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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. 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.

  8. 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

  9. 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.

  10. 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

  11. 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

  12. [NVP-BEZ235 inhibits proliferation and colony-forming capability of CD34(+)CD38(-) human acute myeloid leukemia stem cells].

    PubMed

    Gao, Ying-Ying; Hu, Liang-Shan; Han, Hui-Juan; Song, Chao-Yang; Huang, Yu-Xian; Guo, Kun-Yuan

    2013-04-01

    This study was aimed to explore the effect of NVP-BEZ235, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, on proliferation, cell cycle and colony forming capability of CD34(+)CD38(-) human acute myeloid leukemia (AML) KG1a cells. Flow cytometry was used to detect expression of CD34 and CD38 on the surface of human AML KG1a cells; Trypan blue assay was used to analyze the effect of NVP-BEZ235 at various concentrations on proliferation of KG1a cells; flow cytometry was performed to examine the cell cycle of KG1a cells after NVP-BEZ235 treatment; Soft agar colony-forming experiment was used to detect the colony forming ability of KG1a cells treated with NVP-BEZ235 at various concentrations. The results indicated that the percentage of CD34(+)CD38(-) AML KG1a cells was (98.02 ± 0.72)%. NVP-BEZ235 (0.125 - 1 µmol/L) inhibited the proliferation of KG1a cells in a time-and dose-dependent manner (P < 0.05) and the 50% inhibition concentrations (IC50) at 24 h and 48 h were 0.597 µmol/L and 0.102 µmol/L, respectively. KG1a cells were arrested at G0/G1 phase after treating with 0.5 µmol/L NVP-BEZ235 for 24 h, it was significantly higher than that of control group (83.2 ± 3.80)% vs (43.47 ± 9.60)% (P < 0.05). KG1a cells treated with NVP-BEZ235 (0 - 1 µmol/L) for 14 d and 21 d, the number of colony decreased respectively from (375.67 ± 21.46) per 2500 KG1a cells and (706.33 ± 87.31) per 2500 KG1a cells to 0, with statistical significance (P < 0.05). It is concluded that NVP-BEZ235 can inhibit proliferation and colony-forming capability of CD34(+)CD38(-) human AML KG1a cells.

  13. 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

  14. The PI3-Kinase/mTOR-Targeting Drug NVP-BEZ235 Inhibits Growth and IgE-Dependent Activation of Human Mast Cells and Basophils

    PubMed Central

    Blatt, Katharina; Herrmann, Harald; Mirkina, Irina; Hadzijusufovic, Emir; Peter, Barbara; Strommer, Sabine; Hoermann, Gregor; Mayerhofer, Matthias; Hoetzenecker, Konrad; Klepetko, Walter; Ghanim, Viviane; Marth, Katharina; Füreder, Thorsten; Wacheck, Volker; Valenta, Rudolf; Valent, Peter

    2012-01-01

    The phosphoinositide 3-kinase (PI3-kinase) and the mammalian target of rapamycin (mTOR) are two major signaling molecules involved in growth and activation of mast cells (MC) and basophils (BA). We examined the effects of the dual PI3-kinase/mTOR blocker NVP-BEZ235 on growth of normal and neoplastic BA and MC as well as immunoglobulin E (IgE)-dependent cell activation. Growth of MC and BA were determined by measuring 3H-thymidine uptake and apoptosis. Cell activation was determined in histamine release experiments and by measuring upregulation of CD63 and CD203c after challenging with IgE plus anti-IgE or allergen. We found that NVP-BEZ235 exerts profound inhibitory effects on growth of primary and cloned neoplastic MC. In the MC leukemia cell line HMC-1, NVP-BEZ235 showed similar IC50 values in the HMC-1.1 subclone lacking KIT D816V (0.025 µM) and the HMC-1.2 subclone expressing KIT D816V (0.005 µM). Moreover, NVP-BEZ235 was found to exert strong growth-inhibitory effects on neoplastic MC in a xenotransplant-mouse model employing NMR1-Foxn1nu mice. NVP-BEZ235 also exerted inhibitory effects on cytokine-dependent differentiation of normal BA and MC, but did not induce growth inhibition or apoptosis in mature MC or normal bone marrow cells. Finally, NVP-BEZ235 was found to inhibit IgE-dependent histamine release in BA and MC (IC50 0.5–1 µM) as well as anti-IgE-induced upregulation of CD203c in BA and IgE-dependent upregulation of CD63 in MC. In summary, NVP-BEZ235 produces growth-inhibitory effects in immature neoplastic MC and inhibits IgE-dependent activation of mature BA and MC. Whether these potentially beneficial drug effects have clinical implications is currently under investigation. PMID:22299028

