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.

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

PubMed

Bhatia, Dimple R; Thiagarajan, Padma

2016-01-01

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

Effects of endoplasmic reticulum stress on the autophagy, apoptosis, and chemotherapy resistance of human breast cancer cells by regulating the PI3K/AKT/mTOR signaling pathway.

PubMed

Zhong, Jia-Teng; Yu, Jian; Wang, Hai-Jun; Shi, Yu; Zhao, Tie-Suo; He, Bao-Xia; Qiao, Bin; Feng, Zhi-Wei

2017-05-01

Nowadays, although chemotherapy is an established therapy for breast cancer, the molecular mechanisms of chemotherapy resistance in breast cancer remain poorly understood. This study aims to explore the effects of endoplasmic reticulum stress on autophagy, apoptosis, and chemotherapy resistance in human breast cancer cells by regulating PI3K/AKT/mTOR signaling pathway. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to detect the cell viability of six human breast cancer cell lines (MCF-7, ZR-75-30, T47D, MDA-MB-435s, MDA-MB-453, and MDA-MB-231) treated with tunicamycin (5 µM), after which MCF-7 cells were selected for further experiment. Then, MCF-7 cells were divided into the control (without any treatment), tunicamycin (8 µ), BEZ235 (5 µ), and tunicamycin + BEZ235 groups. Cell viability of each group was testified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Western blotting was applied to determine the expressions of endoplasmic reticulum stress and PI3K/AKT/mTOR pathway-related proteins and autophagy- and apoptosis-related proteins. Monodansylcadaverine and Annexin V-fluorescein isothiocyanate/propidium iodide staining were used for determination of cell autophagy and apoptosis. Furthermore, MCF-7 cells were divided into the control (without any treatment), tunicamycin (5 µM), cisplatin (16 µM), cisplatin (16 µM) + BEZ235 (5 µM), tunicamycin (5 µM) + cisplatin (16 µM), and tunicamycin (5 µM) + cisplatin (16 µM) + BEZ235 groups. Cell viability and apoptosis were also evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Annexin V-fluorescein isothiocyanate/propidium iodide staining. In MCF-7 cells treated with tunicamycin, cell viability decreased significantly, but PEAK, eIF2, and CHOP were upregulated markedly and p-PI3K, p-AKT, and p-MTOR were downregulated in dose- and time-dependent manners. In the tunicamycin + BEZ

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

PubMed

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

2013-05-01

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

High frequency of loss of PTEN expression in human solid salivary adenoid cystic carcinoma and its implication for targeted therapy.

PubMed

Liu, Han; Du, Li; Wang, Ru; Wei, Chao; Liu, Bo; Zhu, Lei; Liu, Pixu; Liu, Qiang; Li, Jiang; Lu, Shi-Long; Xiao, Jing

2015-05-10

Salivary gland tumor (SGT) is one of the least studied cancers due to its rarity and heterogeneous histological types. Here, we reported that loss of PTEN expression was most frequently found in the poorly differentiated, high grade solid adenoid cystic carcinomas. Loss of PTEN expression correlated with activation of mTOR by increased phosphorylated S6 ribosome protein. We further functionally studied the role of PTEN in a pair of human SACC cell lines, SACC-83 and SACC-LM. Reduced PTEN level was correlated with the metastasis potential. When we knocked down PTEN in the SACC-83 cell line, we observed increased proliferation and enhanced migration/invasion in vitro, and increased tumor size in vivo. We further tested the therapeutical effect by applying a PI3K/mTOR inhibitor NVP-BEZ235 to both SACC cell lines. Decreased cell proliferation, increased apoptosis, as well as reduced cell migration/invasion were observed in both cell lines upon the NVP-BEZ235 treatment. Moreover, the NVP-BEZ235 treatment in a SGT xenograft mouse model significantly reduced primary tumor size and lung metastasis. Taken together, our results demonstrated that PTEN is a potent tumor suppressor in human SGTs, and targeting PI3K/mTOR pathway may be effective in the targeted therapy for human SGT patients with loss of PTEN expression.

Targeting BCR-ABL-Independent TKI Resistance in Chronic Myeloid Leukemia by mTOR and Autophagy Inhibition.

PubMed

Mitchell, Rebecca; Hopcroft, Lisa E M; Baquero, Pablo; Allan, Elaine K; Hewit, Kay; James, Daniel; Hamilton, Graham; Mukhopadhyay, Arunima; O'Prey, Jim; Hair, Alan; Melo, Junia V; Chan, Edmond; Ryan, Kevin M; Maguer-Satta, Véronique; Druker, Brian J; Clark, Richard E; Mitra, Subir; Herzyk, Pawel; Nicolini, Franck E; Salomoni, Paolo; Shanks, Emma; Calabretta, Bruno; Holyoake, Tessa L; Helgason, G Vignir

2018-05-01

Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment. By modeling ponatinib resistance and testing samples from these CML patients, it is hoped that an alternative drug target can be identified and inhibited with a novel compound. Two CML cell lines with acquired BCR-ABL-independent resistance were generated following culture in ponatinib. RNA sequencing and gene ontology (GO) enrichment were used to detect aberrant transcriptional response in ponatinib-resistant cells. A validated oncogene drug library was used to identify US Food and Drug Administration-approved drugs with activity against TKI-resistant cells. Validation was performed using bone marrow (BM)-derived cells from TKI-resistant patients (n = 4) and a human xenograft mouse model (n = 4-6 mice per group). All statistical tests were two-sided. We show that ponatinib-resistant CML cells can acquire BCR-ABL-independent resistance mediated through alternative activation of mTOR. Following transcriptomic analysis and drug screening, we highlight mTOR inhibition as an alternative therapeutic approach in TKI-resistant CML cells. Additionally, we show that catalytic mTOR inhibitors induce autophagy and demonstrate that genetic or pharmacological inhibition of autophagy sensitizes ponatinib-resistant CML cells to death induced by mTOR inhibition in vitro (% number of colonies of control[SD], NVP-BEZ235 vs NVP-BEZ235+HCQ: 45.0[17.9]% vs 24.0[8.4]%, P = .002) and in vivo (median survival of NVP-BEZ235- vs NVP-BEZ235+HCQ-treated mice: 38.5 days vs 47

Nebenwirkungen von TNF-alpha-Inhibitoren am Hautorgan.

