with male dominance hierarchies where receptive periods of females do not overlap, high male reproductive skew would be predicted. However, the existence of female multiple mating and alternative male mating strategies can call into question single-male monopolization of paternity in groups. Ring-tailed lemurs (Lemur catta) are seasonally breeding primates that live in multi-male, multi-female groups. Although established groups show male dominance hierarchies, male dominance relationships can break down during mating periods. In addition, females are the dominant sex and mate with multiple males during estrus, including group residents, and extra-group males-posing the question of whether there is high or low male paternity skew in groups. In this study, we analyzed paternity in a population of wild L. catta from the Bezà Mahafaly Special Reserve in southwestern Madagascar. Paternity was determined with 80-95% confidence for 39 offspring born to nine different groups. We calculated male reproductive skew indices for six groups, and our results showed a range of values corresponding to both high and low reproductive skew. Between 21% and 33% of offspring (3 of 14 or three of nine, counting paternity assignments at the 80% or 95% confidence levels, respectively) were sired by extra-troop males. Males siring offspring within the same group during the same year appear to be unrelated. Our study provides evidence of varying male reproductive skew in different L. catta groups. A single male may monopolize paternity across one or more years, while in other groups, >1 male can sire offspring within the same group, even within a single year. Extra-group mating is a viable strategy that can result in extra-group paternity for L. catta males. © 2016 The Authors. American Journal of Primatology Published by Wiley Periodicals, Inc.

  17. Role of gluten-free diet in pathogenesis of type 1 diabetes - what new?

    PubMed

    Chwalba, Artur; Otto-Buczkowska, Ewa

    2015-01-01

    W ostatnich dekadach związek pomiędzy występowaniem celiakii a innymi autoimmunologicznymi schorzeniami, takimi jak autoimmunologiczne schorzenia tarczycy czy cukrzyca typu 1, został ustalony w wielu badaniach i jest do dziś przedmiotem klinicznych i naukowych obserwacji na całym świecie. Cukrzyca typu 1 (T1DM) i choroba trzewna (CD) mają podobne tło genetyczne związane z genotypem HLA-DQ2 / DQ8. Współzależność pomiędzy spożywaniem glutenu a późniejszym rozwojem cukrzycy typu 1 została wykazana w badaniach u ludzi i u zwierząt doświadczalnych. Badania te dowiodły, że dieta bez zawartości glutenu obniża poziom receptora NKG2D i ekspresje jego ligandów u myszy (GF). Tak więc gluten może rzutować na rozwój cukrzycy poprzez wpływ na modyfikację wzoru stosunku cytokiny/chemokiny, powodującą profil zapalny. Potwierdza to ważną rolę spożycia glutenu w patogenezie cukrzycy typu 1. Uzasadnione jest prowadzenie dalszych badań w celu wyjaśnienia, czy dieta bezglutenowa może zapobiec chorobie u osób predysponowanych lub czy może być zastosowana u pacjentów ze świeżo rozpoznaną cukrzycą w celu zatrzymania jej rozwoju. Te obserwacje mogę być ważne w pierwotnej prewencji cukrzycy.

  18. [Drugs in artistic works of Stanislaw Ignacy Witkiewicz (1885-1939) on the Background of polish modernism at the turn of XIX and XX century].

    PubMed

    Płonka-Syroka, B

    1997-01-01

    At the turn of XIX and XX century in the Polish artistic circles it became widespread a modernist moral model, created among other by Baudelair's, Mallarme's Rimbaud's and Verlain's works. One of its elements was striving for getting into different status of conscience with help of narcotics and alcohol. A strong presence of narcotics in life of the Polish artistic circles at a time of mocernism has been a subject to analysis carried out by Tadeusz Boy-Zeleénski in his work "Cyganeria krakowska" [Crakow Bohemians]. He has shown their role of easing emotional tensions connected with striving for fame and with a competition. Underestimation, misery and social alienation of some artists have been inducing them to search in narcotics the way to artificial reality. In some Polish artistic circles the narcotics have become a stimulant of cult character (see Antoni Lange "Ballady pijackie", Stanisław Przybyszewski "Synowie ziemi", "Moi współcześni", Henryk Sienkiewicz "Bez dogmatu"). Stanisław Ignacy Witkiewicz (1885-1939), Polish painter and dramatist, creating in the first half of XX century, has continued a tradition of modernist customs, taken over by him from the artistic circle he was brought up. He used narcotics as direct creative stimulus, inspiring creation of his paintings, including a superb series of portraits. In paintings made under influence of the drugs, Witkiewicz was placing the symbols of stimulants taken earlier. He has specially appreciated cocaine, though he has been using also opium, morphine, hashish and mixes of various psychotropic agents. Paintings of Witkacy are characterised by original colouring of a very strong artistic expression. ...

  19. H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation via heregulin production and activation of HER3

    PubMed Central

    Chakrabarty, Anindita; Rexer, Brent N.; Wang, Shizhen Emily; Cook, Rebecca S.; Engelman, Jeffrey A.; Arteaga, Carlos, L.

    2010-01-01

    Hyperactivation of phosphatidylinositol-3 kinase (PI3K) can occur as a result of somatic mutations in PIK3CA, the gene encoding the p110α subunit of PI3K. The HER2 oncogene is amplified in 25% of all breast cancers and some of these tumors also harbor PIK3CA mutations. We examined mechanisms by which mutant PI3K can enhance transformation and confer resistance to HER2-directed therapies. We introduced the PI3K mutations E545K and H1047R in MCF10A human mammary epithelial cells that also overexpress HER2. Both mutants conferred a gain of function to MCF10A/HER2 cells. Expression of H1047R PI3K but not E545K PI3K markedly upregulated the HER3/HER4 ligand heregulin (HRG). HRG siRNA inhibited growth of H1047R but not E545K-expressing cells and synergized with the HER2 inhibitors trastuzumab and lapatinib. The PI3K inhibitor BEZ235 markedly inhibited HRG and pAKT levels and, in combination with lapatinib, completely inhibited growth of cells expressing H1047R PI3K. These observations suggest that PI3K mutants enhance HER2-mediated transformation by amplifying the ligand-induced signaling output of the ErbB network. This also counteracts the full effect of therapeutic inhibitors of HER2. These data also suggest that mammary tumors that contain both HER2 gene amplification and PIK3CA mutations should be treated with a combination of HER2 and PI3K inhibitors. PMID:20581867

  20. Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas.

    PubMed

    Graillon, Thomas; Defilles, Céline; Mohamed, Amira; Lisbonis, Christophe; Germanetti, Anne-Laure; Chinot, Olivier; Figarella-Branger, Dominique; Roche, Pierre-Hugues; Adetchessi, Tarek; Fuentes, Stéphane; Metellus, Philippe; Dufour, Henry; Enjalbert, Alain; Barlier, Anne

    2015-08-01

    Treatment for recurrent and aggressive meningiomas remains an unmet medical need in neuro-oncology, and chemotherapy exhibits limited clinical activity, if any. Merlin expression, encoded by the NF2 gene, is lost in a majority of meningiomas, and merlin is a negative regulator of mTORC1. The sst2 somatostatin receptor, targeted by octreotide, is highly expressed in meningiomas. To investigate new therapeutic strategies, we evaluated the activity of everolimus (mTOR inhibitor), BKM-120 and BEZ-235 (new Pi3K/Akt/mTOR inhibitors), octreotide and a combined treatment (octreotide plus everolimus), on cell proliferation, signaling pathways, and cell cycle proteins, respectively. The in vitro study was conducted on human meningioma primary cells extracted from fresh tumors, allowing the assessment of somatostatin analogs at the concentration levels used in patients. The results were correlated to WHO grades. Further, everolimus decreased cell viability of human meningiomas, but concomitantly, induced Akt activation, reducing the antiproliferative effect of the drug. The new Pi3K inhibitors were not more active than everolimus alone, limiting their clinical relevance. In contrast, a clear cooperative inhibitory effect of octreotide and everolimus was observed on cell proliferation in all tested meningiomas, including WHO grades II-III. Octreotide not only reversed everolimus-induced Akt phosphorylation but also displayed additive and complementary effects with everolimus on downstream proteins involved in translation (4EB-P1), and controlling cell cycle (p27Kip1 and cyclin D1). We have demonstrated a co-operative action between everolimus and octreotide on cell proliferation in human meningiomas, including aggressive ones, establishing the basis for a clinical trial.

  1. Differential effects of rapalogues, dual kinase inhibitors on human ovarian carcinoma cells in vitro.

    PubMed

    Rogers-Broadway, Karly-Rai; Chudasama, Dimple; Pados, George; Tsolakidis, Dimitris; Goumenou, Anastasia; Hall, Marcia; Karteris, Emmanouil

    2016-07-01

    Ovarian cancer is the second most common gynaecological malignancy and was diagnosed in over 7,000 women in 2011 in the UK. There are currently no reliable biomarkers available for use in a regular screening assay for ovarian cancer and due to characteristic late presentation (78% in stages III and IV) ovarian cancer has a low survival rate (35% after 10 years). The mTOR pathway is a central regulator of growth, proliferation, apoptosis and angiogenesis; providing balance between available resources such as amino acids and growth factors, and stresses such as hypoxia, to control cellular behaviour accordingly. Emerging data links mTOR with the aetiopathogenesis of ovarian cancer. We hypothesised that mTOR inhibitors could play a therapeutic role in ovarian cancer treatment. In this study we began by validating the expression of four main mTOR pathway components, mTOR, DEPTOR, rictor and raptor, at gene and protein level in in vitro models of endometrioid (MDAH‑2774) and clear cell (SKOV3) ovarian cancer using qPCR and ImageStream technology. Using a wound healing assay we show that inhibition of the mTOR pathway using rapamycin, rapalogues, resveratrol and NVP BEZ-235 induces a cytostatic and not cytotoxic response up to 18 h in these cell lines. We extended these findings up to 72 h with a proliferation assay and show that the effects of inhibition of the mTOR pathway are primarily mediated by the dephosphorylation of p70S6 kinase. We show that mTOR inhibition does not involve alteration of mTOR pathway components or induce caspase 9 cleavage. Preclinical studies including ovarian tissue of ovarian cancer patients, unaffected controls and patients with unrelated gynaecological conditions show that DEPTOR is reliably upregulated in ovarian cancer.

  2. Mathematical Model of Forecasting the Formation of Sinkhole Using Salustowicz's Theory / Model Matematyczny Prognozowania Zapadlisk Przy Wykorzystaniu Teorii Sklepienia Ciśnień Sałustowicza

    NASA Astrophysics Data System (ADS)

    Strzałkowski, Piotr

    2015-03-01

    órej wykorzystano teorię sklepienia ciśnień (Sałustowicz, 1956). Teoria ta znakomicie nadaje się do tego celu, gdyż jako jedyna z wielu w tym zakresie pozwala określić, czy pustka związana z wyrobiskiem znajduje się w stanie stateczności. Znane są bowiem przypadki, gdy płytkie wyrobiska górnicze, bez obudowy przez wiele lat pozostają w stanie nienaruszonym. W ramach pracy dokonano szczegółowych obliczeń pola strefy odprężonej nad wyrobiskiem, bez stosowania uproszczeń przyjętych przez autora metody. Stosując podobne założenia jak w innych, znanych z literatury rozwiązaniach, podano warunki, mówiące o tym kiedy gruzowisko skalne zapełni szczelnie pustkę, bez powstania pustki wtórnej, a kiedy pustka wtórna powstanie. Zależy to od wymiarów i głębokości lokalizacji pustki oraz własności górotworu nad pustką. Warunkiem wystąpienia zapadliska jest aby strefa odprężona, związana z pustką pierwotną lub wtórną osiągnęła wysokość, przy której obejmować będzie nadkład, zbudowany ze skał luźnych. W dalszej kolejności zaproponowano wzory umożliwiające określenie wymiarów zapadlisk. Wyróżniono przy tym dwa przypadki: • gdy strop pustki osiąga spąg nadkładu - wzór (15), • gdy strefa odprężona obejmuje swym zasięgiem luźne skały nadkładu - wzór (19). Dalszym etapem badań prowadzonych przez autora jest sformułowanie warunków, pozwalających stwierdzić, kiedy eksploatacja górnicza prowadzona pod pustką może wywołać jej samopodsadzenie, a w konsekwencji spowodować powstanie zapadliska na powierzchni. Prowadzone są również prace związane z utworzeniem oprogramowania komputerowego, wykorzystującego podane wzory i z weryfikacją rozwiązania w oparciu o przypadki znane z praktyki górniczej.

  3. Mechanical food properties and dental topography differentiate three populations of Lemur catta in southwest Madagascar.