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. 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

  13. 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.

  14. 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

  15. 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…

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 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

  6. Cultural Resource Investigations for the Lyons Ferry Fish Hatchery Project, Near Lyons Ferry, Washington.

    DTIC Science & Technology

    1983-01-01

    Region of North Amerioa. Ph.D. dissertation, University of Arizona , Tuscon. Weatherford, Claudine 1971 Tr(de BeZ7s o the Southern Plateau: Their Use ...even post on rock sill techniques. Most likely, posts on block construction was used for the above ground struc- tures. In Mr. Fife’s photo (Figure 13...bone with a few fire-cracked rocks and flakes. This feature occurred in levels 6-8 in the northwest corner of the pit and probably represents a bone

  7. 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

  8. 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.

  9. 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.

  10. 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

  11. Update: Therapie der Necrobiosis lipoidica.

    PubMed

    Peckruhn, Melanie; Tittelbach, Jörg; Elsner, Peter

    2017-02-01

    Die Necrobiosis lipoidica ist eine seltene granulomatöse Erkrankung von bisher unzureichend geklärter Ätiologie. Häufig stellt die bei Diabetikern gehäuft zu beobachtende und zur Ulzeration neigende Dermatose eine starke Belastung für die Patienten dar. Bezüglich der Therapie existieren aktuell keine deutschen oder europäischen Leitlinien. Gleichzeitig lässt sich unter der aktuellen Standardtherapie, der lokalen oder intraläsionalen Anwendung von Glukokortikoiden, nicht immer ein zufriedenstellendes Ansprechen beobachten. Daher wurde untersucht, ob seit dem Jahr 2000 publizierte Therapiemodalitäten das Therapiespektrum relevant und erfolgversprechend erweitern. Es erfolgte eine Betrachtung aller Arbeiten im oben genannten Zeitraum, bei denen mehr als ein Einzelfallbericht je Therapiemodalität publiziert wurde. Insgesamt wurden in einem systematischen Review die Daten von 16 verschiedenen, seit 2000 publizierten Therapieverfahren in 49 Publikationen analysiert. Im Ergebnis zeigte sich, dass die meisten Erfahrungen bezüglich der topischen PUVA-Therapie, der photodynamischen Therapie (PDT) und der systemischen Therapie mit Fumarsäureestern vorliegen. Allerdings ist auffällig, dass mit steigender Zahl der pro Behandlungsmodalität behandelten Patienten der Anteil der Patienten, bei denen eine Abheilung bzw. eine teilweise Abheilung berichtet wurde, sinkt. Wir interpretieren diese Beobachtung als Publikationsbias. Daher kann für keines der besprochenen Verfahren eine klare Empfehlung als Therapie der zweiten Wahl nach Versagen der lokalen bzw. intraläsionalen Steroidtherapie gegeben werden.

  12. 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.

  13. 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.

  14. [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.

  15. 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.

  16. 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

  17. 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.

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 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

  6. 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.

  7. [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.

  8. Desire and reality--teaching and assessing communicative competencies in undergraduate medical education in German-speaking Europe--a survey.