PubMed

Lindhaus, Claudia; Tittelbach, Jörg; Elsner, Peter

2017-03-01

TNF-alpha-Inhibitoren werden seit Anfang der 1990er Jahre erfolgreich zur Behandlung diverser immunvermittelter entzündlicher Erkrankungen eingesetzt. Inzwischen gibt es eine umfangreiche Datenlage bezüglich ihrer Sicherheit. Nebenwirkungen sind bezogen auf die Häufigkeit der Anwendung selten und meist nicht schwerwiegend. Zu den Nebenwirkungen am Hautorgan zählen lokale injektionsassoziierte Reaktionen, Infektionen, immunvermittelte Reaktionen sowie Neoplasien. Die häufigsten schwerwiegenden Nebenwirkungen sind infektiöser Natur. Mykobakterielle Infektionen, aber auch non-mykobakterielle Erreger, Viren und Pilze können potenziell letale, systemische Infektionen auslösen. Im Folgenden wird eine Übersicht über das gegenwärtige Wissen bezüglich der Nebenwirkungen von TNFα-Inhibitoren am Hautorgan gegeben. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

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

Dual PI3K/mTOR inhibitors induce rapid over-activation of the MEK/ERK pathway in human pancreatic cancer cells through suppression of mTORC2

PubMed Central

Soares, Heloisa P.; Ming, Ming; Mellon, Michelle; Young, Steven H.; Han, Liang; Sinnet-Smith, James; Rozengurt, Enrique

2015-01-01

PI3K/AKT/mTOR pathway which is aberrantly stimulated in many cancer cells, has emerged as a target for therapy. However, mTORC1/S6K also mediates negative feedback loops that attenuate upstream signaling. Suppression of these feedback loops opposes the growth-suppressive effects of mTOR inhibitors and leads to drug resistance. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic ductal adenocarcinoma (PDAC) cells with the dual PI3K/mTOR kinase inhibitor (PI3K/TOR-KI) NPV-BEZ235 blocked mTORC1/S6K activation (scored by S6 phosphorylation at Ser240/244), mTORC1/4E-BP1 (assayed by 4E-BP1 phosphorylation at Thr37/46) and mTORC2-mediated AKT phosphorylation at Ser473, in a concentration-dependent manner. Strikingly, NPV-BEZ235 markedly enhanced the MEK/ERK pathway in a dose-dependent manner. Maximal ERK over-activation coincided with complete inhibition of phosphorylation of AKT and 4E-BP1. ERK over-activation was induced by other PI3K/TOR-KIs, including PKI-587 and GDC-0980. The MEK inhibitors U126 or PD0325901 prevented ERK over-activation induced by PI3K/TOR-KIs. The combination of NPV-BEZ235 and PD0325901 caused a more pronounced inhibition of cell growth than that produced by each inhibitor individually. Mechanistic studies assessing PI3K activity in single PDAC cells indicate that PI3K/TOR-KIs act through a PI3K-independent pathway. Doses of PI3K/TOR-KIs that enhanced MEK/ERK activation coincided with those that inhibited mTORC2-mediated AKT phosphorylation on Ser473, suggesting a role of mTORC2. Knockdown of Rictor via transfection of siRNA markedly attenuated the enhancing effect of NVP-BEZ235 on ERK phosphorylation. We propose that dual PI3K/mTOR inhibitors suppress a novel negative feedback loop mediated by mTORC2 thereby leading to enhanced MEK/ERK pathway activity in pancreatic cancer cells. PMID:25673820

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.

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.

The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition.

PubMed

Haagensen, E J; Kyle, S; Beale, G S; Maxwell, R J; Newell, D R

2012-04-10

Combined targeting of MAPK and PI3K signalling pathways may be necessary for optimal therapeutic activity in cancer. This study evaluated the MEK inhibitors AZD6244 and PD0325901, alone and in combination with the dual mTOR/PI3K inhibitor NVP-BEZ235 or the PI3K inhibitor GDC-0941, in three colorectal cancer cell lines. Growth inhibition, survival and signal transduction were measured using the Sulforhodamine B assay, clonogenicity and western blotting, respectively, in HCT116, HT29 and DLD1 cell lines. All MEK/PI3K inhibitor combinations exhibited marked synergistic growth inhibition; however, GDC-0941 displayed greater synergy in combination with either MEK inhibitor. NVP-BEZ235 exhibited stronger inhibition of 4EBP1 phosphorylation, and similar inhibition of S6 and AKT phosphorylation, compared with GDC-0941. Both PD0325901 and AZD6244 inhibited ERK phosphorylation, and with MEK/PI3K inhibitor combinations inhibition of S6 phosphorylation was increased. The reduced synergy exhibited by NVP-BEZ235 in combination with MEK inhibitors, compared with GDC-0941, may be due to inhibition of mTOR, and the addition of the mTORC1/2 inhibitor KU0063794 compromised the synergy of GDC-0941:PD0325901 combinations. These studies confirm that dual targeting of PI3K and MEK can induce synergistic growth inhibition; however, the combination of specific PI3K inhibitors, rather than dual mTOR/PI3K inhibitors, with MEK inhibitors results in greater synergy.

The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition

PubMed Central

Haagensen, E J; Kyle, S; Beale, G S; Maxwell, R J; Newell, D R

2012-01-01

Background: Combined targeting of MAPK and PI3K signalling pathways may be necessary for optimal therapeutic activity in cancer. This study evaluated the MEK inhibitors AZD6244 and PD0325901, alone and in combination with the dual mTOR/PI3K inhibitor NVP-BEZ235 or the PI3K inhibitor GDC-0941, in three colorectal cancer cell lines. Methods: Growth inhibition, survival and signal transduction were measured using the Sulforhodamine B assay, clonogenicity and western blotting, respectively, in HCT116, HT29 and DLD1 cell lines. Results: All MEK/PI3K inhibitor combinations exhibited marked synergistic growth inhibition; however, GDC-0941 displayed greater synergy in combination with either MEK inhibitor. NVP-BEZ235 exhibited stronger inhibition of 4EBP1 phosphorylation, and similar inhibition of S6 and AKT phosphorylation, compared with GDC-0941. Both PD0325901 and AZD6244 inhibited ERK phosphorylation, and with MEK/PI3K inhibitor combinations inhibition of S6 phosphorylation was increased. The reduced synergy exhibited by NVP-BEZ235 in combination with MEK inhibitors, compared with GDC-0941, may be due to inhibition of mTOR, and the addition of the mTORC1/2 inhibitor KU0063794 compromised the synergy of GDC-0941:PD0325901 combinations. Conclusion: These studies confirm that dual targeting of PI3K and MEK can induce synergistic growth inhibition; however, the combination of specific PI3K inhibitors, rather than dual mTOR/PI3K inhibitors, with MEK inhibitors results in greater synergy. PMID:22415236

Inhibition profiles of phosphatidylinositol 3-kinase inhibitors against PI3K superfamily and human cancer cell line panel JFCR39.