    PubMed

    Yamashita, Nayuta; Cuozzo, Frank P; Sauther, Michelle L; Fitzgerald, Emily; Riemenschneider, Andrea; Ungar, Peter S

    2016-09-01

    Determining the proximate causes of tooth wear remains a major focus of dental study. Here we compare the diets of three ring-tailed lemur (Lemur catta) populations and examine how different dietary components may contribute to patterns of wear-related tooth shape. Casts were made from dental impressions collected between 2003 and 2010 from lemurs in the gallery and spiny/mixed forests of the Bezá Mahafaly Special Reserve (BMSR; Parcels 1 and 2) and the spiny/mixed forests of Tsimanampesotse National Park (TNP), Madagascar. Tooth shape variables (occlusal relief and slope, angularity) were analyzed using dental topographic analysis. Focal observations and food mechanical properties (FMPs: toughness, hardness, elastic modulus) were conducted and tested, respectively, during wet and dry seasons from 2008 to 2012. We found that FMPs correlate with patterns of dental topography in these three populations. Specifically, food toughness and elastic modulus correlate with the dental variables, but hardness does not. Average food toughness and elastic modulus, but not hardness, are highest in BMSR Parcel 2, followed by BMSR Parcel 1 and TNP. Occlusal relief and slope, which serve as proxies for tooth wear, show the greatest wear in Parcel 2 and the least in TNP. Angularity is also more pronounced in TNP. Further, dental topographic patterns correspond to reliance on Tamarindus indica (tamarind) fruit. Both BMSR populations consume tamarind at high frequencies in the dry season, but the fruits are rare at TNP and only occasionally consumed. Thus, high seasonal tamarind consumption and its mechanical values help explain the low dental relief and slope among BMSR lemurs. By investigating the ecology of a single widespread species across a variety of habitats, we have been able to link specific components of diet to patterns of dental topography in this species. This provides a context for interpreting wear-related tooth shape changes more generally, illustrating that

  4. Surgical site infection among patients after colorectal cancer surgery.

    PubMed

    Banaszkiewicz, Zbigniew; Cierzniakowska, Katarzyna; Tojek, Krzysztof; Kozłowska, Elżbieta; Jawień, Arkadiusz

    2017-02-28

    Wstęp: Zakażenie miejsca operowanego występuje u 2,5-22,3% operowanych chorych. Jest ono wykładnikiem jakości leczenia na oddziałach zabiegowych i ma duży wpływ na jego koszt. Materiał i metodyka: Analizie poddano chorych, u których w obserwacji 30-dniowej wystąpiło zakażenie miejsca operowanego. Grupę wyjściową stanowiło 1581 chorych z rozpoznaniem raka jelita grubego poddanych zabiegowi operacyjnemu w jednym ośrodku. Kryteriami wyłączającymi z badania były: brak wiarygodnej dokumentacji leczenia (szpitalnego lub ambulatoryjnego) i zgon chorego przed 30. dniem po operacji bez rozpoznanego zakażenia miejsca operowanego. Analizę statystyczną wykonano przy użyciu programu Statistica 10. Wyniki: Powikłania pooperacyjne wystąpiły u 262 chorych (16,6%). Najczęściej występującym było zakażenie miejsca operowanego (198 pacjentów; 12,52%). Stwierdzono, że wystąpienie tego powikłania zależne było od zaawansowania klinicznego raka, wieku chorych, chorób współtowarzyszących (cukrzyca i choroby kardiologiczne). Ponadto zauważono, że powikłanie to występowało znamiennie częściej u chorych operowanych w trybie pilnym z powodu powikłań oraz u tych, u których wyłoniono stomię jelitową. Nie stwierdzono natomiast zależności wystąpienia tego powikłania od płci chorych i lokalizacji guza nowotworowego. Wniosek: U chorych po operacji raka jelita grubego największe zagrożenie wystąpienia zakażenia miejsca operowanego wystąpiło u chorych po 75. roku życia, obciążonych cukrzycą i chorobami kardiologicznymi, z dużym zaawansowaniem klinicznym raka, operowanych w trybie ostrego dyżuru, u których konieczne było wyłonienie stomii jelitowej (a szczególnie kolostomii).

  5. Benefits and risks of benzodiazepines and Z-drugs: comparison of perceptions of GPs and community pharmacists in Germany.

    PubMed

    Hoffmann, Falk

    2013-01-01

    Hintergrund und Fragestellung: Die neueren Benzodiazepinrezeptor-Agonisten Zolpidem und Zopiclon (“Z-Drugs”) werden in letzter Zeit häufiger als Hypnotika vom Benzodiazepintyp verschrieben, obwohl keine Belege für Unterschiede bezüglich des Nutzens und Schaden existieren. Ziel dieser Studie war es zu vergleichen, wie Hausärzte und Apotheker erwünschte und unerwünschte Wirkungen dieser Mittel einschätzen.Methoden: Ein schriftlicher Fragebogen wurde 2012 an eine Zufallsauswahl von 1.350 Hausärzten und 600 Apothekenleitern versendet. Die gleichen Items wurden auf einer 5-Punkte-Likert-Skala sowohl für Benzodiazepine wie Z-Drugs abgefragt. Zum Vergleich zwischen Hausärzten und Apothekern wurden Wilcoxon Signed Rank Tests durchgeführt. Aufgrund der zahlreichen Tests wurden nur p-Werte ≤0,01 als statistisch signifikant angesehen.Ergebnisse: Insgesamt antworteten 458 Hausärzte und 202 Apotheker (Rücklauf 33,9% und 33,7%). Hausärzte waren durchschnittlich 53,3 Jahre (40,6% weiblich) und Apotheker 48,8 Jahre alt (59,2% weiblich). Keine Unterschiede in der Einschätzung des Nutzens von Benzodiazepinen (bzw. Z-Drugs) fanden sich bei 3 (bzw. 2) von 5 Items. Keine Unterschiede zeigten sich auch bei 3 von 5 Items zu unerwünschten Wirkungen von Benzodiazepinen. Hingegen schätzten Apotheker, dass 4 der 5 untersuchten unerwünschten Wirkungen von Z-Drugs häufiger vorkamen als Hausärzte (p=0,003 oder kleiner). Beispielsweise antworteten 45,2% der Apotheker, dass Entzugserscheinungen häufig bzw. sehr häufig/immer unter Z-Drugs auftreten, hingegen nur 28,3% der Hausärzte.Schlussfolgerungen: Obwohl es insgesamt schwierig ist, eindeutige Schlussfolgerungen aus diesen Befunden zu ziehen, scheinen Apotheker einen kritischeren Blick auf Z-Drugs und deren unerwünschte Wirkungen zu haben.

  6. Development and validation of a generic questionnaire for the implementation of complex medical interventions.

    PubMed

    Kramer, Lena; Hirsch, Oliver; Becker, Annette; Donner-Banzhoff, Norbert

    2014-01-01

    Norm/wahrgenommene Verhaltenskontrolle wurde akzeptiert. Die erklärte Varianz im Rahmen der ordinalen Regression war gering (Nagelkerke’s R(2)=.12). Weder Einstellung noch Intention konnten die Verwendung oder Nichtverwendung von arriba-lib vorhersagen (attitude: p=.68, intention: p=.44). Für den kombinierten Faktor subjektive Norm/wahrgenommene Verhaltenskontrolle zeigte sich ein signifikanter, aber kleiner Effekt (p=.03). Schlussfolgerung: Die TGV ist kein angemessener theoretischer Rahmen für die Entwicklung eines generischen Fragebogens im Kontext der Implementierung komplexer Interventionen. Um eine erfolgreiche Implementierung komplexer medizinischer Interventionen zu erreichen, muss der komplette Entwicklungs- und Evaluationsprozess des MRC-Modells bearbeitet werden. Des Weiteren sollte diskutiert werden, ob ein generisches Instrument valide und nützlich sein kann. Hinsichtlich der TGV könnte ein Publikationsbias bezüglich der praktischen Anwendung der Theorie vorliegen.

  7. The subjective experience of collaboration in interprofessional tutor teams: A qualitative study.

    PubMed

    Weber, Tobias; Hoffmann, Henriette

    2016-01-01

    Zielsetzung: Das Medizinische Interprofessionelle Trainingszentrum der Medizinischen Fakultät Carl Gustav Carus an der Technischen Universität Dresden bietet seit dem Wintersemester 2014/2015 Lehrveranstaltungen mit interprofessionellen Inhalten an. Die Besonderheit dieser Lehreinheiten besteht darin, dass sowohl studentische TutorInnen der Medizin als auch SchülertutorInnen der Gesundheits- und Krankenpflege gemeinsam die Lehreinheiten betreuen. Die Studie untersucht das subjektive Erleben der TutorInnen während der gemeinsamen Ausarbeitung und Durchführung dieser Lehreinheiten mit dem Ziel, die Effekte der gleichberechtigten Zusammenarbeit auf die Wahrnehmung und Einschätzung der jeweils anderen Berufsgruppe herauszuarbeiten. Methode: Es wurden teilstrukturierte Leitfadeninterviews mit sechs zufällig ausgewählten TutorInnen durchgeführt. Diese werden mittels inhaltlich-strukturierender Inhaltsanalyse ausgewertet.Ergebnisse: Die Ergebnisse zeigen, dass das gemeinsame Arbeiten vor allem bei den studentischen TutorInnen zu einer Reflexion bestehender Einstellungen geführt hat, jedoch wurden die jeweiligen Co-TutorInnen bei beiden Berufsgruppen in unterschiedlichem Grad als Repräsentanten ihrer Profession wahrgenommen. Durch die Bewältigung einer gemeinsamen Aufgabe in einem nicht-klinischen Kontext begegneten sich die Angehörigen der verschiedenen Berufsgruppen auf Augenhöhe, wenngleich die Medizinstudierenden bereits mehr didaktische Erfahrung aufwiesen und somit im Zuge der Erarbeitung und der Umsetzung der Lehreinheiten meist eine Mentoren-Rolle übernahmen. Die SchülertutorInnen waren vorwiegend auf ihre Rolle als TutorIn konzentriert. Hervorgehoben wurde von beiden Berufsgruppen, dass sie vor der Zusammenarbeit mangelnde oder keine Vorstellungen bezüglich des theoretischen Wissens und der praktischen Fertigkeiten der jeweils anderen Berufsgruppe besaßen. Das Projekt insgesamt wurde als gewinnbringend eingeschätzt und der Ansatz der

  8. New oral anticoagulants in the treatment of acute venous thromboembolism - a systematic review with indirect comparisons.

    PubMed

    Hirschl, Mirko; Kundi, Michael

    2014-09-01

    Hintergrund: Für Jahrzehnte waren Heparine und Vitamin K Antagonisten (VKA) der Goldstandard der Therapie der venösen Thromboembolie (VTE). Nun stehen mit Faktor IIa und Xa Inhibitoren neue Therapiemöglichkeiten zur Verfügung. Ziel dieser Analyse ist ein Vergleich dieser neuen oralen Antikoagulantien (NOACs) mit der Standardtherapie und - da es wahrscheinlich nie direkte Vergleichsstudien geben wird - ein indirekter Vergleich zwischen den NOACs. Patienten und Methoden: Insgesamt 27024 Patienten wurden in RE-COVER, RE-COVER II, EINSTEIN DVT und PE, AMPLIFY und HOKUSAI eingeschlossen, 13511 im VKA-Arm und 13513 im NOAC-Arm. Relative Risiken (RR) und absolute Risikoreduktionen (ARR) wurden für Effizienz- und Sicherheitsendpunkte in Relation zu VKA berechnet. Der indirekte Vergleich zwischen den NOACs erfolgte nach ISPOR Leitlinie. Ergebnisse: Bezüglich rekurrenter VTE und Tod findet sich zwischen NOACs und VKA kein Unterschied. Blutungen waren bei NOACs signifikant seltener: schwere Blutungen bei Rivaroxaban (RR 0,55; 0,38 - 0,81) und Apixaban (RR 0,31; 0,17 - 0,55), schwere Blutungen kombiniert mit klinisch relevanten nicht schweren Blutungen bei Dabigatran (RR 0,63; 0,51 - 0,77), bei Apixaban (RR 0,44; 0,36 - 0,55) und Edoxaban (RR 0,81; 0,71 - 0,93). Die ARR beträgt für Rivaroxaban und Apixaban etwa 1 % für schwere Blutungen, für die klinisch relevanten Blutungen war die ARR 3,2 % für Dabigatran, 5,4 % für Apixaban und 1.9 % für Edoxaban. Der indirekte Vergleich zeigt bzgl. der Effizienz keine Unterschiede zwischen den NOACs. Apixaban reduziert schwere Blutungen mehr als Dabigatran und Edoxaban. Den kombinierten Blutungsendpunkt senkt Dabigatran besser als Rivaroxaban und Edoxaban und Apixaban mehr als alle anderen NOACs. Schlussfolgerungen: NOACs sind zur Behandlung der VTE gleich effizient wie VKA, bei seltener auftretenden Blutungskomplikationen. Der indirekte Vergleich zeigt verschieden stark ausgeprägte Reduktion der Blutungskomplikationen

  9. Die Bedeutung der blauen Farbe in der Dermatoskopie.

    PubMed

    Popadić, Mirjana; Sinz, Christoph; Kittler, Harald

    2017-03-01

    Hautläsionen mit blauer Färbung werden häufig chirurgisch entfernt, um Malignität auszuschließen zu können. Das Ziel der vorliegenden Studie war es, die Bedeutung der blauen Färbung zu untersuchen. Wir untersuchten dermatoskopische Bilder retrospektiv auf blaue Farbe und klassifizierten sie gemäß der Musteranalyse. Von 1.123 pigmentierten Hautläsionen wiesen 144 (12,8 %) eine blaue Färbung auf. Von diesen waren 92 (63,9 %) bösartig. Unter den Läsionen mit Blaufärbung waren Nävi (n = 35, 24,3 %) und seborrhoische Keratosen (n = 8, 5,6 %) die häufigsten gutartigen Diagnosen. Von 103 (71,5 %) Läsionen mit einem strukturlosen blauen Muster waren acht (7,8 %) vollständig blau gefärbt und 95 (92,2 %) teilweise blau, davon zeigten 81 (78,6 %) periphere oder fleckige und 14 (13.6 %) eine zentrale Blaufärbung. Die meisten Läsionen mit peripherer oder fleckiger blauer Färbung waren Melanome (n = 47, 58 %), wohingegen die meisten Läsionen mit zentraler Blaufärbung Nävi darstellten (n = 9, 64,3 %). Von 28 Läsionen mit blauen Schollen waren 17 (60,7 %) Basalzellkarzinome. Bezüglich der Malignität war der positive prädiktive Wert der blauen Farbe 63,9 % (95 % KI: 56,0-71,8 %). Unter blaugefärbten bösartigen Läsionen ist eine strukturlose periphere oder fleckige blaue Farbe ein Hinweis auf Melanome, während blaue Schollen auf ein Basalzellkarzinom hinweisen. Als Fallstricke können sich seborrhoische Keratosen erweisen, die eine Blaufärbung zeigen können, sowie einige Nävi, vor allem kombinierte. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  10. Output space compaction for testing and concurrent checking

    NASA Astrophysics Data System (ADS)

    Seuring, Markus

    2001-02-01

    The objective of this thesis is to provide new space compaction techniques for testing or concurrent checking of digital circuits. In particular, the work focuses on the design of space compactors that achieve high compaction ratio and minimal loss of testability of the circuits. In the first part, the compactors are designed for combinational circuits based on the knowledge of the circuit structure. Several algorithms for analyzing circuit structures are introduced and discussed for the first time. The complexity of each design procedure is linear with respect to the number of gates of the circuit. Thus, the procedures are applicable to large circuits. In the second part, the first structural approach for output compaction for sequential circuits is introduced. Essentially, it enhances the first part. For the approach introduced in the third part it is assumed that the structure of the circuit and the underlying fault model are unknown. The space compaction approach requires only the knowledge of the fault-free test responses for a precomputed test set. The proposed compactor design guarantees zero-aliasing with respect to the precomputed test set. In der Dissertation werden neue Entwurfsmethoden für Kompaktoren für die Ausgänge von digitalen Schaltungen beschrieben, die die Anzahl der zu testenden Ausgänge drastisch verkleinern und dabei die Testbarkeit der Schaltungen nur wenig oder gar nicht verschlechtern. Der erste Teil der Arbeit behandelt für kombinatorische Schaltungen Methoden, die die Struktur der Schaltungen beim Entwurf der Kompaktoren berücksichtigen. Verschiedene Algorithmen zur Analyse von Schaltungsstrukturen werden zum ersten Mal vorgestellt und untersucht. Die Komplexität der vorgestellten Verfahren zur Erzeugung von Kompaktoren ist linear bezüglich der Anzahl der Gatter in der Schaltung und ist damit auf sehr große Schaltungen anwendbar. Im zweiten Teil wird erstmals ein solches Verfahren für sequentielle Schaltkreise beschrieben

  11. Multi-level suppression of receptor-PI3K-mTORC1 by fatty acid synthase inhibitors is crucial for their efficacy against ovarian cancer cells.