    PubMed

    Härtl, Anja; Bachmann, Cadja; Blum, Katharina; Höfer, Stefan; Peters, Tim; Preusche, Ingrid; Raski, Bianca; Rüttermann, Stefan; Wagner-Menghin, Michaela; Wünsch, Alexander; Kiessling, Claudia

    2015-01-01

    Zielsetzung: An deutschsprachigen medizinischen Fakultäten (n=43, Deutschland, Österreich, Schweiz; (D-A-CH)) sind kommunikative Kompetenzen zunehmend fest in Lehre und Prüfungen verankert. Zur Unterstützung der weiteren curricularen Entwicklung bezüglich kommunikativer Kompetenzen arbeitet die Umfrage des GMA Ausschusses „Kommunikative und soziale Kompetenzen“ (KusK) systematisch auf, in welchem Umfang und in welcher Form unterrichtet und geprüft wird.Methodik: Der iterativ in Zusammenarbeit mit „KusK“ entwickelte Onlinefragebogen umfasst 70 Fragen zu Unterricht (n=14), Prüfungen (n=48), lokalen Bedingungen (n=5) und drei Felder für sonstige Anmerkungen. Pro Standort wurden zwei bis drei Personen, die mit dem Curriculum vor Ort vertraut sind, zur Teilnahme an der Umfrage eingeladen.Ergebnisse: Es beteiligten sich 39 medizinische Fakultäten (40 Studiengänge) an der Umfrage. In allen Studiengängen werden kommunikative Kompetenzen unterrichtet. Zehn Studiengänge haben ein longitudinales Curriculum für kommunikative Kompetenzen, in 25 Studiengängen existiert dies teilweise. 16 der 40 Studiengänge orientieren sich am Baseler Consensus Statement. In über 80 % der Studiengänge werden kommunikative Kompetenzen im zweiten und dritten Studienjahr unterrichtet. Fast alle arbeiten mit Simulationspatienten (n=38) und Feedback (n=37). Geprüft wird nur summativ (n=11), nur formativ (n=3) und sowohl summativ als auch formativ (n=16). Am häufigsten wird im vierten bzw. fünften Studienjahr geprüft (n=22 bzw. n=20). Neben schriftlichen Tests (n=15) und Referaten (n=9) sind vor allem praktische Prüfungen implementiert (OSCE (n=31); WPA (n=8)), meist mit selbst entwickelten Beurteilungsskalen (OSCE: n=19). Bezüglich der Schulungen der Prüfer sowie der Art und Weise der Ergebnisrückmeldung an Studierende besteht eine hohe Varianz.Schlussfolgerung: Der Unterricht von kommunikativen Kompetenzen wurde an allen beteiligten 39 medizinischen Fakult

  9. 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

  10. 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.

  11. 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

  12. Risk of psychiatric and neurological diseases in patients with workplace mobbing experience in Germany: a retrospective database analysis.