PubMed

Kong, Dexin; Dan, Shingo; Yamazaki, Kanami; Yamori, Takao

2010-04-01

As accumulating evidences suggest close involvement of phosphatidylinositol 3-kinase (PI3K) in various diseases particularly cancer, considerable competition occurs in development of PI3K inhibitors. Consequently, novel PI3K inhibitors such as ZSTK474, GDC-0941 and NVP-BEZ235 have been developed. Even though all these inhibitors were reported to inhibit class I PI3K but not dozens of protein kinases, whether they have different molecular targets remained unknown. To investigate such molecular target specificity, we have determined the inhibitory effects of these novel inhibitors together with classical PI3K inhibitor LY294002 on PI3K superfamily (including classes I, II, and III PI3Ks, PI4K and PI3K-related kinases) by using several novel non-radioactive biochemical assays. As a result, ZSTK474 and GDC-0941 indicated highly similar inhibition profiles for PI3K superfamily, with class I PI3K specificity much higher than NVP-BEZ235 and LY294002. We further investigated their growth inhibition effects on JFCR39, a human cancer cell line panel which we established for molecular target identification, and analysed their cell growth inhibition profiles (fingerprints) by using COMPARE analysis programme. Interestingly, we found ZSTK474 exhibited a highly similar fingerprint with GDC-0941 (r=0.863), more similar than with that of either NVP-BEZ235 or LY294002, suggesting that ZSTK474 shares more in molecular targets with GDC-0941 than with either of the other two PI3K inhibitors, consistent with the biochemical assay result. The biological implication of the difference in molecular target specificity of these PI3K inhibitors is under investigation. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

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…

Mononuclear Pd(II) complex as a new therapeutic agent: Synthesis, characterization, biological activity, spectral and DNA binding approaches

NASA Astrophysics Data System (ADS)

Saeidifar, Maryam; Mirzaei, Hamidreza; Ahmadi Nasab, Navid; Mansouri-Torshizi, Hassan

2017-11-01

The binding ability between a new water-soluble palladium(II) complex [Pd(bpy)(bez-dtc)]Cl (where bpy is 2,2‧-bipyridine and bez-dtc is benzyl dithiocarbamate), as an antitumor agent, and calf thymus DNA was evaluated using various physicochemical methods, such as UV-Vis absorption, Competitive fluorescence studies, viscosity measurement, zeta potential and circular dichroism (CD) spectroscopy. The Pd(II) complex was synthesized and characterized using elemental analysis, molar conductivity measurements, FT-IR, 1H NMR, 13C NMR and electronic spectra studies. The anticancer activity against HeLa cell lines demonstrated lower cytotoxicity than cisplatin. The binding constants and the thermodynamic parameters were determined at different temperatures (300 K, 310 K and 320 K) and shown that the complex can bind to DNA via electrostatic forces. Furthermore, this result was confirmed by the viscosity and zeta potential measurements. The CD spectral results demonstrated that the binding of Pd(II) complex to DNA induced conformational changes in DNA. We hope that these results will provide a basis for further studies and practical clinical use of anticancer drugs.

Metabolic biomarkers for response to PI3K inhibition in basal-like breast cancer

PubMed Central

2013-01-01

Introduction The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in cancer cells through numerous mutations and epigenetic changes. The recent development of inhibitors targeting different components of the PI3K pathway may represent a valuable treatment alternative. However, predicting efficacy of these drugs is challenging, and methods for therapy monitoring are needed. Basal-like breast cancer (BLBC) is an aggressive breast cancer subtype, frequently associated with PI3K pathway activation. The objectives of this study were to quantify the PI3K pathway activity in tissue sections from xenografts representing basal-like and luminal-like breast cancer before and immediately after treatment with PI3K inhibitors, and to identify metabolic biomarkers for treatment response. Methods Tumor-bearing animals (n = 8 per treatment group) received MK-2206 (120 mg/kg/day) or BEZ235 (50 mg/kg/day) for 3 days. Activity in the PI3K/Akt/mammalian target of rapamycin pathway in xenografts and human biopsies was evaluated using a novel method for semiquantitative assessment of Aktser473 phosphorylation. Metabolic changes were assessed by ex vivo high-resolution magic angle spinning magnetic resonance spectroscopy. Results Using a novel dual near-infrared immunofluorescent imaging method, basal-like xenografts had a 4.5-fold higher baseline level of pAktser473 than luminal-like xenografts. Following treatment, basal-like xenografts demonstrated reduced levels of pAktser473 and decreased proliferation. This correlated with metabolic changes, as both MK-2206 and BEZ235 reduced lactate concentration and increased phosphocholine concentration in the basal-like tumors. BEZ235 also caused increased glucose and glycerophosphocholine concentrations. No response to treatment or change in metabolic profile was seen in luminal-like xenografts. Analyzing tumor sections from five patients with BLBC demonstrated that two of these patients had an elevated pAktser473 level

Einleitung

NASA Astrophysics Data System (ADS)

Ha, Suk-Woo

Der Einsatz von Implantaten zielt auf die Unterstützung oder den Ersatz von Zelloder Gewebefunktionen im menschlichen Körper. Die Werkstoffauswahl für diese Implantate hängt dabei von der Art und der Funktion des zu ersetzenden Gewebes ab. Die Anforderungen an den Implantatwerkstoff bezüglich Eigenschaften und Struktur können je nach Implantationsort und Funktionalität ganz unterschiedlich sein. Implantate, die im Knochengewebe Funktionen der Lasteinleitung und -überleitung ausüben, sind hohen mechanischen Anforderungen (optimale Bauteilsteifigkeit, Dauerfestigkeit) unterworfen, während bei Blutgefässimplantaten die Werkstoffoberfläche, primär in ihrer chemischen Zusammensetzung derart gestaltet sein muss, dass eine minimale Thrombogenität resultiert. Für den Erfolg des Implantatwerkstoffes oder -bauteils sind folgende drei Faktoren relevant: (a) Biokompatibilität, (b) Gesundheitszustand des Patienten und (c) Verlauf der Operation und der nachfolgenden Therapie. Bei Vorliegen einer Erkrankung, wie z. B. die allergische Sensibilisierung gegenüber Metallionen (Nickelallergie) oder Osteoporose im Fall der Verankerung von Hüftprothesen, ist der Implantatwerkstoff höheren Anforderungen bezüglich der Biokompatibilität unterworfen als bei organisch gesunden Patienten.

Approaching Resistance to Targeted Inhibition of PI3K in Breast Cancer

DTIC Science & Technology

2011-10-01

promise, there are concerns that drug resistance may emerge within the cancerous cells, thus limiting clinical efficacy. Using genetically defined human...mechanism of such resistance. Using genetically defined human mammary epithelial cells (HMECs), a model system which has previously been used for PI3K...pathway driven transformation due to its dependence on oncogenic PI3K signaling, we screened for emergence of BEZ235-resistance and identified genetic

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.

Dual inhibition of Bcl-2 and Bcl-xL strikingly enhances PI3K inhibition-induced apoptosis in human myeloid leukemia cells through a GSK3- and Bim-dependent mechanism.