    PubMed

    Wagner, Renate; Stübiger, Gerald; Veigel, Daniel; Wuczkowski, Michael; Lanzerstorfer, Peter; Weghuber, Julian; Karteris, Emmanouil; Nowikovsky, Karin; Wilfinger-Lutz, Nastasia; Singer, Christian F; Colomer, Ramón; Benhamú, Bellinda; López-Rodríguez, María Luz; Valent, Peter; Grunt, Thomas W

    2017-01-10

    Receptor-PI3K-mTORC1 signaling and fatty acid synthase (FASN)-regulated lipid biosynthesis harbor numerous drug targets and are molecularly connected. We hypothesize that unraveling the mechanisms of pathway cross-talk will be useful for designing novel co-targeting strategies for ovarian cancer (OC). The impact of receptor-PI3K-mTORC1 onto FASN is already well-characterized. However, reverse actions-from FASN towards receptor-PI3K-mTORC1-are still elusive. We show that FASN-blockade impairs receptor-PI3K-mTORC1 signaling at multiple levels. Thin-layer chromatography and MALDI-MS/MS reveals that FASN-inhibitors (C75, G28UCM) augment polyunsaturated fatty acids and diminish signaling lipids diacylglycerol (DAG) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) in OC cells (SKOV3, OVCAR-3, A2780, HOC-7). Western blotting and micropatterning demonstrate that FASN-blockers impair phosphorylation/expression of EGF-receptor/ERBB/HER and decrease GRB2-EGF-receptor recruitment leading to PI3K-AKT suppression. FASN-inhibitors activate stress response-genes HIF-1α-REDD1 (RTP801/DIG2/DDIT4) and AMPKα causing mTORC1- and S6-repression. We conclude that FASN-inhibitor-mediated blockade of receptor-PI3K-mTORC1 occurs due to a number of distinct but cooperating processes. Moreover, decrease of PI3K-mTORC1 abolishes cross-repression of MEK-ERK causing ERK activation. Consequently, the MEK-inhibitor selumetinib/AZD6244, in contrast to the PI3K/mTOR-inhibitor dactolisib/NVP-BEZ235, increases growth inhibition when given together with a FASN-blocker. We are the first to provide deep insight on how FASN-inhibition blocks ERBB-PI3K-mTORC1 activity at multiple molecular levels. Moreover, our data encourage therapeutic approaches using FASN-antagonists together with MEK-ERK-inhibitors.

  12. High-Temperature Nuclear Reactors (Overview. Part 1) / Augstas Temperatūras Kodolreaktori (Pārskata raksts) 1. daļa

    NASA Astrophysics Data System (ADS)

    Ekmanis, J.; Tomsons, E.; Zeltiņš, N.

    2013-02-01

    At the Generation IV International Forum (GIF) of 2001 the measures were approved which are necessary for the development of future generation nuclear reactors (NRs). Six best high-temperature NR technologies were selected, with the main criteria being the safe and economically profitable operation, long-term use, protection against the employment of nuclear material for military purposes and terroristic attacks as well as technologies of fuel close cycle in order to increase the amount of fission material and decrease the amount of highly radioactive waste. In four of the technologies, apart from electricity production also hydrogen is obtained. Part 1 presents a generalized description of the high-temperature NRs, their comparative characteristics and history, with the stopped and operational HTNRs outlined. The properties of different type nuclear fuels are described in detail Ceturtās paaudzes kodolreaktoru starptautiskā forumā 2001.gadā nolēma par nepieciešamiem pasākumiem nākamās paaudzes kodolreaktoru izstrādei. Ir atlasītas sešas reaktoru tehnoloģijas, kuras lietderīgi turpmāk izstrādāt. Tās atlasītas ņemot vērā to drošu un ekonomiski izdevīgu darbību, ilgtspējīgu izmantošanu, aizsardzību pret materiālu izmantošanu militārām vajadzībām un teroristu uzbrukumiem, slēgtā degvielas cikla izmantošanu, lai palielinātu kodoldalīšanās materiālu daudzumu un samazinātu augstas aktivitātes atkritumu daudzumu, kurus būs jāapglabā. Četras no plānotām tehnoloģijām bez elektroenerģijas ieguves varēs ražot ūdeņradi. 1. daļā ietverts vispārīgs apraksts par augstas temperatūras kodolreaktoriem, to salīdzinājums pēc raksturlielumiem, pēc attīstības vēstures. Apskatīti gan apturētie, gan strādājošie reaktori, to kodoldegvielas

  13. Pore-fluid chemistry along the main axis of an active lobe at the Congo deep-sea fan

    NASA Astrophysics Data System (ADS)

    Croguennec, C.; Ruffine, L.; Guyader, V.; Le Bruchec, J.; Ruesch, B.; Caprais, J.; Cathalot, C.; de Prunelé, A.; Germain, Y.; Bollinger, C.; Dennielou, B.; Olu, K.; Rabouille, C.

    2013-12-01

    channel system of the Zaire deep-sea fan, Mar. Pet. Geol., 19, 445-467. Savoye, B., Babonneau, N., Dennielou, B. & Bez, M., 2009. Geological overview of the Angola-Congo margin, the Congo deep-sea fan and its submarine valleys, Deep-Sea Res. Part II-Top. Stud. Oceanogr., 56, 2169-2182. Vangriesheim, A., Khripounoff, A. & Crassous, P., 2009. Turbidity events observed in situ along the Congo submarine channel, Deep-Sea Res. Part II-Top. Stud. Oceanogr., 56, 2208-2222. Zabel, M. & Schulz, H.D., 2001. Importance of submarine landslides for non-steady state conditions in pore water systems - lower Zaire (Congo) deep-sea fan, Mar. Geol., 176, 87-99.

  14. Damage of chromosoms under irradiation of human blood lymphocytes and development of bystander effect.

    PubMed

    Shemetun, O V

    2016-12-01

    Meta: doslidzhennia rozpodilu radiatsiy̆no indukovanykh poshkodzhen' sered khromosom i ïkh bendiv v oprominenykh in vitro limfotsytakh krovi liudyny ta v neoprominenykh klitynakh svidkakh.Material i metody doslidzhennia: kul'tyvuvannia limfotsytiv peryferychnoï krovi liudyny za napivmikrometodom D. A. Hungerford, modeliuvannia radiatsiy̆no indukovanogo efektu svidka v zmishanykh kul'turakh z oprominenykh in vitro ta neoprominenykh limfotsytiv krovi osib riznoï stati, GTG zabarvlennia metafaznykh khromosom ta ïkh tsytoge netychnyy̆ analiz.Rezul'taty. Identyfikovano tochky rozryviv khromosom pry formuvanni aberatsiy̆ v oprominenykh in vitro v dozakh 0,25 Gr (95 rozryviv v 1248 klitynakh) i 1,0 Gr (227 rozryviv v 726 klitynakh) limfotsytakh peryferychnoï krovi liu dyny ta v neoprominenykh klitynakh svidkakh pry ïkh sumisnomu kul'tyvuvanni z oprominenymy in vitro limfotsyta my liudyny (51 rozryv v 1137 klitynakh pry oprominenni sumizhnoï populiatsiï limfotsytiv v dozi 0,25 Gr ta 75 roz ryviv v 1321 klityni pry oprominenni sumizhnoï populiatsiï limfotsytiv v dozi 1 Gr). Doslidzheno rozpodil za reiestrovanykh poshkodzhen' sered khromosom ta ïkh bendiv.Vysnovky. V oprominenykh in vitro limfotsytakh peryferychnoï krovi liudyny ta klitynakh svidkakh chastota poshkod zhenykh bendiv ta kil'kist' rozryviv, iaki lokalizuvalys' v nykh, perevyshchuvala kontrol'nu (r < 0,01). Iak pry bez poseredn'omu poshkodzhenni ionizuiuchoiu radiatsiieiu, tak i pry formuvanni rozryviv vnaslidok induktsiï efektu svidka, khromosomy poshkodzhuvalys' vidpovidno do ïkh vidnosnoï dovzhyny. Roztashuvannia bendiv, v iakykh za reiestrovano bil'shu kil'kist' rozryviv, spivpadalo z «gariachymy tochkamy» poshkodzhuvanosti khromosom pry op rominenni ta fragil'nymy say̆tamy. Chutlyvishymy do poshkodzhennia buly G negatyvni eukhromatynovi smugy khro mosom, v iakykh lokalizuvalys' 82 88 % rozryviv. Poshkodzhuvanist' telomernykh ray̆oniv v oprominenykh klitynakh ne mala

  15. Differential effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway in acute lymphoblastic leukemia.

    PubMed

    Badura, Susanne; Tesanovic, Tamara; Pfeifer, Heike; Wystub, Sylvia; Nijmeijer, Bart A; Liebermann, Marcus; Falkenburg, J H Frederik; Ruthardt, Martin; Ottmann, Oliver G

    2013-01-01

    Aberrant PI3K/AKT/mTOR signaling has been linked to oncogenesis and therapy resistance in various malignancies including leukemias. In Philadelphia chromosome (Ph) positive leukemias, activation of PI3K by dysregulated BCR-ABL tyrosine kinase (TK) contributes to the pathogenesis and development of resistance to ABL-TK inhibitors (TKI). The PI3K pathway thus is an attractive therapeutic target in BCR-ABL positive leukemias, but its role in BCR-ABL negative ALL is conjectural. Moreover, the functional contribution of individual components of the PI3K pathway in ALL has not been established. We compared the activity of the ATP-competitive pan-PI3K inhibitor NVP-BKM120, the allosteric mTORC1 inhibitor RAD001, the ATP-competitive dual PI3K/mTORC1/C2 inhibitors NVP-BEZ235 and NVP-BGT226 and the combined mTORC1 and mTORC2 inhibitors Torin 1, PP242 and KU-0063794 using long-term cultures of ALL cells (ALL-LTC) from patients with B-precursor ALL that expressed the BCR-ABL or TEL-ABL oncoproteins or were BCR-ABL negative. Dual PI3K/mTOR inhibitors profoundly inhibited growth and survival of ALL cells irrespective of their genetic subtype and their responsiveness to ABL-TKI. Combined suppression of PI3K, mTORC1 and mTORC2 displayed greater antileukemic activity than selective inhibitors of PI3K, mTORC1 or mTORC1 and mTORC2. Inhibition of the PI3K/mTOR pathway is a promising therapeutic approach in patients with ALL. Greater antileukemic activity of dual PI3K/mTORC1/C2 inhibitors appears to be due to the redundant function of PI3K and mTOR. Clinical trials examining dual PI3K/mTORC1/C2 inhibitors in patients with B-precursor ALL are warranted, and should not be restricted to particular genetic subtypes.

  16. Differential Effects of Selective Inhibitors Targeting the PI3K/AKT/mTOR Pathway in Acute Lymphoblastic Leukemia

    PubMed Central

    Badura, Susanne; Tesanovic, Tamara; Pfeifer, Heike; Wystub, Sylvia; Nijmeijer, Bart A.; Liebermann, Marcus; Falkenburg, J. H. Frederik; Ruthardt, Martin; Ottmann, Oliver G.