    PubMed

    Kostev, Karel; Rex, Juliana; Waehlert, Lilia; Hog, Daniela; Heilmaier, Christina

    2014-01-01

    Einleitung: Mobbing am Arbeitsplatz hat in den letzten Jahren deutlich zugenommen und ist heutzutage ein weltweites Phänomen in der arbeitenden Bevölkerung. Da es bedeutende sozioökonomische Konsequenzen hat, ist es wichtig, Vorläufer zu kennen, um präventiv tätig werden zu können.Material & Methoden: Mithilfe einer umfangreichen Datenbank (IMS(®) Disease Analyzer, IMS Health, Deutschland) haben wir die Daten von Allgemeinmedizinern in Deutschland zwischen Januar 2003 und Dezember 2012 analysiert. Es wurden alle Patienten in die Studie eingeschlossen, die zum ersten Mal mit Mobbing am Arbeitsplatz konfrontiert waren, wobei dieser Zeitpunkt als „Index-Datum“ gesetzt wurde. Zunächst wurden sämtliche Krankheiten notiert, die innerhalb eines Jahres vor dem „Index-Datum“ erstmals aufgetreten sind und mit einer Kontrollgruppe verglichen, die der Untersuchungsgruppe bezüglich Geschlecht, Alter und Versicherungsstatus entsprachen. Danach wurden die Prävalenz von Depressionen, Angst-, somatoformen und Schlafstörungen nach stattgefundenem Mobbing berechnet. Anschließend wurden nach Adjustierung bezüglich Mobbings die Odds Ratio dieser Erkrankungen in einem logistischen Regressionsmodel bestimmt.Ergebnisse: Die Studiengruppe bestand aus n=2.625 Patienten und derselben Anzahl an Kontrollen, von denen zwei Drittel männlich waren. Die Zahl der dokumentierten Mobbing-Fälle stieg kontinuierlich von 2003 bis 2011 an und blieb auch 2012 auf hohem Niveau. Patienten, die in der Folge Opfer von arbeitsplatzbezogenem Mobbing wurden, hatten generell eine bedeutend höhere Krankheitsprävalenz, wobei diese nicht auf den neurologisch-psychiatrischen Formenkreis beschränkt waren. Nach dem Auftreten von Mobbing war in der Studiengruppe verglichen mit der Kontrollgruppe eine signifikant höhere Prävalenz von Depressionen, Angst-, somatoformen und Schlafstörungen nachzuweisen (für alle Erkrankungen: p<0,05). Ähnliches war im Hinblick auf die Odds Ratio zu sehen

  13. 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.

  14. 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

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. Zum Stellenwert der Unterdruck-Instillationstherapie in der Dermatologie.

    PubMed

    Müller, Cornelia Sigrid Lissi; Burgard, Barbara; Zimmerman, Monika; Vogt, Thomas; Pföhler, Claudia

    2016-08-01

    Die Methoden zur Behandlung akuter und chronischer Wunden unterliegen einer steten Weiterentwicklung, Reevaluierung und Anwendung innovativer Therapieformen. Die Vakuumtherapie zur Wundbehandlung gehört zu den etablierten Behandlungsmodalitäten. Ein innovatives Verfahren kombiniert die Vakuumtherapie mit der automatisierten, kontrollierten Zufuhr und Drainage wirkstoffhaltiger Lösungen zur topischen Wundbehandlung im Wundbett und auch wirkstofffrei durch Instillation physiologischer Kochsalzlösung (Unterdruck-Instillationstherapie). Hierdurch können die Effekte der konventionellen Vakuumtherapie mit denen der lokalen Antisepsis kombiniert werden. Hierdurch kommt es zu einer Reduktion der Wundfläche, einer Induktion von Granulationsgewebe sowie einer Reduktion der Keimbesiedelung der Wunden. Bisher publizierte Studien konzentrieren sich auf die Anwendung dieses Therapieverfahrens zur Behandlung orthopädisch-chirurgischer Krankheiten. Die Datenlage bezüglich der Vakuum-Instillationstherapie in der Dermatochirurgie beschränkt sich derzeit auf Fallberichte und Einzelfallerfahrungen. Randomisierte, prospektive Studien zum Vergleich der Vakuum-Instillationstherapie zur Behandlung dermatologischer Krankheitsbilder existieren bislang nicht. Ziele des vorliegenden Artikels sind die Vorstellung der Vakuumtherapie mit Instillation einschließlich ihres Wirkprinzips, deren mögliche Komplikationen, die Diskussion erdenklicher Kontraindikationen sowie eine Übersicht über die aktuell verfügbare Datenlage. Zusammenfassend scheint sich die Evidenz zu verdichten, dass mittels Unterdruck-Instillationstherapie sowohl einfache als auch komplizierte Wunden effizient behandelt werden können, was sich in einer deutlichen Beschleunigung der Wundgranulation mit konsekutiv früher möglichem Defektverschluss äußert.

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. [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.

  1. 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.

  2. [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. ...