PubMed

Rahmani, Mohamed; Aust, Mandy Mayo; Attkisson, Elisa; Williams, David C; Ferreira-Gonzalez, Andrea; Grant, Steven

2013-02-15

Effects of concomitant inhibition of the PI3K/AKT/mTOR pathway and Bcl-2/Bcl-xL (BCL2L1) were examined in human myeloid leukemia cells. Tetracycline-inducible Bcl-2 and Bcl-xL dual knockdown sharply increased PI3K/AKT/mTOR inhibitor lethality. Conversely, inducible knockdown or dominant-negative AKT increased, whereas constitutively active AKT reduced lethality of the Bcl-2/Bcl-xL inhibitor ABT-737. Furthermore, PI3K/mTOR inhibitors (e.g., BEZ235 and PI-103) synergistically increased ABT-737-mediated cell death in multiple leukemia cell lines and reduced colony formation in leukemic, but not normal, CD34+ cells. Notably, increased lethality was observed in four of six primary acute myelogenous leukemia (AML) specimens. Responding, but not nonresponding, samples exhibited basal AKT phosphorylation. PI3K/mTOR inhibitors markedly downregulated Mcl-1 but increased Bim binding to Bcl-2/Bcl-xL; the latter effect was abrogated by ABT-737. Combined treatment also markedly diminished Bax/Bak binding to Mcl-1, Bcl-2, or Bcl-xL. Bax, Bak, or Bim (BCL2L11) knockdown or Mcl-1 overexpression significantly diminished regimen-induced apoptosis. Interestingly, pharmacologic inhibition or short hairpin RNA knockdown of GSK3α/β significantly attenuated Mcl-1 downregulation and decreased apoptosis. In a systemic AML xenograft model, dual tetracycline-inducible knockdown of Bcl-2/Bcl-xL sharply increased BEZ235 antileukemic effects. In a subcutaneous xenograft model, BEZ235 and ABT-737 coadministration significantly diminished tumor growth, downregulated Mcl-1, activated caspases, and prolonged survival. Together, these findings suggest that antileukemic synergism between PI3K/AKT/mTOR inhibitors and BH3 mimetics involves multiple mechanisms, including Mcl-1 downregulation, release of Bim from Bcl-2/Bcl-xL as well as Bak and Bax from Mcl-1/Bcl-2/Bcl-xL, and GSK3α/β, culminating in Bax/Bak activation and apoptosis. They also argue that combining PI3K/AKT/mTOR inhibitors with BH3

National Guard Logistics (NGLOG) Study

DTIC Science & Technology

1989-05-01

ROCiRE.ME-., NSTRUiMENr, DE ,’TrF CA7:0.%,JU’,BEZ ORGANIZATION (dfappiicaolei National Guard Bureau NGB-ARL 8C ADDRESS (City, State. inc ZI Code) 𔃺 SOURCE...which is accounted for by the USPFO of a state. This property can be distributed inter - and intrastate and redistributed without permission of any...reuimesso to upae then C-aigs, Stfor equipment funhes (Ea ofy uts within thean An. Not:l incositAenc betweenSA) dAOCentin interates handsutoaned rethatA which

Developing a novel dual PI3K–mTOR inhibitor from the prodrug of a metabolite

PubMed Central

Zhou, Yan; Zhang, Genyan; Wang, Feng; Wang, Jin; Ding, Yanwei; Li, Xinyu; Shi, Chongtie; Li, Jiakui; Shih, Chengkon; You, Song

2017-01-01

This study presents a process of developing a novel PI3K–mTOR inhibitor through the prodrug of a metabolite. The lead compound (compound 1) was identified with similar efficacy as that of NVP-BEZ235 in a tumor xenograft model, but the exposure of compound 1 was much lower than that of NVP-BEZ235. After reanalysis of the blood sample, a major metabolite (compound 2) was identified. Compound 2 exerted similar in vitro activity as compound 1, which indicated that compound 2 was an active metabolite and that the in vivo efficacy in the animal model came from compound 2 instead of compound 1. However, compound 1 was metabolized into compound 2 predominantly in the liver microsomes of mouse, but not in the liver microsomes of rat, dog, or human. In order to translate the efficacy in the animal model into clinical development or predict the pharmacokinetic/pharmacodynamic parameters in the clinical study using a preclinical model, we developed the metabolite (compound 2) instead of compound 1. Due to the low bioavailability of compound 2, its prodrug (compound 3) was designed and synthesized to improve the solubility. The prodrug was quickly converted to compound 2 through both intravenous and oral administrations. Because the prodrug (compound 3) did not improve the oral exposure of compound 2, developing compound 3 as an intravenous drug was considered by our team, and the latest results will be reported in the future. PMID:29118584

Abtasttheorem

NASA Astrophysics Data System (ADS)

Plaßmann, Wilfried

Das Abtasttheorem von Shannon ist von grundlegender Bedeutung für die Nachrichtentechnik, besonders aber für den Fall, dass ein Analogsignal in ein digital codiertes Signal überführt werden soll. Es legt fest, wie oft ein analoges Signal abgetastet werden muss, um es, digital codiert, wieder ″fehlerfrei″ in ein analoges Signal zurückwandeln zu können. Außerdem ist bezüglich der im Analogsignal enthaltenen Frequenzen eine bestimmte Bedingung zu erfüllen. Die Ableitung ist hier in verkürzter Form dargestellt.

Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy.

PubMed

Zhang, Yi-Xiang; van Oosterwijk, Jolieke G; Sicinska, Ewa; Moss, Samuel; Remillard, Stephen P; van Wezel, Tom; Bühnemann, Claudia; Hassan, Andrew B; Demetri, George D; Bovée, Judith V M G; Wagner, Andrew J

2013-07-15

Chondrosarcomas are notoriously resistant to cytotoxic chemotherapeutic agents. We sought to identify critical signaling pathways that contribute to their survival and proliferation, and which may provide potential targets for rational therapeutic interventions. Activation of receptor tyrosine kinases (RTK) was surveyed using phospho-RTK arrays. S6 phosphorylation and NRAS mutational status were examined in chondrosarcoma primary tumor tissues. siRNA or small-molecule inhibitors against RTKs or downstream signaling proteins were applied to chondrosarcoma cells and changes in biochemical signaling, cell cycle, and cell viability were determined. In vivo antitumor activity of BEZ235, a phosphoinositide 3-kinase (PI3K)/mTOR inhibitor, was evaluated in a chondrosarcoma xenograft model. Several RTKs were identified as critical mediators of cell growth, but the RTK dependencies varied among cell lines. In exploration of downstream signaling pathways, strong S6 phosphorylation was found in 69% of conventional chondrosarcomas and 44% of dedifferentiated chondrosarcomas. Treatment with BEZ235 resulted in dramatic reduction in the growth of all chondrosarcoma cell lines. Tumor growth was similarly inhibited in a xenograft model of chondrosarcoma. In addition, chondrosarcoma cells with an NRAS mutation were sensitive to treatment with a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor. Functional NRAS mutations were found in 12% of conventional central chondrosarcomas. RTKs are commonly activated in chondrosarcoma, but because of their considerable heterogeneity, targeted inhibition of the PI3K/mTOR pathway represents a rational therapeutic strategy. Chondrosarcomas with NRAS mutations may benefit from treatment with MEK inhibitors.