    2013-01-01

    Purpose Aberrant PI3K/AKT/mTOR signaling has been linked to oncogenesis and therapy resistance in various malignancies including leukemias. In Philadelphia chromosome (Ph) positive leukemias, activation of PI3K by dysregulated BCR-ABL tyrosine kinase (TK) contributes to the pathogenesis and development of resistance to ABL-TK inhibitors (TKI). The PI3K pathway thus is an attractive therapeutic target in BCR-ABL positive leukemias, but its role in BCR-ABL negative ALL is conjectural. Moreover, the functional contribution of individual components of the PI3K pathway in ALL has not been established. Experimental Design We compared the activity of the ATP-competitive pan-PI3K inhibitor NVP-BKM120, the allosteric mTORC1 inhibitor RAD001, the ATP-competitive dual PI3K/mTORC1/C2 inhibitors NVP-BEZ235 and NVP-BGT226 and the combined mTORC1 and mTORC2 inhibitors Torin 1, PP242 and KU-0063794 using long-term cultures of ALL cells (ALL-LTC) from patients with B-precursor ALL that expressed the BCR-ABL or TEL-ABL oncoproteins or were BCR-ABL negative. Results Dual PI3K/mTOR inhibitors profoundly inhibited growth and survival of ALL cells irrespective of their genetic subtype and their responsiveness to ABL-TKI. Combined suppression of PI3K, mTORC1 and mTORC2 displayed greater antileukemic activity than selective inhibitors of PI3K, mTORC1 or mTORC1 and mTORC2. Conclusions Inhibition of the PI3K/mTOR pathway is a promising therapeutic approach in patients with ALL. Greater antileukemic activity of dual PI3K/mTORC1/C2 inhibitors appears to be due to the redundant function of PI3K and mTOR. Clinical trials examining dual PI3K/mTORC1/C2 inhibitors in patients with B-precursor ALL are warranted, and should not be restricted to particular genetic subtypes. PMID:24244612

  17. Power estimation on functional level for programmable processors

    NASA Astrophysics Data System (ADS)

    Schneider, M.; Blume, H.; Noll, T. G.

    2004-05-01

    In diesem Beitrag werden verschiedene Ansätze zur Verlustleistungsschätzung von programmierbaren Prozessoren vorgestellt und bezüglich ihrer Übertragbarkeit auf moderne Prozessor-Architekturen wie beispielsweise Very Long Instruction Word (VLIW)-Architekturen bewertet. Besonderes Augenmerk liegt hierbei auf dem Konzept der sogenannten Functional-Level Power Analysis (FLPA). Dieser Ansatz basiert auf der Einteilung der Prozessor-Architektur in funktionale Blöcke wie beispielsweise Processing-Unit, Clock-Netzwerk, interner Speicher und andere. Die Verlustleistungsaufnahme dieser Bl¨ocke wird parameterabhängig durch arithmetische Modellfunktionen beschrieben. Durch automatisierte Analyse von Assemblercodes des zu schätzenden Systems mittels eines Parsers können die Eingangsparameter wie beispielsweise der erzielte Parallelitätsgrad oder die Art des Speicherzugriffs gewonnen werden. Dieser Ansatz wird am Beispiel zweier moderner digitaler Signalprozessoren durch eine Vielzahl von Basis-Algorithmen der digitalen Signalverarbeitung evaluiert. Die ermittelten Schätzwerte für die einzelnen Algorithmen werden dabei mit physikalisch gemessenen Werten verglichen. Es ergibt sich ein sehr kleiner maximaler Schätzfehler von 3%. In this contribution different approaches for power estimation for programmable processors are presented and evaluated concerning their capability to be applied to modern digital signal processor architectures like e.g. Very Long InstructionWord (VLIW) -architectures. Special emphasis will be laid on the concept of so-called Functional-Level Power Analysis (FLPA). This approach is based on the separation of the processor architecture into functional blocks like e.g. processing unit, clock network, internal memory and others. The power consumption of these blocks is described by parameter dependent arithmetic model functions. By application of a parser based automized analysis of assembler codes of the systems to be estimated the input

  18. NASA's Best-Observed X-Class Flare of All Time

    NASA Image and Video Library

    2017-09-27

    This close-up of the sunspot underneath the March 29, 2014, flare shows incredible detail. The image was captured by the G-band camera at Sacramento Peak in New Mexico. This instrument can focus on only a small area at once, but provide very high resolution. Ground-based telescope data can be hindered by Earth's atmosphere, which blocks much of the sun's ultraviolet and X-ray light, and causes twinkling even in the light it does allow through. As it happens, the March 29 flare occurred at a time of day in New Mexico that often results in the best viewing times from the ground. Credit: Kevin Reardon (National Solar Observatory), Lucia Kleint (BAER Institute) -- On March 29, 2014 the sun released an X-class flare. It was observed by NASA's Interface Region Imaging Spectrograph, or IRIS; NASA's Solar Dynamics Observatory, or SDO; NASA's Reuven Ramaty High Energy Solar Spectroscopic Imager, or RHESSI; the Japanese Aerospace Exploration Agency's Hinode; and the National Solar Observatory's Dunn Solar Telescope located at Sacramento Peak in New Mexico. To have a record of such an intense flare from so many observatories is unprecedented. Such research can help scientists better understand what catalyst sets off these large explosions on the sun. Perhaps we may even some day be able to predict their onset and forewarn of the radio blackouts solar flares can cause near Earth - blackouts that can interfere with airplane, ship and military communications. Read more: 1.usa.gov/1kMDQbO Join our Google+ Hangout on May 8 at 2:30pm EST: go.nasa.gov/1mwbBEZ Credit: NASA Goddard NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram

  19. Predictive value of laboratory hematological parameters for thromboses development in patients with spontaneous and radiation associated Ph negative myeloproliferative neoplasms.

    PubMed

    Mishcheniuk, O Yu; Klymenko, S V

    2015-12-01

    Meta. Vstanovyty, iaki z gematologichnykh pokaznykiv maiut' dyskryminatsiynu zdatnist' dlia prognozuvannia rozvyt ku tromboziv pry spontannykh ta radiatsiyno asotsiyovanykh Rh negatyvnykh miieloproliferatyvnykh novoutvoren niakh (MPN).Materialy i metody doslidzhennia. Proanalizovano gematologichni pokaznyky 85 khvorykh na spravzhniu politsy temiiu (SP), 43 – esentsial'nu trombotsytemiiu (ET) ta 40 – pervynnyy miielofibroz (PMF). Osnovnu grupu sklaly patsiienty (SP = 18, ET = 6, PMF = 18), iaki zaznaly diI ionizuiuchoI radiatsiI vnaslidok avariI na ChAES, a kontrol'nu – khvori (SP = 67, ET = 37, PMF = 22) bez vplyvu avariynogo radiatsiynogo oprominennia v anamnezi.Rezul'taty. Predyktyvne shchodo rozvytku tromboziv pry spontanniy SP znachennia gematokrytu ta leykotsytiv sta novyt' > 55 % ta > 13,2 · 109/l vidpovidno, a zagal'nogo kholesterynu – > 5,7 mmol'/l. Efektyvnist' dlia progno zuvannia tromboziv faktora „gematokryt > 55 % (ploshcha pid kryvoiu – PPK = 0,67; r = 0,023) ta „leykotsyty > 13,2 · 109/l ” (PPK = 0,66; r = 0,011) ie seredn'oiu, a „zagal'nyy kholesteryn > 5,7 mmol'/l ” (PPK = 0,92; r < 0,0001) – vidminnoiu. Prognostychnoiu shchodo vynyknennia tromboziv pry radiatsiyno asotsiyovaniy SP ta spontanniy ET vyia vylas' kil'kist' trombotsytiv < 440,0 · 109/l ta leykotsytiv > 10,0 · 109/l vidpovidno, iaka kharakteryzuiet'sia duzhe dobroiu (PPK = 0,84; r = 0,0002 ta PPK = 0,72; r = 0,019 vidpovidno) predyktyvnoiu potuzhnistiu. V osnovniy ta kontrol'niy grupi khvorykh na SP vyznacheno odnakovi PPK zastosuvannia dlia prognozuvannia tromboziv pokaznyka „gematokryt > 55 % ” (r = 0,800) ta „leykotsyty > 13,2 · 109/l ” (r = 0,831), prote rizni PPK rozrakhovano dlia mar kera „trombotsyty < 440,0 · 109/l ” (r = 0,0004). Tomu pokaznyk „trombotsyty < 440,0·109/l ” dorechno vrakhovuvaty pry otsintsi ymovirnosti trombozu za radiatsiyno asotsiyovanoI SP, a „gematokryt > 55% ” ta „leykotsyty > 13,2 · 109/l ”

  20. Sellar reconstruction without intrasellar packing after endoscopic surgery of pituitary macroadenomas is better than its reputation.

    PubMed

    Ismail, Mostafa; Fares, Abd Alla; Abdelhak, Balegh; D'Haens, Jean; Michel, Olaf

    2016-01-01

    Ziele: Die Rekonstruktion der Sella mit intrasellärer Tamponade nach endoskopischer Resektion von Hypophysenmakroadenomen bleibt in der klinischen und radiologischen Diskussion umstritten, besonders wenn keine Liquorfistel vorhanden ist. Diese Studie wurde durchgeführt, um unsere Erfahrungen mit der Sellarekonstruktion nach einer endoskopischen Standardresektion von Hypophysenmakroadenomen ohne intraoperative Liquorfistel zur laufenden Diskussion über Techniken mit und ohne intrasellärer Tamponade beizutragen.Methoden: Eine konsekutive Serie von 47 Hypophysenmakroadenomen, die in einem chirurgischen Standardverfahren endoskopisch über einen endonasalen transsphenoidalen Zugang ohne ersichtliche intraoperative Liquorfistel entfernt wurden, wurde nachträglich während einer durchschnittlich zehnmonatigen Nachbeobachtungszeit ausgewertet. Bezüglich der sellären Rekonstuktionstechnik konnten drei Gruppen identifiziert werden: Gruppe A – ohne intraselläre Tamponade, Gruppe B – mit Tamponade aus hämostatischen Materialien und Gruppe C – mit Bauchfetttamponade. Die postoperative klinische und radiologische Bewertung der drei Gruppen wurde dokumentiert und auf Unterschiede in den Ergebnissen hin analysiert.Ergebnisse: Die postoperative klinische Beurteilung ergab keine signifikanten Unterschiede zwischen den drei Gruppen. In der Gruppe A wurden postoperativ weder Liquorfistel noch Keilbeinhöhlenentzündung oder Empty-Sella-Syndrom beobachtet. Allerdings konnte ein signifikanter Unterschied in der radiologischen Bewertung identifiziert werden: die Interpretation von sellären Inhalten bei der postoperativen MRT der Gruppe A gelang früher und zuverlässiger als in anderen Gruppen mit intrasellärer Tamponade.Schlussfolgerung: Es gibt keinen Unterschied in der Inzidenz von postoperativen Liquorfisteln und Empty-Sella-Syndromen bei den verschiedenen rekonstruktiven Techniken mit und ohne intrasellärer Tamponade, unabhängig von Größe und Ausdehnung des

  1. Single-cell mass cytometry reveals intracellular survival/proliferative signaling in FLT3-ITD-mutated AML stem/progenitor cells.

    PubMed

    Han, Lina; Qiu, Peng; Zeng, Zhihong; Jorgensen, Jeffrey L; Mak, Duncan H; Burks, Jared K; Schober, Wendy; McQueen, Teresa J; Cortes, Jorge; Tanner, Scott D; Roboz, Gail J; Kantarjian, Hagop M; Kornblau, Steven M; Guzman, Monica L; Andreeff, Michael; Konopleva, Marina

    2015-04-01

    Understanding the unique phenotypes and complex signaling pathways of leukemia stem cells (LSCs) will provide insights and druggable targets that can be used to eradicate acute myeloid leukemia (AML). Current work on AML LSCs is limited by the number of parameters that conventional flow cytometry (FCM) can analyze because of cell autofluorescence and fluorescent dye spectral overlap. Single-cell mass cytometry (CyTOF) substitutes rare earth elements for fluorophores to label antibodies, which allows measurements of up to 120 parameters in single cells without correction for spectral overlap. The aim of this study was the evaluation of intracellular signaling in antigen-defined stem/progenitor cell subsets in primary AML. CyTOF and conventional FCM yielded comparable results on LSC phenotypes defined by CD45, CD34, CD38, CD123, and CD99. Intracellular phosphoprotein responses to ex vivo cell signaling inhibitors and cytokine stimulation were assessed in myeloid leukemia cell lines and one primary AML sample. CyTOF and conventional FCM results were confirmed by western blotting. In the primary AML sample, we investigated the cell responses to ex vivo stimulation with stem cell factor and BEZ235-induced inhibition of PI3K and identified activation patterns in multiple PI3K downstream signaling pathways including p-4EBP1, p-AKT, and p-S6, particularly in CD34(+) subsets. We evaluated multiple signaling pathways in antigen-defined subpopulations in primary AML cells with FLT3-ITD mutations. The data demonstrated the heterogeneity of cell phenotype distribution and distinct patterns of signaling activation across AML samples and between AML and normal samples. The mTOR targets p-4EBP1 and p-S6 were exclusively found in FLT3-ITD stem/progenitor cells, but not in their normal counterparts, suggesting both as novel targets in FLT3 mutated AML. Our data suggest that CyTOF can identify functional signaling pathways in antigen-defined subpopulations in primary AML, which may

  2. Clinical practice and self-awareness as determinants of empathy in undergraduate education: a qualitative short survey at three medical schools in Germany.