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. Evaluation of clinical trials by Ethics Committees in Germany--results and a comparison of two surveys performed among members of the German Association of Research-Based Pharmaceutical Companies (vfa).

    PubMed

    Russ, Hagen; Busta, Susanne; Jost, Bertfried; Bethke, Thomas D

    2015-01-01

    hnlich ist. Die häufigsten Einwände betreffen die Patienteninformation und Einwilligungserklärung, in absteigender Reihenfolge gefolgt von Einwänden bezüglich Prüfplaninhalten, nicht-kategorisierende Einwände („Andere“), Einwände zu „Sonstigen Antragsunterlagen“ nach § 7 (2) und (3) GCP-V, Formmängel nach § 8 (1) GCP-V sowie Einwände, die sich auf Unterlagen zur Prüfer- und Prüfstellenqualifikation beziehen. Tendenziell zu beobachten war eine leicht erhöhte Rate von Einwänden bezüglich der Patienteninformation und Einwilligungserklärung (+4%) sowie eine geringfügige Abnahme von Einwänden, die sich auf Unterlagen zur Prüfer- und Prüfstellenqualifikation bezogen (–2%).Wie in 2007 ist etwa jeder sechste Antrag unvollständig und weist formale Einwände zu den Antragsunterlagen auf. Während der Anteil der Studienanträge mit Einwänden bezüglich der Patienteninformation und Einwilligungserklärung (+7,2%), den Prüfplaninhalten (+11,6%) und „Sonstigen Antragsunterlagen“ nach § 7 (2) und (3) GCP-V (+11,8%) in 2011 im Vergleich zu 2007 zunahm, nahm der Anteil der Studienanträge mit Einwänden, die Unterlagen zur Prüfer- und Prüfstellenqualifikation betrafen, um 6,3% ab.Schlussfolgerungen: Die Ergebnisse der ersten Umfrage in 2008 im Hinblick auf die Quantität, die Qualität und die Schwerpunkte der Einwände seitens der EKs, finden sich überwiegend auch in der Umfrage 2012. Dies zeigt ein übereinstimmendes Verständnis von Auftraggebern (Sponsoren) und EKs hinsichtlich der anzuwendenden Maßnahmen und Kriterien zur Sicherstellung der Rechte und des Wohlergehens der Patienten, der Datenintegrität und einer qualitativ hochwertigen Dokumentation in klinischen Prüfungen.

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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 ”

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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

  19. 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

  20. 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 %.

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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.

  8. 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

  9. Monitoring the impact of the DRG payment system on nursing service context factors in Swiss acute care hospitals: Study protocol.

    PubMed

    Spirig, Rebecca; Spichiger, Elisabeth; Martin, Jacqueline S; Frei, Irena Anna; Müller, Marianne; Kleinknecht, Michael

    2014-01-01

    2011 konnte die quantitative Datensammlung durchgeführt werden. Daran anschliessend wurden im Sommer 2012 die qualitativen Daten mittels Fokusgruppeninterviews gesammelt, die dabei halfen, die den quantativen Daten zugrunde liegenden Prozesse besser zu verstehen. Dazu wird 2013 und 2014 der Integrationsprozess durchgeführt, mit dem die quantitativen und qualitativen Daten ergänzend, vergleichend und kontrastierend betrachtet werden.Schlussfolgerung: Die Studie hat bezüglich den interessierenden Pflegekontextfaktoren eine Datenbasis geschaffen, die die Ausgangslage vor der Einführung der DRG-basierten Finanzierung in Schweizer Akutspitälern wiederspiegelt. Zudem konnte ein theoretisches Monitoringmodell mitsamt seiner Methodologie erarbeitet werden, dessen Daten inskünftig Spitaldirektionen und Pflegeleitungen dabei unterstützen kann, Ressourcen effektiv zu verteilt.Die Studie wurde von den Ethikkommissionen der Kantone Basel, Bern, Solothurn und Zürich geprüft.

  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. 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

  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. 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

  14. 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.

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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