Co-targeting deoxyribonucleic acid-dependent protein kinase and poly(adenosine diphosphate-ribose) polymerase-1 promotes accelerated senescence of irradiated cancer cells.

PubMed

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

2014-02-01

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. 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. 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. 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. Copyright © 2014. Published by Elsevier Inc.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Azad, Arun, E-mail: arun.azad@bccancer.bc.ca; Department of Pathology, St. Vincent's Hospital, University of Melbourne, Parkville, Victoria; Bukczynska, Patricia

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,more » 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.« less

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. ©2016 American Association for Cancer Research.

Insulin induces drug resistance in melanoma through activation of the PI3K/Akt pathway

PubMed Central

Chi, Mengna; Ye, Yan; Zhang, Xu Dong; Chen, Jiezhong

2014-01-01

Introduction There is currently no curative treatment for melanoma once the disease spreads beyond the original site. Although activation of the PI3K/Akt pathway resulting from genetic mutations and epigenetic deregulation of its major regulators is known to cause resistance of melanoma to therapeutic agents, including the conventional chemotherapeutic drug dacarbazine and the Food and Drug Administration-approved mutant BRAF inhibitors vemurafenib and dabrafenib, the role of extracellular stimuli of the pathway, such as insulin, in drug resistance of melanoma remains less understood. Objective To investigate the effect of insulin on the response of melanoma cells to dacarbazine, and in particular, the effect of insulin on the response of melanoma cells carrying the BRAFV600E mutation to mutant BRAF inhibitors. An additional aim was to define the role of the PI3K/Akt pathway in the insulin-triggered drug resistance. Methods The effect of insulin on cytotoxicity induced by dacarbazine or the mutant BRAF inhibitor PLX4720 was tested by pre-incubation of melanoma cells with insulin. Cytotoxicity was determined by the MTS assay. The role of the PI3K/Akt pathway in the insulin-triggered drug resistance was examined using the PI3K inhibitor LY294002 and the PI3K and mammalian target of rapamycin dual inhibitor BEZ-235. Activation of the PI3K/Akt pathway was monitored by Western blot analysis of phosphorylated levels of Akt. Results Recombinant insulin attenuated dacarbazine-induced cytotoxicity in both wild-type BRAF and BRAFV600E melanoma cells, whereas it also reduced killing of BRAFV600E melanoma cells by PLX4720. Nevertheless, the protective effect of insulin was abolished by the PI3K and mTOR dual inhibitor BEZ-235 or the PI3K inhibitor LY294002. Conclusion Insulin attenuates the therapeutic efficacy of dacarbazine and PLX4720 in melanoma cells, which is mediated by activation of the PI3K/Akt pathway and can be overcome by PI3K inhibitors. PMID:24600206

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. Georg Thieme Verlag KG Stuttgart · New York.

Response of head and neck squamous cell carcinoma cells carrying PIK3CA mutations to selected targeted therapies.

PubMed

Wirtz, Eric D; Hoshino, Daisuke; Maldonado, Anthony T; Tyson, Darren R; Weaver, Alissa M

2015-06-01

The PIK3CA mutation is one of the most common mutations in head and neck squamous cell carcinoma (HNSCC). Through this research we attempt to elicit the role of oncogene dependence and effects of targeted therapy on this PIK3CA mutation. (1) To determine the role of oncogene dependence on PIK3CA-one of the more common and targetable oncogenes in HNSCC, and (2) to evaluate the consequence of this oncogene on the effectiveness of newly developed targeted therapies. This was a cell culture-based, in vitro study performed at an academic research laboratory assessing the viability of PIK3CA-mutated head and neck cell lines when treated with targeted therapy. PIK3CA-mutated head and neck cell lines were treated with 17-AAG, GDC-0941, trametinib, and BEZ-235. Assessment of cell viability of HNSCC cell lines characterized for PIK3CA mutations or SCC25 cells engineered to express the PIK3CA hotspot mutations E545K or H1047R. Surprisingly, in engineered cell lines, the hotspot E545K and H1047R mutations conferred increased, rather than reduced, IC50 assay measurements when treated with the respective HSP90, PI3K, and MEK inhibitors, 17-AAG, GDC-0941, and trametinib, compared with the SCC25 control cell lines. When treated with BEZ-235, H1047R-expressing cell lines showed increased sensitivity to inhibition compared with control, whereas those expressing E545K showed slightly increased sensitivity of unclear significance. (1) The PIK3CA mutations within our engineered cell model did not lead to enhanced oncogene-dependent cell death when treated with direct inhibition of the PI3K enzyme yet did show increased sensitivity compared with control with dual PI3K/mTOR inhibition. (2) Oncogene addiction to PIK3CA hotspot mutations, if it occurs, is likely to evolve in vivo in the context of additional molecular changes that remain to be identified. Additional study is required to develop new model systems and approaches to determine the role of targeted therapy in the treatment of

Response of Head and Neck Squamous Cell Carcinoma Cells Carrying PIK3CA Mutations to Select Targeted Therapies

PubMed Central

Wirtz, Eric D; Hoshino, Daisuke; Maldonado, Anthony T; Tyson, Darren R; Weaver, Alissa M

2015-01-01

Importance The PIK3CA mutation is one of the most common mutations in Head and Neck Squamous Cell Carcinoma (HNSCC). Through this research we attempt to elicit the role of oncogene dependence and effects of targeted therapy on this PIK3CA mutation. Objectives 1) To determine the role of oncogene dependence on one of the more common and targetable oncogenes in HNSCC – PIK3CA; 2) To evaluate the consequence of this oncogene on the effectiveness of newly developed targeted therapies. Study Design In vitro study. Setting Academic research laboratory. Participants Cell culture based study assessing the viability of PIK3CA mutated head and neck cell lines when treated with targeted therapy. Exposures PIK3CA mutated head and neck cell lines were treated with 17-AAG, GDC-0941, trametinib, and BEZ-235. Main Outcome and Measures Assessment of cell viability of HNSCC cell lines characterized for PIK3CA mutations or SCC25 cells engineered to express the PIK3CA hotspot mutations E545K or H1047R Results Surprisingly, in engineered cell lines, the hotspot E545K and H1047R mutations conferred decreased, rather than increased, sensitivity as measured by IC50 when treated with the respective HSP90, PI3K, and MEK inhibitors, 17-AAG, GDC-0941, and trametinib, compared to the SCC25 control cell lines. When treated with BEZ-235, H1047R-expressing cell lines showed increased sensitivity to inhibition compared to control while those expressing E545K showed slightly increased sensitivity of unclear significance. Conclusions and Relevance 1) The PIK3CA mutations within our engineered cell model did not lead to enhanced oncogene-dependent cell death when treated with direct inhibition of the PI3K enzyme yet did show increased sensitivity compared to control with dual PI3K/mTOR inhibition. 2) Oncogene addiction to PIK3CA hot spot mutations, if it occurs, is likely to evolve in vivo molecular changes that remain to be identified. Additional study is required to develop new model systems and

Effects of anisotropy in permeability on the two-phase flow and heat transfer in a porous cavity

NASA Astrophysics Data System (ADS)

Zhang, X. L.; Nguyen, T. Hung; Kahawita, R.