    PubMed

    Ahrweiler, Florian; Scheffer, Christian; Roling, Gudrun; Goldblatt, Hadass; Hahn, Eckhart G; Neumann, Melanie

    2014-01-01

    Ziel der Studie: Ärztliche Empathie ist ein Outcome-relevantes Ziel der medizinischen Ausbildung. Faktoren, die die ärztliche Empathie fördern oder hemmen, sind jedoch vor allem in Deutschland noch nicht ausreichend erforscht. In der vorliegenden Studie untersuchten wir die Sichtweise deutscher Medizinstudentinnen und -studenten auf die Faktoren, die ihre Empathie fördern und hemmen und darauf, in welcher Beziehung ihre Erfahrungen zu den jeweiligen Curricula standen. Methoden: Es wurde eine qualitative Kurzumfrage an drei Universitäten durchgeführt: an der Ruhr-Universität Bochum, an der Universität zu Köln und an der Universität Witten/Herdecke. Die Studierenden wurden gebeten, einen anonymen Fragebogen mit offenen Fragen über Ausbildungsinhalte und Situationen während ihres Medizinstudiums auszufüllen, die einen positiven oder negativen Einfluss auf ihre Empathie hatten. Die Daten wurden mit einer qualitativen Inhaltsanalyse nach Green und Thorogood ausgewertet.Ergebnisse: Insgesamt nahmen 115 Studierende an der Umfrage teil. Die Befragten gaben an, dass eine praxisorientierte Ausbildung mit Patientenkontakt sowie Lehre mit Bezug zur klinischen Praxis und der Sichtweise der Patienten ihre Empathie förderten, während das Fehlen dieser Faktoren ihre Empathie hemmte. Auch die persönliche Reaktion der Studierenden auf die Patienten, wie Sympathie für oder Abneigung gegen Patienten, Vorurteile und die innere Haltung wurden als Einflussfaktoren auf ihre Empathie betrachtet. Obwohl jede Universität einen anderen Ansatz bei der Vermittlung sozialer Kompetenzen verfolgt, ergaben sich aus den Antworten der jeweiligen Studierenden keine relevanten Unterschiede bezüglich möglicher Einflussfaktoren von Empathie. Schlussfolgerung: Mehr Lehre mit Praxisbezug und häufigerer Patientenkontakt könnten sich fördernd auf die Empathie der Studierenden auswirken. Sie benötigen Unterstützung bei der Entwicklung einer therapeutischen Beziehung zum Patienten

  3. Multipoint targeting of the PI3K/mTOR pathway in mesothelioma

    PubMed Central

    Zhou, S; Liu, L; Li, H; Eilers, G; Kuang, Y; Shi, S; Yan, Z; Li, X; Corson, J M; Meng, F; Zhou, H; Sheng, Q; Fletcher, J A; Ou, W-B

    2014-01-01

    Background: Mesothelioma is a notoriously chemotherapy-resistant neoplasm, as is evident in the dismal overall survival for patients with those of asbestos-associated disease. We previously demonstrated co-activation of multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET, and AXL in mesothelioma cell lines, suggesting that these kinases could serve as novel therapeutic targets. Although clinical trials have not shown activity for EGFR inhibitors in mesothelioma, concurrent inhibition of various activated RTKs has pro-apoptotic and anti-proliferative effects in mesothelioma cell lines. Thus, we hypothesised that a coordinated network of multi-RTK activation contributes to mesothelioma tumorigenesis. Methods: Activation of PI3K/AKT/mTOR, Raf/MAPK, and co-activation of RTKs were evaluated in mesotheliomas. Effects of RTK and downstream inhibitors/shRNAs were assessed by measuring mesothelioma cell viability/growth, apoptosis, activation of signalling intermediates, expression of cell-cycle checkpoints, and cell-cycle alterations. Results: We demonstrate activation of the PI3K/AKT/p70S6K and RAF/MEK/MAPK pathways in mesothelioma, but not in non-neoplastic mesothelial cells. The AKT activation, but not MAPK activation, was dependent on coordinated activation of RTKs EGFR, MET, and AXL. In addition, PI3K/AKT/mTOR pathway inhibition recapitulated the anti-proliferative effects of concurrent inhibition of EGFR, MET, and AXL. Dual targeting of PI3K/mTOR by BEZ235 or a combination of RAD001 and AKT knockdown had a greater effect on mesothelioma proliferation and viability than inhibition of individual activated RTKs or downstream signalling intermediates. Inhibition of PI3K/AKT was also associated with MDM2-p53 cell-cycle regulation. Conclusions: These findings show that PI3K/AKT/mTOR is a crucial survival pathway downstream of multiple activated RTKs in mesothelioma, underscoring that PI3K/mTOR is a compelling target for

  4. Limit Analysis of Geometrically Hardening Composite Steel-Concrete Systems / Stany Graniczne Geometrycznie Wzmacniających Się Konstrukcji Zespolonych

    NASA Astrophysics Data System (ADS)

    Alawdin, Piotr; Urbańska, Krystyna

    2015-03-01

    połączony z płytą betonową. Analizowano cztery przypadki skratownia podciągu wykonanego z prętów stalowych o przekroju kołowym i znacznej sztywności słupów. Pokazano znaczący wpływ orientacji słupów podciągu na nośność konstrukcji. Drugi przykład numeryczny wykonano dla uproszczonego modelu wiaduktu WD-22 znajdującego się na węźle "Pyrzyce" na drodze ekspresowej S3. Dla obu przykładów realizowano dwa przypadki obciążania konstrukcji, bez uwzgłędnienia i z uwzgłędnieniem stałego równoważącego obciążenia z dociążeniem. Obliczenia numeryczne wykonano w środowisku systemu Abaqus/Standard stosując analizę geometrycznie nieliniową (Nlgeom). W obliczeniach przyjęto następujące modele materiałowe: dla belki żelbetowej - idealnie sprężysto-plastyczny natomiast dla prętów stalowych podciągu - sprężysty. Celem analizy była obserwacja zachowania się konstrukcji po osiągnięciu obciążenia granicznego dla różnych przypadków skratowania oraz oszacowanie nośności granicznej dla konstrukcji bez stałego obciążenia oraz ze stałym obciążeniem i dociążeniem. Na podstawie przeprowadzonych obliczeń numerycznych i analitycznych stwierdzono, że w różnych konstrukcjach o pewnych wymiarach skratowania obserwuje się wzmocnienie geometryczne po osiągnięciu przez system nośności granicznej. Uwzględnienie obciążenia stałego równoważącego oraz dodatkowego dociążenia powoduje wzrost nośności granicznej konstrukcji geometrycznie wzmacniających się o około 20 %.

  5. Unique Project of Single-Cutting Head Longwall Shearer Used for Thin Coal Seams Exploitation / Projekt Jednoorganowego Kombajnu ŚCIANOWEGO O Specjalnej Konstrukcji Przeznaczonego do Eksploatacji POKŁADÓW Cienkich

    NASA Astrophysics Data System (ADS)

    Bołoz, Łukasz

    2013-12-01

    ): • praca w systemie ścianowym, • zastosowanie frezowania jako metody skrawania, • rozdzielenie procesu frezowania od procesu ładowania, • zastosowanie pełnej automatyzacja pracy, • zastosowanie cięgnowego systemu posuwu, • możliwość rozpoczynania nowego skrawu bez konieczności zawrębiania, • gabaryty dostosowane do pracy w ścianach o wysokości od 1.0 m do 1.6 m, praca systemem dwukierunkowym. Fig. 2 przedstawia koncepcję kombajnu jednoorganowego. Kombajn ten składa się z kadłuba 2, jednego zamocowanego centralnie organu urabiającego 1 oraz dwóch rozkładanych ładowarek odkładniowych 3 i 4. Ładowarka 3 znajduje się w pozycji czynnej, natomiast ładowarka 4 w biernej. Kombajn jest ciągnięty po rynnach przenośnika 5 za pomocą łańcucha 6. Łańcuch 7 jest gałęzią bierną dla przedstawionego zwrotu prędkości. Podane, orientacyjne wymiary wynikają z analizy dotychczasowych rozwiązań kombajnów, głowic strugowych oraz założonego zakresu wysokości wyrobiska ścianowego (Krauze, 2006; Bołoz, 2012). Dla zaproponowanego rozwiązania przyjęto szereg koniecznych wielkości i przeprowadzono analizę możliwego do uzyskania wydobycia dobowego. Zestawione tabelarycznie wyniki umożliwiają określenie wydobycia dobowego możliwego do uzyskania przy określonych wartościach parametrów geometrycznych ściany, kinematycznych kombajnu oraz organizacyjnych pracy ściany. Dla założonych parametrów można stwierdzić, że minimalne wydobycie dobowe na poziomie Vd = 4032 Mg/d uzyskano dla L = 180 m, tp = 11 min, H = 1.0 m oraz T = 12 h/d. Maksymalne wydobycie dobowe na poziomie Vd = 11 612 Mg/d uzyskać można dla L = 300 m, tp = 0 min, H = 1.6 m oraz T = 18 h/d. Na wydobycie dobowe największy wpływ ma dobowy czas pracy ściany a następnie czas przekładki (Bołoz, 2012). Średnica organu dla takiego kombajnu dobierana jest do grubości pokładu. W przedmiotowym rozwiązaniu przyjęto organ o konstrukcji przestrzennej (belki no

  6. Impact of numerical information on risk knowledge regarding human papillomavirus (HPV) vaccination among schoolgirls: a randomised controlled trial.

    PubMed

    Steckelberg, Anke; Albrecht, Martina; Kezle, Anna; Kasper, Jürgen; Mühlhauser, Ingrid

    2013-01-01

    Einführung: In Deutschland wurde die Implementierung der Humanen Papillomavirus (HPV)-Impfung für 12–17-jährige Mädchen von diversen Kampagnen begleitet. Evidenz-basierte Informationen, die Zahlenangaben beinhalten, wurden nicht zur Verfügung gestellt. Stattdessen führten die Standardinformationen zu einer Überschätzung des Krebsrisikos und den Effekten der HPV-Impfung. Das Vertrauen in die Fähigkeit von Kindern mit Risiken umzugehen ist gering, insbesondere wenn es sich um sozial benachteiligte Schüler handelt. Das Ziel dieser Studie ist ein Vergleich der Effekte eines Standard-Flyers mit einem Informationsflyer, der Zahlenangaben beinhaltet, hinsichtlich des Risikowissens über die HPV-Impfung bei Schülerinnen. Methoden: Randomisiert-kontrollierte Kurzzeitstudie. Es wurden alle 108 Schülerinnen aus sieben Schulklassen auf die Teilnahme angesprochen und 105 stimmten zu. Die Teilnehmerinnen waren Berufsfachschülerinnen, die den Abschluss der 10. Klasse anstrebten und zur Zielgruppe für eine HPV-Impfung gehörten. Die Kontrollgruppe wurde gebeten, den Standardflyer des Nationalen Netzwerks Frauen und Gesundheit zu lesen. Die Interventionsgruppe erhielt den gleichen Flyer, der jedoch mit numerischen Informationen zum Krebsrisiko und zu den angenommenen Effekten der HPV-Impfung auf die Krebsprävention ergänzt worden war. Als Basischarakteristika wurden Alter, Impfstatus, Einstellung zur HPV-Impfung und Aspekte bezüglich des Migrationshintergrunds erhoben. Der primäre Endpunkt war Risikowissen. Die Fragebogenerhebungen erfolgten unter experimentellen Bedingungen. Die individuelle Randomisierung, die Teilnehmerinnen und die intention-to-treat Datenanalyse waren verblindet. Die Studie wurde vom Ministerium für Bildung und Kultur des Landes Schleswig-Holstein und der Ethikkommission der Hamburger Ärztekammer genehmigt. Ergebnisse: Risikowissen wurde für alle 105 randomisierten Teilnehmerinnen analysiert. Die Basischarakteristika der beiden Gruppen

  7. Significant improvement of a clinical training course in physical examination after basic structural changes in the teaching content and methods.

    PubMed

    Sonne, Carolin; Vogelmann, Roger; Lesevic, H; Bott-Flügel, Lorenz; Ott, I; Seyfarth, Melchior

    2013-01-01

    Hintergrund: Die regelmäßigen Evaluationen der Studierenden der Technischen Universität München deuten auf einen Verbesserungsbedarf des klinischen Untersuchungskurses hin. Ziel der vorliegenden Studie war es, zu prüfen, ob gezielte Maßnahmen zur Umstrukturierung und Verbesserung eines Untersuchungskurstages zu einer höheren Zufriedenheit der Studierenden und zu einer besseren Selbsteinschätzung der von ihnen erlernten Untersuchungstechniken führen.Methoden: In drei medizinischen Kliniken der Technischen Universität München wurden im Sommersemester 2010 die quantitativen Evaluationsergebnisse (deutsches Schulnotensystem, Noten 1-6) von insgesamt 49 Studierenden von einem Kurstag vor und einem Kurstag nach strukturierten Verbesserungsmaßnahmen des klinischen Untersuchungskurses verglichen. Zum Einsatz kamen strukturierte Instruktion der Dozenten, Handouts und über das Internet verfügbares Zusatzmaterial.Ergebnisse: Es wurden 47 Evaluationsbögen vor und 34 Evaluationsbögen nach den Verbesserungsmaßnahmen ausgefüllt. Die oben genannten Maßnahmen führten zu signifikanten Verbesserungen der Evaluationsnoten in folgenden Bereichen: Einführen ins jeweilige Kursthema (von 2,4±1,2 auf 1,7±1,0, p=0,002) und in hygienische Maßnahmen (von 3,8±1,9 auf 2,5±1,8, p=0,004), strukturiertes Vorführen der einzelnen Untersuchungsschritte (von 2,9±1,5 auf 1,8±1, p=0,001), Üben der Untersuchungsschritte (von 3,1±1,8 auf 2,2±1,4, p=0,030), strukturiertes Feedback zur Untersuchungstechnik (von 3,0±1,4 auf 2,3±1,0, p0,=0,007), Verwenden von Handouts (von 5,2±1,4 auf 1,8±1,4, p<0,001), Tipps zu weiterem Lernmaterial (von 5,0±1,4 auf 3,4±2,0, p<0,001), Lernerfahrung insgesamt (von 2,4±0,9 auf 1,9±0,8, p=0,017) und Selbsteinschätzung der Studenten bezüglich der Sicherheit bei der Durchführung einer körperlichen Untersuchung (von 3,5±1,3 auf 2,5±1,1, p<0,001).Zusammenfassung: Strukturierte Verbesserungsmaßnahmen führten zu signifikanten

  8. Evolution of the Structure and Mechanical Strength of a Coal Particle During Combustion in the Atmosphere of Air and the Mixture of Oxygen and Carbon Dioxide / Ewolucja Struktury Oraz Wytrzymałości Mechanicznej Ziarna Węgla Podczas Spalania W Atmosferze Powietrza Oraz Mieszaninie Tlenu I Dwutlenku Węgla

    NASA Astrophysics Data System (ADS)

    Pełka, Piotr; Golański, Grzegorz; Wieczorek, Paweł

    2013-09-01

    : wytrzymałość na ściskanie, twardości Vickersa oraz współczynnik kruchości. Analizę uzupełniono zdjęciami mikroskopowymi powierzchni ziaren wykonanymi za pomocą mikroskopu sił atomowych. Otrzymane rezultaty wskazują na bardzo wyraźne zmiany wytrzymałościowe węgla podczas jego spalania, szczególnie w chwili zapłonu karbonizatu. Uzyskane wyniki bardzo dobrze korelują z opisywanymi przez innych autorów procesami rozdrabniania węgla (Basu, 1999; Chirone et al., 1991) podczas spalania w warunkach cyrkulacyjnej warstwy fluidalnej. Tłumaczą gwałtowną zmianę podatności na erozję w warunkach bez spalania oraz z towarzyszącym spalaniem. Rezultaty badań mogą posłużyć jako parametry wytrzymałościowe w modelowaniu ubytku masy ziaren węgla w trudnych do opisania warunkach cyrkulacyjnej warstwy fluidalnej.