Zusammenfassung In der Arbeit wird über die Ergebnisse einer numerischen Studie, betreffend die stationäre Konvektionsströmung und den stationären Wärmeübergang in einer rechteckigen, mit einem porösen, phasenveränderlichen Medium (PCM) verfüllten Kavität, berichtet. Den zwei vertikalen Berandungen der Kavität sind zwei, den Schmelzpunkt des PCM einschließende Temperaturen aufgeprägt, während die beiden horizontalen Berandungen adiabat gehalten werden. Das poröse Medium ist durch einen anisotropen Permeabilitätstensor charakterisiert, dessen Hauptachsen bezüglich des Gravitationsvektors beliebig orientiert sein können. Das Problem ist durch das Seitenverhältnis A, die Rayleigh-Zahl Ra, das Anisotropienverhältnis R und den Orientierungswinkel Θ des Permeabilitätstensor bestimmt. Hauptaugenmerk gilt dem Einfluß der anisotropen Permeabilität auf das Strömungsverhalten und den Wärme-übergang beim Phasenwechselprozeß flüssig/fest. Die Lösungsmethode basiert auf dem Kontrollvolumenprinzip in Verbindung mit der Landau-Transformation über welche das irreguläre Strömungsgebiet in ein rechteckiges abgebildet wird. Ergebnisse bezüglich Strömungsfeld, Temperaturverteilung, Phasengrenzenort und Wärmeübergang werden fürA=2,5Ra=40 0<=Θ<=π 0,25<=R<=4 mitgeteilt. Es zeigte sich, daß der Gleichgewichtszustand des Phasenwechselsprozesses fest/flüssig sowohl durch das Anisotropieverhältnis R als auch durch den Orientierungswinkel Θ des Permeabilitätstensors wesentlich beeinflußt werden kann. Zum einen existiert bei festgehaltenen ParameternA, Ra undR eine optimale Orientierung Θmax, bei der die Stromstärke, das Flüssigkeitsvolumen und der Wärmestrom Maximalwerte erreichen, während für Θmin=Θmax+π/2 Minimalwerte resultieren. Ist das anisotrope Medium entlang der Optimalrichtung Θmax orientiert, so ergibt sich zum anderen, daß eine Vergrößerung der in diese Richtung fallenden Permeabilitätskomponente die Stromstärke und den W�

Medizintechnik in der Tumororthopädie

NASA Astrophysics Data System (ADS)

Burgkart, Rainer; Gollwitzer, Hans; Holzapfel, Boris; Rudert, Maximilian; Rechl, Hans; Gradinger, Reiner

Die Behandlung der Knochentumoren unterlag in den letzten 20 Jahren einem raschen und stetigen Wandel, was zum einen auf die verbesserten Therapieerfolge durch den Einsatz von neoadjuvanten Therapieformen zurückzuführen ist, und andererseits von medizintechnischen Entwicklungen bezüglich moderner Schnittbilddiagnostik, neuer 3D Operationsplanungsverfahren wie das Rapid Prototyping und adaptiv modularer Tumorendoprothesensystemen u. a. begleitet wurde. Gerade die technischen Entwicklungen haben dazu geführt, daß im Bereich der Extremitäten und der Wirbelsäule radikalere Eingriffe durchgeführt werden können, was die lokale Tumorkontrolle wesentlich verbessert hat. In zunehmenden Maße werden deshalb nicht nur Kurzzeiterfolge sondern auch mittel- und langfristige Fortschritte bei der Behandlung der malignen Knochentumoren einschließlich der Metastasenbehandlung erreicht. Grundlage der Therapie ist dabei immer primär die Sicherung der Diagnose mittels Biopsie und die bildgebende sowie histologische Stadieneinteilung des malignen Tumors. Nach der Tumorresektion kann die Rekonstruktion biologisch oder mit Endoprothesensystemen erfolgen. Gerade die weiterentwickelten modularen Systeme führen zu guten funktionellen Ergebnissen mit langen Standzeiten und einer reduzierten Komplikationsrate. Individuell angefertigte Implantate sind vor allem im Bereich der Rekonstruktion komplexer Beckentumoren von großer klinischer Bedeutung.

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

NASA Image and Video Library

2014-05-07

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

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.

Synergistic targeted inhibition of MEK and dual PI3K/mTOR diminishes viability and inhibits tumor growth of canine melanoma underscoring its utility as a preclinical model for human mucosal melanoma.

PubMed

Wei, Bih-Rong; Michael, Helen T; Halsey, Charles H C; Peer, Cody J; Adhikari, Amit; Dwyer, Jennifer E; Hoover, Shelley B; El Meskini, Rajaa; Kozlov, Serguei; Weaver Ohler, Zoe; Figg, William D; Merlino, Glenn; Simpson, R Mark

2016-11-01

Human mucosal melanoma (MM), an uncommon, aggressive and diverse subtype, shares characteristics with spontaneous MM in dogs. Although BRAF and N-RAS mutations are uncommon in MM in both species, the majority of human and canine MM evaluated exhibited RAS/ERK and/or PI3K/mTOR signaling pathway activation. Canine MM cell lines, with varying ERK and AKT/mTOR activation levels reflective of naturally occurring differences in dogs, were sensitive to the MEK inhibitor GSK1120212 and dual PI3K/mTOR inhibitor NVP-BEZ235. The two-drug combination synergistically decreased cell survival in association with caspase 3/7 activation, as well as altered expression of cell cycle regulatory proteins and Bcl-2 family proteins. In combination, the two drugs targeted their respective signaling pathways, potentiating reduction of pathway mediators p-ERK, p-AKT, p-S6, and 4E-BP1 in vitro, and in association with significantly inhibited solid tumor growth in MM xenografts in mice. These findings provide evidence of synergistic therapeutic efficacy when simultaneously targeting multiple mediators in melanoma with Ras/ERK and PI3K/mTOR pathway activation. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.

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

NASA Image and Video Library

2014-05-07

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

Prä- und perioperative Aspekte der Versorgung dermatochirurgischer Patienten.