  9. Influence of the Plow Filling and Thread Angle onto the Plow Head Efficiency / Wpływ Współczynnika Wypełnienia Organu Oraz Kąta Nawinięcia Płata Ślimaka Na Sprawność Ładowania Frezującymi Organami Ślimakowymi

    NASA Astrophysics Data System (ADS)

    Wydro, Tomasz

    2015-03-01

    ędniono wpływ jednego z parametrów konstrukcyjnych organu, a mianowicie kąta nawinięcia płata ślimaka α2 na sprawność ładownia, a także jaki wpływ ma współczynnik wypełnienia organu kw i współczynnik rozluzowania urobku kr, na sprawność ładowania (Wydro, 2011). Po przeprowadzonych badaniach wstępnych przyjęto, że kryteria oceny procesu ładowania będą różne dla organu wyposażonego w ładowarkę kryterium oceny procesu ładowania będzie pobór mocy silnika organu i posuwu, natomiast dla organu bez ładowarki kryterium jego oceny będzie sprawność ładowania. Za sprawność ładowania uznano stosunek pola przekroju pryzmy urobku załadowanego do pola przekroju całkowitego pryzmy urobku przemieszczonego, co szerzej zostało opisane w dalszej części artykułu (Wydro, 2011). Przedmiotowe badania miały na celu, sprawdzenie w jakim stopniu wybrany parametr konstrukcyjny, kąt nawinięcia płatów ślimaka α2 oraz współczynnik wypełnienia organu kw i współczynnik rozluzowania kr urobku mają wpływ na sprawność ładowania i przy jakich ich wartościach organy ślimakowe uzyskują największą sprawność ładowania. Wartości i zakresy tych współczynników, zostały określone na podstawie badań empirycznych. Jak podaje literatura (Hamala & Wydro, 2005; Krauze, 1997) współczynniki przyjmowane są w granicach kw= 0÷1, kr > 1 na podstawie doświadczenia konstruktora dla nowo projektowanych organów ślimakowych. Parametr konstrukcyjny, który został przyjęty do badań, to kąt nawinięcia płatów ślimaka α2 i według literatury (Bednarz, 2003; Krauze, 2000) przyjmuje optymalną wartość w zakresie 19°, a 23°. W związku z powyższym, w przedmiotowych badaniach chciano sprawdzić jaki wpływ na proces ładowania mają kąty poniżej i powyżej wspomnianego zakresu, a także sprawdzenia, czy można określić jakie wartości współczynników kw i kr należy przyjmować podczas określania parametrów konstrukcyjnych i

  10. Critical heat flux in pool boiling on a vertical heater

    NASA Astrophysics Data System (ADS)

    Monde, M.; Inoue, T.; Mitsutake, Y.

    Critical heat flux during pool boiling on a vertical heater of wire or plate has been measured employing water and R113. The experiment was made for a wire of 0.5 to 2 mm in diameter and for a plate of 5, 7 and 30 mm in width and from 20 to 300 mm in height. The pressure was 1 and 2 bar for water and 1, 2, 3 and 4 bar for R113. The experiment shows that for the case of both wire and plate of 5, 7 mm, a large coalesced bubble entirely surrounds the vertical heater and rises surrounding it, while for the case of w = 30 mm, a large bubble cannot surround and rises along its surface. The characteristic of CHF can be divided into two regimes depending on the flow condition when CHF takes place. Correlations are proposed for the CHF of the wire and the plate of w = 5, and 7 mm, yielding good accuracy. The CHF for the plate of w = 30 mm has a similar tendency to that in one side headed surface and can be predicted reasonably by existing correlation for one side heated surface. Zusammenfassung Der kritische Wärmefluß beim Behältersieden an einem vertikalen Heizkörper (Draht oder Platte) wurde mit den Versuchsmedien Wasser und R113 gemessen. Die Experimente bezogen sich auf Drähte von 0,5 bis 2 mm Durchmesser und Platten von 5, 7 und 30 mm Breite und 20 bis 300 mm Höhe. Die Drücke betrugen 1 und 2 bar bei Wasser und 1, 2, 3 und 4 bar bei R113. In den Experimenten zeigte sich bei Drähten und Platten mit 5 und 7 mm Breite eine große zusammengewachsene Blase, die, den Heizkörper vollständig umschließend, an diesem aufstieg. Bei der 30 mm breiten Platte vermochte die große Blase den Heizkörper nicht mehr zu umschließen sie stieg an dessen Oberfläche auf. Die Charakteristik des kritischen Wärmeflusses läßt sich in zwei Bereiche unterteilen, und zwar in Abhängigkeit von den Strömungsbedingungen, unter welchen er auftrat. Vorgeschlagene Berechnungsgleichungen für den kritischen Wärmefluß liefern bezüglich der Drähte und der Platten mit 5 und 7 mm Breite

  11. Airborne laser-spark for ambient desorption/ionisation.

    PubMed

    Bierstedt, Andreas; Riedel, Jens

    2016-01-01

    Desorption als auch die Ionisation erfolgen hierbei durch ein laserbetriebenes Luftplasma. Die Abwesenheit fester oder flüssiger Elektroden hat zur Folge, dass die Methode weder unter chemischen Interferenzen noch unter Verschleiß durch Korrosionsbrand oder abgetragenes Elektrodenmaterial leidet. Insgesamt betrachtet herrscht in dem Plasma Elektroneutralität, wodurch Aufladungseffekte minimiert werden, die andernfalls zu einer langfristigenÄderung der Flugbahnen von Ionen während der Experimente führen kann. In dem Ansatz eine freischwebende Luftentladung bei Atmosphärendruck zu verwenden agiert die Luft nicht nur als Plasmamedium sondert dient zusätzlich als Badgas für die stoßinduzierte Kühlung der entstehenden Ionen. Die Ionisierung der Analytmoleküle erfolgt nicht unmittelbar im Plasma sondern in dessen direkter Umgebung durch Wechselwirkung mit freigesetzten ionischen Luftspezies, freien Elektronen oder Photonen im kurzwelligen ultravioletten Bereich. Jede Laserentladung erzeugt eine hörbare Stoßwelle, in welcher neu produzierte reaktive Spezies freigesetzt werden, welche sich konzentrisch ausbreiten, so dass eine Diffusion der Analytmoleküle ins heiße Innere des Plasmas verhindert wird. Daraus folgt, dass im Interaktionsvolumen zwischen Plasma und Analyt der Temperaturgrenzwert für eine thermische Dissoziation oder Fragmentierung der Moleküle nicht überschritten wird. Experimentell konnte belegt werden, dass das vorgestellte Ionisierungsschema sehr unselektiv bezüglich der chemischen Analytklasse ist und kaum Fragmentierungsprodukte beobachtet werden können. Messungen einer breitgefächerten Auswahl unterschiedlicher Testsubstanzen, wie beispielsweise polarer und unpolarer Kohlenwasserstoffe, Zuckern, niedermolekularer pharmazeutischer Wirkstoffe, sowie natürlicher Biomoleküle in Lebensmittelproben unmittelbar aus ihren komplexen Matrizes, führten zu aussagekräftigen Massenspektren. Zumal das Lasermedium feuchte Luft ist, scheint der

  12. Projects of High-Temperature Nuclear Reactors

    NASA Astrophysics Data System (ADS)

    Ekmanis, J.; Tomsons, E.; Zeltiņš, N.

    2013-04-01

    Part 2 of the overview gives emphasis to the projects of high-temperature NRs, whose development is an area of active engagement for the specialists from the USA, France, Japan, Russia, China, the Netherlands, and Germany. Projects of several powerful NRs of the HTGR type for commercial use had been worked out in the USA and Germany already by 1970 but not yet implemented. Augstas temperatūras ar gāzes dzesēšanu HTGR (High Temperature Gas cooled Reactor) tipa kodolreaktoru (KR) izstrādes koncepcija bija piedāvāta 1956. gadā Lielbritānijā. Apmēram tanī pašā laikā minētā tipa KR izstrādi uzsāka Vācijā un ASV. HTGR tipa KR kodoldegviela un kodoldegvielas atražošanas materiāla sīkās daļiņas ar diametru apmēram 0.5 mm pārklātas ar vairākām aizsargkārtām un atrodas grafīta neitronu palēninātājā, kas aizsargā daļiņas no neitronu palēninātāja un dzesētāja iedarbes. Augstas temperatūras KR bez hēlija gāzes siltumnesēja var izmantot šķidrus metālus (nātriju, svinu vai svina-bismuta sakausējumu) un izkausētu sāli. Pašlaik darbojās divi augstas temperatūras ar hēlija gāzi dzesēti eksperimentālie HTGR tipa KR. Viens Japānā "HTTR" no 1998. gada oktobra (sākts būvēt 1991. gada 15. martā) ar 30 MWth siltuma jaudu. Otrs Ķīnā "HTR-10" no 2000.gada decembra (sākts būvēt 1995. gada14. jūnijā) ar 10 MWth siltuma jaudu. Ķīnā Shandong provincē 2011.gada aprīlī uzsāka augstas temperatūras "HTR-PM" (High Temperature Gas-cooled Reactor - Pebble bed Module) tipa kodolreaktora celtniecību ar 250 MWth siltuma jaudu. Augstas temperatūras kodolreaktoru izstrādē pašlaik aktīvi iesaistīti ASV, Francijas, Japānas, Krievijas, Ķīnas, Nīderlandes un Vācijas speciālisti.

  13. Infrastructure of Baltic Region Transmission System: Analysis of Technical and Economic Factors of its Development

    NASA Astrophysics Data System (ADS)

    Obushevs, A.; Oleinikova, I.; Mutule, A.

    2014-08-01

    The operational conditions of new networks dictate new requirements for the transmission planning, which would include the electricity market figures and a sizable involvement of renewable generation. This paper focuses on the transmission expansion planning techniques based on the calculations of optimal power flows and on the concept of development planning and sustainability. A description is given for the mathematical model of calculations and analysis of transmission system. The results have shown that the Baltic transmission system infrastructure can successfully be analyzed based on the proposed methodology and developed mathematical model Baltijas valstu (Latvijas, Lietuvas un Igaunijas) energosistēmas ir cieši saistītas vēsturiski, un to darbība nav iespējama bez savstarpējas sadarbības attīstības un darba režīmu jautājumos. Ekonomisko attiecību īstenošanu enerģētikas sektorā paātrināja elektroenerģijas tirgus attīstība. Baltijas valstu enerģētikas politika ir integrēta ES enerģētikas stratēģijas sastāvdaļa, nosakot trīs galvenos mērķus: enerģētikas nozares konkurētspēja, ilgtspējīga attīstība un drošība. Visas trīs Baltijas energosistēmas veica lielu darba apjomu iekārtu modernizācijā un standartu saskaņošanā, kuras ir saskaņā ar Eiropas Savienības prasībām, kā arī par tirgus attiecību un tehnoloģiju standartu ieviešanu, lai nodrošinātu energoapgādes drošību un elektroenerģijas pieejamību patērētājiem Tomēr, ņemot vērā strauji mainīgos ārējos apstākļus, it īpaši ģeopolitiskos faktorus, Baltijas valstu enerģētikas politika būtu jāizskata ar mērķi novērtēt, kā šie faktori ietekmē energosistēmas ilgtspējīgu attīstību kopumā. No iepriekš minētā izriet, ka nepieciešama jauna nacionāla enerģētikas stratēģija, kura stiprinātu efektīvu ekonomisko un sociālo pamatu ilgtspējīgu attīstību Baltijas valstu nacionālā ekonomikā. Šī darba m

  14. Fused Deposition Modelling as Rapid Prototyping for Structural Material Improvement: Analytical Solution / Ātrās Prototipēšanas Ar Kausēšanas Metodi Strukturālā Uzlabojuma Analītisks Risinājums

    NASA Astrophysics Data System (ADS)

    Brensons, I.; Polukoshko, S.

    2013-10-01

    Fused deposition modelling (FDM) is one of the most effective rapid prototyping (RP) techniques due to its low cost, available materials and versatility. In FDM, a part of material (usually plastic) is made by heating this material to the molten state, and from the melt it is extruded through a nozzle and deposited on a surface. In the article, an alternative RP method is considered for improvement of the mechanical properties of a rapid prototype. The authors propose an analytical solution which allows for achievement of this purpose via advanced technologies. The base materials applied in RP technology can be combined with liquid resin which solidifies after a definite time. This makes it possible to create a channel through the prototype and fill it with another material having better mechanical properties. The optimal channel sizes can be chosen in order to raise the strength of material parts. Darbā tiek apskatīts ātrās prototipēšanas veids, kura pamatā ir detaļas veidošana, izmantojot kausētu materiālu parasti plastmasu. Šī detaļu veidošanas metode ir kļuvusi par vienu no visizplatītākajām tās zemo izmaksu, pieejamo materiālu un daudzpusības dēļ. Šī raksta mērķis ir izpētīt alternatīvu veidu, kā uzlabot prototipu mehāniskās īpašības, tādējādi palielinot printētu detaļu izmantošanu kā gala produktu. Raksts piedāvā analītisku risinājumu, kā uzlabot ātro prototipu mehāniskās īpašības, uzlabojot tehnoloģiskos procesus, kas iesaistīti detaļu izgatavošanā. Darba pamatā tiek izmantota 3D printēšanas tehnoloģijas iespēja veidot iekšējus kanālus bez ģeometriskiem ierobežojumiem, kā rezultātā ir iespējams izveidot iekšēju kanālu shēmu, ko pēc tam piepilda ar citu materiālu, kam ir labākas mehāniskās īpašības kā pamata materiālam. Pildīšanai izmantotais materiāls ir epoksīda sveķi, kas pieļauj vieglu iepildīšanu šķidrā fāzē, un sniedz labas mehāniskās īpašības p

  15. Estimating Volume of Roof Fall in the Face of Longwall Mining by Using Numerical Methods / Estymacja Objętości Zawału Stropu W Rejonie Przodka Ścianowego W Oparciu O Metody Numeryczne

    NASA Astrophysics Data System (ADS)

    Saeedi, Gholamreza; Shahriar, Korosh; Rezai, Bahram

    2013-09-01

    Dilution is one of many challenges confronting professionals in mining and milling, and is perhaps one of the oldest. Longwall mining is one of the mining methods that is often affected by out-of-seam dilution (OSD). In this method, roof falls play a significant role in increasing OSD in the prop-free front of the face area. Thus, estimating the volume of roof fall can be extremely helpful to assess dilution of the run of mine coal without a sampling process. This paper presents the effect of exposed area geometry on potential roof falls using the 2D numerical modelling program FLAC. In this respect, a half-prolate ellipsoid was considered as the low stress level or plasticity zone under yield tension which roof material fall. Since FLAC software does not show roof falls in prop-free front of the face, a series of two-dimensional numerical models are developed using UDEC software. The comparison of the results of two numerical models clearly indicates that volumes of roof fall obtained by means of these methods are in good agreement with each other. Ścienianie warstw jest jednym z najpoważniejszych wyzwań stojących przed inżynierami górnikami i specjalistami z zakresu obróbki - jest to też jeden z najstarszych problemów. Wybieranie ścianowe jest metodą urabiania, w której często mamy do czynienia ze ścienianiem warstwy złoża. W metodzie tej strop odgrywa kluczową rolę w zapewnieniu stabilności w tych rejonach przodka, gdzie nie zastosowano obudów. Dlatego też estymacja objętości zawału stropu może być pomocna przy obliczaniu ścieniania warstwy węgla bez konieczności próbkowania. W artykule tym przeanalizowano wpływ geometrii powierzchni odkrytych na potencjalny zawał stropu przy użyciu metod modelowania numerycznego z wykorzystaniem oprogramowania FLAC. Uzyskano wydłużoną elipsoidę jako model strefy niskich naprężeń lub strefę plastyczności przed zawałem stropu. Ponieważ oprogramowanie FLAC nie pokazuje zawałów stropu w

  16. Non-Steroid Anti-Infflamatory Drugs in Municipal Wastewater and Surface Waters/ Niesteroidowe Leki Przeciwzaplane W Ściekach Mieskich I Wodach Powierzchniowych

    NASA Astrophysics Data System (ADS)

    Płuciennik-Koropczuk, Ewelina

    2014-09-01

    Increased production and consumption of drugs influences the pollution pharmaceuticals. Recent years have seen a significant increase in the consumption of non-prescription medicines, among which, are a large group of non-steroidal anti-inflammatory drugs (NSAIDs). Research conducted in Poland and abroad showed the presence of NSAIDs, both in treated wastewater in surface waters and drinking waters. One of the most frequently detected drugs in the environment is diclofenac, belongs to NSAID. Its concentration in surface waters range from 9 to 3363 ng/L. Traditional wastewater treatment plants are not specialized enough in removing the pharmaceuticals and their metabolites, and with purified wastewater are introduced into surface waters. Diclofenac concentrations in treated wastewater range from 0.29 to 2.5 μg/L, the average removal efficiency is about 40%. Wzrost produkcji i spożycia leków wpływa na zanieczyszczenie środowiska farmaceutykami. W ostatnich latach zaobserwowano zdecydowany wzrost spożycia leków dostępnych bez recepty, wśród których znaczną grupę stanowią niesteroidowe leki przeciwzapalne (NLPZ). Badania prowadzone na świecie i w Polsce wykazały obecność niesteroidowych leków przeciwzapalnych zarówno w ściekach oczyszczonych, w wodach powierzchniowych oraz w wodach pitnych. Jednym z najczęściej wykrywanych leków w środowisku jest diklofenak należący NLPZ. Jego stężenia w wodach powierzchniowych wynoszą od 9 do 3633 ng/dm3. Tradycyjne układy technologiczne oczyszczania nie eliminują zupełnie farmaceutyków i ich metabolitów i wraz ze ściekami oczyszczonymi są one wprowadzane do wód powierzchniowych. Stężenia diklofenaku w ściekach oczyszczonych wynoszą od 0,29 do 2,5 μg/dm3, a średnia skuteczność usuwania jest na poziomie ok 40%. Należy zaznaczyć, że dane te nie odzwierciedlają stanu rzeczywistego, gdyż badania są prowadzone wyrywkowo. W 2013 r. Komisja Europejska w dyrektywie Parlamentu Europejskiego i

  17. Heat for wounds - water-filtered infrared-A (wIRA) for wound healing - a review.

    PubMed

    Hoffmann, Gerd; Hartel, Mark; Mercer, James B

    2016-01-01

    Hintergrund: Wassergefiltertes Infrarot A (wIRA) ist eine spezielle Form der Wärmestrahlung mit hohem Eindringvermögen in das Gewebe und geringer thermischer Belastung der Hautoberfläche. wIRA entspricht dem Großteil der die Erdoberfläche in gemäßigten Klimazonen durch Wasser und Wasserdampf der Atmosphäre gefiltert erreichenden Sonnenwärmestrahlung. wIRA fördert die Heilung akuter und chronischer Wunden sowohl über thermische und temperaturabhängige als auch über nicht-thermische und temperaturunabhängige zelluläre Effekte.Methoden: Diese Publikation schließt eine Literaturübersicht mit Suche in PubMed/Medline nach “water-filtered infrared-A” und “wound”/”ulcus” oder “wassergefiltertes Infrarot A” und “Wunde”/”Ulkus” (Publikationen in Englisch und Deutsch) und zusätzliche Analysen von Studiendaten ein. 7 prospektive klinische Studien (davon 6 randomisierte kontrollierte Studien (RCT), die größte Studie mit n=400 Patienten) wurden gefunden und eingeschlossen. Alle randomisierten kontrollierten klinischen Studien vergleichen eine Kombination aus Therapie auf hohem Niveau plus wIRA-Therapie vs. Therapie auf hohem Niveau allein. Die mit „vs.“ gekennzeichneten Ergebnisse unten zeigen diese Vergleiche. Ergebnisse: wIRA steigert die Temperatur (+2,7°C in 2 cm Gewebetiefe) und den Sauerstoffpartialdruck im Gewebe (+32% in 2 cm Gewebetiefe) und die Gewebedurchblutung (Größe der Effekte innerhalb der wIRA-Gruppe). wIRA fördert sowohl die normale als auch die gestörte Wundheilung, indem es Entzündung und Sekretion mindert, Infektionsabwehr und Regeneration fördert und Schmerzen lindert (bezüglich Schmerzlinderung ausnahmslos während 230 Bestrahlungen, 13.4 vs. 0,0 auf einer visuellen Analogskala (VAS 0–100), mediane Differenz zwischen den Gruppen 13.8, 95%-Konfidenzinterval (KI) 12.3/16.7, p<0,000001) mit relevant weniger Analgetikabedarf (52–69% weniger in den drei Gruppen mit wIRA verglichen mit den drei

  18. Analytical Design of Water-Free Production in Horizontal Wells Using Hodograph Method / Zastosowanie metody hodografu do określenia krytycznego wydatku poziomych otworów produkcyjnych

    NASA Astrophysics Data System (ADS)

    Qin, Wenting; Wojtanowicz, Andrew K.; White, Christopher D.

    2013-06-01

    żków wodnych prowadzących do zawodnienia otworu. Jednakże duża powierzchnia kontaktu ze złożem staje się wadą otworów poziomych gdy stożek wodny dostanie się do otworu. Następuje wtedy gwałtowne zawodnienie otworu i szybka utrata produktywności. Z tego powodu wydatek otworu musi być utrzymany poniżej wartości wydatku krytycznego, tzn. maksymalnego wydatku bez udziału stożka wodnego. Istniejące modele analityczne wydatku krytycznego są albo zbyt uproszczone lub też niedokładne w opisie lokalnej powierzchni kontaktu między ropą naftową i wodą podścielającą co prowadzi do błędnej oceny wydatku krytycznego. W tym artykule prezentujemy nowy model matematyczny wydatku krytycznego który jest bardziej dokładny przez co lepiej nadaje się do obliczeń projektowych. W przeciwieństwie do istniejących modeli, nasz model uwzględnia ograniczenie dopływu ropy do otworu spowodowane wzrostem stożka wodnego ponad statyczną powierzchnię kontaktu ropy z wodą podścielającą oraz pozwala dokładnie obliczyć wydatek krytyczny oraz opisać kształt powierzchni stożka i zmianę ciśnienia w złożu z odległością od otworu poziomego. Równania modelu zostały wyprowadzone z teorii hodografu połączonej z metodą odwzorowań konforemnych. Wyniki obliczeń przy użyciu równań modelu wykazują zgodność z wynikami symulatora złoża. Stwierdzono również, że typowe dla innych modeli założenie płaskiej powierzchni kontaktu ropa/woda i zaniedbanie efektu kształtu stożka wodnego może prowdzić do 50-procentowej przeceny wartości wydatku krytycznego

  19. Determination of Two-Liquid Mixture Composition by Assessing Dielectric Parameters 1. Precise Measuring System / Divu Šķidrumu Maisījuma Sastāva Noteikšana, Izvērtējot to Dielektriskos Parametrus 1. Precīza Mērīšanas Sistēma

    NASA Astrophysics Data System (ADS)

    Vilitis, O.; Shipkovs, P.; Merkulovs, D.

    2013-08-01

    Concentration measurements are important in bioethanol industries, in the R&D areas, for chemical, medical and microbiological analyses and processing as well as for diagnostics, manufacturing, etc. The overview shows development of the structural design of a system for measuring the concentration of solutions and mixtures consisting of two dielectric liquids. The basic principles of the system's design are given along with relevant equations. The concentration of dielectric liquids is measured using devices with capacitive sensors (1-300 pF). The operational frequency of the developed measuring system is 100.000 kHz. Configuration of the system excludes some errors usually arising at measurements, and broadens its applicability. For testing, the system was calibrated for measuring the concentration of anhydrous ethanol + de-ionized water mixture. Experimental results have shown a stable resolution of ±0.005 pF at measuring the sensor capacitance and a reproducible resolution better than ±0.01% at measuring the ethanol volume concentration Rakstā esam parādījuši iespējas izveidot augstas precizitātes, kompaktu, lētu un ērtu lietošanai dielektrisku šķidrumu mērīšanas sistēmu koncentrācijas noteikšanai. Šī sistēma ir piemērojama kapacitīviem sensoriem, kuru kapacitāte ir atkarīga no sensora izveidojuma kā arī mērāmā šķidruma dielektriskās konstantes vērtības, un kapacitāte var tikt noteikta pie frekvences 100,000 kHz robežās no 1 F līdz 300 pF. Mērīšanas sistēmas pārbaudei, sistēma tika kalibrēta etanola koncentrācijas mērīšanai tilpuma procentos sertificēta bezūdens etanola un dejonizēta ūdens maisījumiem. Pārbaužu rezultāti pierādīja, ka sensora kapacitātes vērtības ir stabili nosakāmas ar izšķirtspēju ne mazāku par ±0,005 pF. Sensora kapacitāšu vērtībām atbilstošā etanola tilpuma koncentrācijas atkārtojamu mērījumu izšķirtspēja visā mērīšanas diapazonā nebija mazāka par ±0

  20. The Modernization of the Energy Sector in Poland vs. Poland's Energy Security / Modernizacja sektora energii w polsce a bezpieczeństwo energetyczne Polski

    NASA Astrophysics Data System (ADS)

    Frączek, Paweł; Kaliski, Maciej; Siemek, Paweł

    2013-06-01

    The paper discusses the essence of Poland's energy security, decisive factors for its attainment and the structure of primary energy sources of the country. It describes the main problem areas in functioning of the energy sector in Poland, as well as the conditions for its modernization. The issues of increasing the natural gas share in the country's structure of primary energy sources and a construction of the first nuclear power plant in Poland have been particularly emphasised. The paper stresses that without modernizing actions it will be impossible for Poland to fulfil international obligations concerning changes in the functioning of the energy sector. The study, analysing the conditions for increasing the role of natural gas in Poland, points at the necessity to expand the gas infrastructure, to increase a scale of gas production from domestic deposits and to complete liberalization of the energy industry. It also emphasises that a potential delay in the construction of the country's first nuclear power plant may limit competitiveness of the economy. W artykule omówiono istotę bezpieczeństwa energetycznego Polski, czynniki decydujące o jego osiągnięciu oraz strukturę źródeł energii pierwotnej w kraju. Przedstawiono główne problemy funkcjonowania sektora energii w Polsce oraz uwarunkowania jego modernizacji. Szczególny nacisk położono na kwestie zwiększenia udziału gazu ziemnego w krajowej strukturze źródeł energii pierwotnej oraz budowy pierwszej elektrownii atomowej w Polsce. Podkreślono, że bez podjęcia działań modernizacyjnych niemożliwe będzie wypełnienie zobowiązań międzynarodowych Polski dotyczących zmian w sposobie funkcjonowania sektora energii. Analizując uwarunkowania zwiększenia znaczenia gazu ziemnego w Polsce, wskazano na konieczność rozbudowy infrastruktury gazowniczej, zwiększenia skali wydobycia gazu ziemnego z krajowych złóż oraz na kwestię dokończenia liberalizacji branży. Podkreślono, że dla zwi