PubMed

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

2017-02-01

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

Aberrant AKT activation drives well-differentiated liposarcoma

PubMed Central

Gutierrez, Alejandro; Snyder, Eric L.; Marino-Enriquez, Adrian; Zhang, Yi-Xiang; Sioletic, Stefano; Kozakewich, Elena; Grebliunaite, Ruta; Ou, Wen-bin; Sicinska, Ewa; Raut, Chandrajit P.; Demetri, George D.; Perez-Atayde, Antonio R.; Wagner, Andrew J.; Fletcher, Jonathan A.; Fletcher, Christopher D. M.; Look, A. Thomas

2011-01-01

Well-differentiated liposarcoma (WDLPS), one of the most common human sarcomas, is poorly responsive to radiation and chemotherapy, and the lack of animal models suitable for experimental analysis has seriously impeded functional investigation of its pathobiology and development of effective targeted therapies. Here, we show that zebrafish expressing constitutively active Akt2 in mesenchymal progenitors develop WDLPS that closely resembles the human disease. Tumor incidence rates were 8% in p53 wild-type zebrafish, 6% in p53 heterozygotes, and 29% in p53-homozygous mutant zebrafish (P = 0.013), indicating that aberrant Akt activation collaborates with p53 mutation in WDLPS pathogenesis. Analysis of primary clinical specimens of WDLPS, and of the closely related dedifferentiated liposarcoma (DDLPS) subtype, revealed immunohistochemical evidence of AKT activation in 27% of cases. Western blot analysis of a panel of cell lines derived from patients with WDLPS or DDLPS revealed robust AKT phosphorylation in all cell lines examined, even when these cells were cultured in serum-free media. Moreover, BEZ235, a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells, impaired viability at nanomolar concentrations. Our findings are unique in providing an animal model to decipher the molecular pathogenesis of WDLPS, and implicate AKT as a previously unexplored therapeutic target in this chemoresistant sarcoma. PMID:21930930

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

NASA Image and Video Library

2014-05-07

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

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

Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

PubMed Central

Lehmann, Brian D.; Bauer, Joshua A.; Chen, Xi; Sanders, Melinda E.; Chakravarthy, A. Bapsi; Shyr, Yu; Pietenpol, Jennifer A.

2011-01-01

Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem–like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted “driver” signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies. PMID:21633166

Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication.

PubMed

Campbell, Grant R; Bruckman, Rachel S; Herns, Shayna D; Joshi, Shweta; Durden, Donald L; Spector, Stephen A

2018-04-20

In this study, we investigated the effects of the dual phosphatidylinositol 3-kinase/mechanistic target of rapamycin (PI3K/MTOR) inhibitor dactolisib (NVP-BEZ235), the PI3K/MTOR/bromodomain-containing protein 4 (BRD4) inhibitor SF2523, and the bromodomain and extra terminal domain inhibitor JQ1 on the productive infection of primary macrophages with human immunodeficiency type-1 (HIV). These inhibitors did not alter the initial susceptibility of macrophages to HIV infection. However, dactolisib, JQ1, and SF2523 all decreased HIV replication in macrophages in a dose-dependent manner via degradation of intracellular HIV through autophagy. Macrophages treated with dactolisib, JQ1, or SF2523 displayed an increase in LC3B lipidation combined with SQSTM1 degradation without inducing increased cell death. LC3B-II levels were further increased in the presence of pepstatin A suggesting that these inhibitors induce autophagic flux. RNA interference for ATG5 and ATG7 and pharmacological inhibitors of autophagosome-lysosome fusion and of lysosomal hydrolases all blocked the inhibition of HIV. Thus, we demonstrate that the mechanism of PI3K/MTOR and PI3K/MTOR/BRD4 inhibitor suppression of HIV requires the formation of autophagosomes, as well as their subsequent maturation into autolysosomes. These data provide further evidence in support of a role for autophagy in the control of HIV infection and open new avenues for the use of this class of drugs in HIV therapy. © 2018 Campbell et al.

Silencing of secretory clusterin sensitizes NSCLC cells to V-ATPase inhibitors by downregulating survivin.

PubMed

Kim, Young-Sun; Jin, Hyeon-Ok; Hong, Sung-Eun; Song, Jie-Young; Hwang, Chang-Sun; Park, In-Chul

2018-01-08

Secretory clusterin (sCLU) is a stress-associated protein that confers resistance to therapy when overexpressed. In this study, we observed that the V-ATPase inhibitors bafilomycin A1 and concanamycin A significantly stimulated sCLU protein expression. Knockdown of sCLU with siRNA sensitized non-small cell lung cancer (NSCLC) cells to bafilomycin A1, suggesting that sCLU expression renders cells resistant to V-ATPase inhibitors. The dual PI3K/AKT and mTOR inhibitor BEZ235 suppressed sCLU expression and enhanced cell sensitivity induced by bafilomycin A1. Notably, sCLU knockdown further decreased the expression of the survivin protein by bafilomycin A1, and the ectopic expression of survivin alleviated the cell sensitivity by bafilomycin A1 and sCLU depletion, suggesting that increased sensitivity to sCLU depletion in the cells with V-ATPase inhibitors is due, at least in part, to the down-regulation of survivin. Taken together, we demonstrated that the depletion of sCLU expression enhances the sensitivity of NSCLC cells to V-ATPase inhibitors by decreasing survivin expression. Inhibition of the PI3K/AKT/mTOR pathway enhances the sensitivity of NSCLC cells to V-ATPase inhibitors, leading to decreased sCLU and survivin expression. Thus, we suggest that a combination of PI3K/AKT/mTOR inhibitors with V-ATPase inhibitors might be an effective approach for NSCLC treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

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

PubMed Central

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

2013-01-01

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

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

PubMed

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

2013-05-22

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

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

NASA Image and Video Library

2014-05-07

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

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

PubMed

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

2017-02-01

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

Sentinel-Lymphknoten-Biopsie des Melanoms mittels Indocyaningrün und "FOVIS"-System.