  1. The Effect of Temperature Glide of R407C Refrigerant on the Power of Evaporator in Air Refrigerators / WPŁYW POŚLIZGU Temperatury Czynnika CHŁODNICZEGO R407C NA Moc Parownika CHŁODZIARKI Powietrza

    NASA Astrophysics Data System (ADS)

    Nowak, Bernard; Życzkowski, Piotr

    2013-12-01

    sprężarkowej chłodziarki powietrza. Mieszaniny zeotropowe podlegają przemianom fazowym, których przebieg znacznie różni się od czynników jednorodnych. W odróżnieniu od jednorodnych czynników chłodniczych, których procesy wrzenia i skraplania odbywają się przy stałej temperaturze, dla mieszanin zeotropowych do jednoznacznego określenia temperatury początku procesu parowania niezbędna jest znajomość stopnia suchości pary. Na przykładzie czynnika chłodniczego R407Copisano metodę wyznaczania temperatury początkowej procesu parowania uwzględniającą zjawisko poślizgu temperatury. Opracowana zależność (7) powstała w oparciu o udowodniony liniowy przebieg izobar w obszarze pary mokrej (rys. 5) i określeniu na tej podstawie wielomianu opisującego ich kąt nachylenia (8). Dodatkowo przedstawiono wzory obliczeniowe temperatury (9) oraz entalpii właściwej (10) pary nasyconej suchej czynnika chłodniczego R407C. Takie podejście do problemu pozwala na wyznaczenie temperatury czynnika chłodniczego R407C na wlocie do parownika bez wymaganej znajomości stopnia suchości pary czynnika. Dotychczas stosowane uproszczone metody wyznaczania temperatury czynnika chłodniczego na wlocie do parownika powodują znaczne odstępstwa obliczonej na ich podstawie mocy parownika od jego wartości rzeczywistej. Przedstawiony przykład obliczeniowy dotyczący górniczej sprężarkowej chłodziarki powietrza pośredniego działania typu TS-450P pokazuje, że odchyłki względne mocy cieplnej parownika mogą przekraczać nawet ponad 20%. W przykładzie obliczeniowym porównano dwie uproszczone metody określenia temperatury parowania zeotropowego czynnika chłodniczego stosowane w obliczeniach porównawczych czynników chłodniczych z metodą zaprezentowaną w niniejszym artykule.

  2. Development of Solar Powered Feeding Scheme for Wireless Sensor Networks in low Solar Density Conditions / Bezvadu Sensoru Tīklu Elektroapgādes Sistēmas Izstrāde, Kas Izmanto Saules Paneļus Un Darbojas Pazeminātas Saules Radiācijas Apstākļos

    NASA Astrophysics Data System (ADS)

    Kondratjevs, K.; Zabasta, A.; Selmanovs-Pless, V.

    2015-08-01

    kontekstā ar reģionālajiem apstākļiem un aprēķināt darba režīmus bezvadu tīkla komponentēm vai pieņemt lēmumus par to funkcionalitātes pielāgošanu. Izstrādātais vadības modulis sastāv no saules paneļa fotoelementu moduļa, uzglabāšanas risinājuma (litija vai līdzvērtīgas baterijas) un elektroapgādes pārvaldības moduļa. Pētījuma novitāte ir elektroapgādes pārvaldības modulis, kas nodrošina stabilu un nepārtrauktu elektronisko iekārto darbību dažādos barošanas režīmos, dažādās situācijās, vienlaikus nodrošinot enerģijas saglabāšanu un moduļa sastāvdaļu ilgtspēju. Izstrādātais risinājums nodrošina nepārtrauktu 5V barošanu elektronikas shēmām bez strāvas pārtraukuma, kad notiek komutācija starp barošanas avotiem un enerģijas plūsmām dažādos virzienos. Elektroapgādes pārvaldības modulis nodrošina stabilu spriegumu mainīgos saules radiācijas apstākļos.

  3. Development and Experimental Study of Phantoms for Mapping Skin Chromophores

    NASA Astrophysics Data System (ADS)

    Silapetere, A.; Spigulis, J.; Saknite, I.

    2014-06-01

    šanu veicinošu serumu (FBS). Šūnu kultivēšanai nepieciešamas vismaz divas nedēļas. Šajā slāņainajā struktūrā ir iespējams pievienot ādas hromoforu simulējošus iekļāvumus. Optiskajā diapazonā no 450-900 nm ādas hromoforas, kurām ir visizteiktākais spektrs, ir bilirubīns, melanīns un hemoglobīns. Lai simulētu ādas hromoforu spektrālās īpašības, tika izmantots sintezēts bilirubīns, eritrocītu masa un nigrozīns. Lai izpētītu šī maketa iekārtu kalibrēšanas potenciālu, tika izveidoti 76 paraugi, kur katros 24 paraugos bija pievienots viens no absorbentiem ar dažādām koncentrācijām. Pilna ādas maketa audzēšanai nepieciešamas divas nedēļas, lai ātrāk tiktu iegūti pirmie rezultāti tika veidoti maketi bez dermālo un epidermālo šūnu piejaukuma. Fibrīna matricas un ādas imitējošā maketa absorbcijas spējas ir mazas salīdzinājumā ar hromoforu absorbcijas spējām. Lai novērtētu maketu, kas paredzēti konkrētu hromoforu spektrālo īpašību imitēšanai, iespējams veikt eksperimentus ar fibrīna matricu, kuras izveidošanai ir nepieciešama viena diena. Sintezētā bilirubīna koncentrācijas tika mainītas robežās no 0,01-2,00 mg/ml, melanīna optisko īpašību simulējošās vielas nigrozīna koncentrācija tika mainīta no 1,5 - 312,8 μg/ml, eritrocītu masas koncentrācija mainījās no 0,2 - 42,4 mg/ml.Mērījumi tika veikti, izmantojot multispektrālās attēlošanas iekārtu Cri Nuance 2.4. (Cambridge Research & Instrumentation, Inc., Amerikas Savienotās Valstis). Absorbcijas spektrs tika apstrādāts, izmantojot Microsoft Office Excel 2007. Iegūtajos rezultātos ir iespējams redzēt, ka piedāvātais ādas makets spēj simulēt ādas optiskās īpašības. Izmantotie absorbenti - sintezētais bilirubīns, nigrozīns un eritrocītu masa - spēj simulēt ādas hromoforu spektrālās īpašības. Palielinot absorbentu koncentrāciju paraugā, palielinās absorbcijas spektra maksimālā intensit

  4. Wirkungen biogener Amine auf die Erregungs-Sekretions-Kopplung in der Speicheldrüse von Periplaneta americana (L.)

    NASA Astrophysics Data System (ADS)

    Rietdorf, Katja

    2003-07-01

    habe gefunden, dass die Aktivität der Na+-K+-ATPase wichtig für die Modifikation des DA-stimulierten Primärspeichels ist. Im Gegensatz dazu ist sie für die Modifikation des 5-HT-stimulierten Primärspeichels nicht von Bedeutung. Bezüglich der Flüssigkeitssekretion habe ich keinen Einfluss der Na+-K+-ATPase-Aktivität auf die DA-stimulierten Sekretionsraten gefunden, dagegen ist die 5-HT-stimulierte Sekretionsrate in Anwesenheit von Ouabain gesteigert. Die Aktivität des NKCC ist für beide sekretorische Prozesse, die Ionen- und die Flüssigkeitssekretion, wichtig. Eine Hemmung des NKCC bewirkt eine signifikante Verringerung der Raten der Flüssigkeitssekretion nach DA- und 5-HT-Stimulierung sowie in beiden Fällen einen signifikanten Abfall der Ionenkonzentrationen im Endspeichel. Im zweiten Teil meiner Arbeit habe ich versucht, Änderungen der intrazellulären Ionenkonzentrationen in den Acinuszellen während einer DA- oder 5-HT-Stimulierung zu messen. Diese Experimente sollten mit der Methode des "ratiometric imaging" durchgeführt werden. Messungen mit dem Ca2+-sensitiven Fluoreszenzfarbstoff Fura-2 zeigten keinen globalen Anstieg in der intrazellulären Ca2+-Konzentration der P-Zellen. Aufgrund von Problemen mit einer schlechten Beladung der Zellen, einer starken und sich während der Stimulierung ändernden Autofluoreszenz der Zellen sowie Änderungen im Zellvolumen wurden keine Messungen mit Na+- und K+-sensitiven Fluoreszenzfarbstoffen durchgeführt. Im dritten Teil dieser Arbeit habe ich die intrazellulären Signalwege untersucht, die zwischen einer 5-HT-Stimulierung der Drüse und der Proteinsekretion vermitteln. Dazu wurde der Proteingehalt im Endspeichel biochemisch mittels eines modifizierten Bradford Assay gemessen. Eine erstellte Dosis-Wirkungskurve zeigt, dass die Rate der Proteinsekretion von der zur Stimulierung verwendeten 5-HT-Konzentration abhängt. In einer Serie von Experimenten habe ich die intrazellulären Konzentrationen von Ca2+, c

  5. Estimation of the genetic correlations between twisted legs and growth or conformation traits in broiler chickens.

    PubMed

    Bihan-Duval, E L; Beaumont, C; Colleau, J J

    1997-01-12

    inciter à surveiller l'impact sur l'incidence des varus des fortes pressions de sélection appliquées actuellement sur les caractères de conformation. ZUSAMMENFASSUNG: Genetische Korrelationen zwischen verbogenen Füßen und Wachstums- und Formmerkmalen in Broilern Genetische Korrelationen zwischen 2 Arten von Beindeformationen, Valgus und Varus Angulationen, und einigen Wachtums- und Formmerkmalen wurden bei zwei kommerziellen Broiler Herkünften geschätzt, 14 264 Hühner beiderlei Geschlechter wurden in Linie A auf Beinfehler bei 6 Wochen Alter und Körpergewicht bei 3 (BW3) und 6 Wochen (BW6) untersucht, in Linie B 8 164 Tiere, wo aber auch Brustwinkel (BRA) und Brustfleisch (BRM) von ca. 70% der Hähne erhoben worden ist. Das für die genetische Analyse von Valgus und Varus Deformationen entwickelte multinomiale logit Modell wurde für die gemeinsame Analyse eines ungeordneten kategorischen Merkmals und einer kontinuierlichen Variablen erweitert. Dieses unterstellt Kompetition zwischen latenter Anfälligkeiten für verschiedene Deformationen und lineare Beziehung zu kontinuierlich verteilter Leistung. Lokationsparameter wurden mittels "Maximum A Posteriori" Ansatz und Dispersionsparameter mittels "Maximum Marginaler Likelihood" unter Verwendung von 'tilde-hat' Approximation geschätzt. Das genetische Modell berücksichtigte Vater-, maternale Großvater- und Muttertier-innerhalb der letzteren-Wirkungen. Beindeformationen zeigen mittlere Heritabilitätswerte, 0.22 für Valgus and Varus aus Vater/maternalem Großvater Komponenten, 0.37 bez. 0.29 aus der Muttertierkomponente. Mit Ausnahme von BRA waren Heritabilitätswerte für Wachstum- und Formmerkmale aus S/MGS-Komponenten (0.18-0.47) kleiner als die aus Muttertierkomponenten (0.41-0.63). Genetische Korrelationen zwischen letzeren und Anfällikeiten waren sehr niedrig: zwischen BW3 und Valgus und Varus -0.03 bzw. -0.05, BW6 +0.05 und 0.01. Simulation zeigte, daß die niedrigen Werte kaum auf negative R

  6. The Application of Coreless Inductors for Displacement Measurements in Laboratory Investigations of Rock Properties

    NASA Astrophysics Data System (ADS)

    Nurkowski, Janusz

    2014-12-01

    ści termicznej (rys. 7). Zmiany częstotliwości z czujnika referencyjnego są poprawkami do wskazań czujnika pomiarowego. Oba czujniki są naprzemiennie podłączane do tego samego generatora poprzez elektroniczny przełącznik (rys. 5). Zastosowanie jednego generatora powoduje, że poprawki te umożliwiają również praktycznie całkowitą eliminację błędu pomiaru ze względu na zmiany temperatury otoczenia i napięcia zasilania na generator i częstościomierz. Charakterystyka przetwornika długość-częstotliwość jest nieliniowa (rys. 3), co wynika z zależności między długością cewki czujnika, więc jej indukcyjnością, a częstotliwością rezonansową obwodu LC (1). Najdokładniej charakterystykę czujnika otrzymać można przez wzorcowanie. Uwzględnione są wtedy głównie pasożytnicze indukcyjności i pojemności połączeń, których wartości trudno obliczyć lub zmierzyć. W pomiarach należy dążyć, na ile to możliwe, do montowania krótkiego czujnika do długich próbek, w ten sposób zmiany długości badanego materiału będą większe, a krótszy czujnik dozna większego odkształcenia, więc czułość pomiaru będzie duża. Jednak zbyt krótki czujnik ma małą indukcyjność i wtedy jego czułość ograniczy indukcyjność połączeń (2). Opracowano dwa podstawowe typy takiego czujnika. Pierwszy, do pomiaru odkształceń liniowych, np. do pomiaru ściśliwości (rys. 2 i 6), o prostej cewce, który jest mocowany do próbki za pośrednictwem zaczepów przytwierdzonych do niej. W ten sposób czujnik nie kontaktuje się bezpośrednio z powierzchnią próbki, i odkształca się bez tarcia, co umożliwia precyzyjny pomiar, szczególnie przy obciążaniu cyklicznym. Bazę pomiarową można dostosowywać do długości próbki, mocując czujnik do zaczepów poprzez łączniki, uzyskując globalny pomiar odkształceń. Czujnik mierzy zmiany długości z rozdzielczością poniżej 1 μm, przy maksymalnych odkształceniach czujnika o kilkadziesi