PubMed

Göppner, Daniela; Nekwasil, Stephan; Jellestad, Anne; Sachse, Alexander; Schönborn, Karl-Heinz; Gollnick, Harald

2017-02-01

Der Nachweis metastatischer Infiltrate im Sentinel-Lymphkoten (SLN) gilt als wesentlicher prognostischer Faktor des Melanoms. Alternativ zur Farbstoffmethode mit Patentblau zum Goldstandard der SLN-Biopsie (SLNB) mittels Radiokolloid wird die fluoreszenzoptische Darstellung mit Hilfe von Indocyaningrün (ICG) und Nahinfrarot (NIR)-Kamerasystem kommuniziert. Im Vergleich zur konventionellen Methode wurde die Wertigkeit des ICG-/NIR-Verfahrens in Abhängigkeit vom Body-Mass-Index (BMI) des Patienten und der Konzentration von ICG bezüglich der Visualisierung des Lymphabstroms und des SLNs untersucht. An zehn Patienten wurde die SLNB mittels Technetium-99m, Patentblau und ICG durchgeführt. Die Fluoreszenz-Darstellung von Lymphbahnen und SLN erfolgte in Echtzeit mittels der NIR-Kameratechnik "FOVIS". Je nach erzielter Bildqualität wurde ICG in einer Dosis von 0,25 mg bis 2,5 mg intrakutan appliziert. Neun der zehn SLN wurden fluoreszenzoptisch identifiziert (90 %), alle zehn radioaktiv (100 %), nur acht (80 %) mittels ICG-Grünfärbung bzw. Patenblau-Markierung. Transdermal wurde ein SLN dargestellt (10 %). In Korrelation zum BMI waren höhere ICG-Mengen, bis zu 2,5 mg intrakutan absolut, in der Darstellung der Lymphbahnen von Vorteil. Die SLN-Fluoreszenzmarkierung mit dem ICG/NIR-Kamera-System "FOVIS" stellt eine sichere Alternative zur Farbstoffmethode mit Patentblau ergänzend zur Radiokolloidmethode mit Technetium-99m dar. Weitere Studien zur optimalen Dosierung von ICG und transdermalen Bildgebung in Relation zum BMI sind notwendig. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

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

Ibrutinib (ImbruvicaTM) potently inhibits ErbB receptor phosphorylation and cell viability of ErbB2-positive breast cancer cells.

PubMed

Grabinski, Nicole; Ewald, Florian

2014-12-01

Ibrutinib (formerly PCI-32765) is a specific, irreversible, and potent inhibitor of Burton's tyrosine kinase (BTK) developed for the treatment of several forms of blood cancer. It is now an FDA-approved drug marketed under the name Imbruvica(TM) (Pharmacyclics, Inc.) and successfully used as an orally administered second-line drug in the treatment of mantle cell lymphoma. Since BTK is predominantly expressed in hematopoietic cells, the sensitivity of solid tumor cells to Ibrutinib has not been analyzed. In this study, we determined the effect of Ibrutinib on breast cancer cells. We demonstrate that Ibrutinib efficiently reduces the phosphorylation of the receptor tyrosine kinases ErbB1, ErbB2 and ErbB3, thereby suppressing AKT and MAPK signaling in ErbB2-positive (ErbB2+) breast cancer cell lines. Treatment with Ibrutinib significantly reduced the viability of ErbB2+ cell lines with IC50 values at nanomolar concentrations, suggesting therapeutic potential of Ibrutinib in breast cancer. Combined treatment with Ibrutinib and the dual PI3K/mTOR inhibitor BEZ235 synergistically reduces cell viability of ErbB2+ breast cancer cells. Combination indices below 0.25 at 50% inhibition of cell viability were determined by the Chou-Talalay method. Therefore, the combination of Ibrutinib and canonical PI3K pathway inhibitors could be a new and effective approach in the treatment of breast cancer with activated ErbB receptors. Ibrutinib could thus become a valuable component of targeted therapy in aggressive ErbB2+ breast cancer.

Genetic wealth, population health: Major histocompatibility complex variation in captive and wild ring-tailed lemurs (Lemur catta).

PubMed

Grogan, Kathleen E; Sauther, Michelle L; Cuozzo, Frank P; Drea, Christine M

2017-10-01

Across species, diversity at the major histocompatibility complex (MHC) is critical to individual disease resistance and, hence, to population health; however, MHC diversity can be reduced in small, fragmented, or isolated populations. Given the need for comparative studies of functional genetic diversity, we investigated whether MHC diversity differs between populations which are open, that is experiencing gene flow, versus populations which are closed, that is isolated from other populations. Using the endangered ring-tailed lemur ( Lemur catta ) as a model, we compared two populations under long-term study: a relatively "open," wild population ( n  = 180) derived from Bezà Mahafaly Special Reserve, Madagascar (2003-2013) and a "closed," captive population ( n  = 121) derived from the Duke Lemur Center (DLC, 1980-2013) and from the Indianapolis and Cincinnati Zoos (2012). For all animals, we assessed MHC-DRB diversity and, across populations, we compared the number of unique MHC-DRB alleles and their distributions. Wild individuals possessed more MHC-DRB alleles than did captive individuals, and overall, the wild population had more unique MHC-DRB alleles that were more evenly distributed than did the captive population. Despite management efforts to maintain or increase genetic diversity in the DLC population, MHC diversity remained static from 1980 to 2010. Since 2010, however, captive-breeding efforts resulted in the MHC diversity of offspring increasing to a level commensurate with that found in wild individuals. Therefore, loss of genetic diversity in lemurs, owing to small founder populations or reduced gene flow, can be mitigated by managed breeding efforts. Quantifying MHC diversity within individuals and between populations is the necessary first step to identifying potential improvements to captive management and conservation plans.

Skp2 regulates androgen receptor through ubiquitin-mediated degradation independent of Akt/mTOR pathways in prostate cancer.

PubMed

Li, Bo; Lu, Wenfu; Yang, Qing; Yu, Xiuping; Matusik, Robert J; Chen, Zhenbang

2014-04-01

The intervention of advanced prostate cancer (PCa) in patients has been commonly depending on androgen deprivation therapy. Despite of tremendous research efforts, however, molecular mechanisms on AR regulation remain poorly understood, particularly for castration resistant prostate cancer (CRPC). Targeting AR and associated factors is considered an effective strategy in PCa treatment. Human prostate cancer cells were used in this study. Manipulations of Skp2 expression were achieved by Skp2 shRNA/siRNA or overexpression of plasmids. Dual luciferase reporter assay was applied for AR activity assessment. Western blot, ubiquitination assay, immunoprecipitation, and immunofluorescence were applied to detect the proteins. Our results demonstrated that Skp2 directly involves the regulation of AR expression through ubiquitination-mediated degradation. Skp2 interacted with AR protein in PCa cells, and enforced expression of Skp2 resulted in a decreased level and activity of AR. By contrast, Skp2 knockdown increased the protein accumulation and activity of AR. Importantly, changes of AR contributed by Skp2 led to subsequent alterations of PSA level in PCa cells. AR ubiquitination was significantly increased upon Skp2 overexpression but greatly reduced upon Skp2 knockdown. AR mutant at K847R abrogated Skp2-mediated ubiquitination of AR. NVP-BEZ235, a dual PI3K/mTOR inhibitor, remarkably inhibited Skp2 level with a striking elevation of AR. The results indicate that Skp2 is an E3 ligase for proteasome-dependent AR degradation, and K847 on AR is the recognition site for Skp2-mediated ubiquitination. Our findings reveal an essential role of Skp2 in AR signaling. © 2013 Wiley Periodicals, Inc.

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

NASA Image and Video Library

2014-05-07

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

Mycobacterium leprae genomes from naturally infected nonhuman primates

PubMed Central

Pfister, Luz-Andrea; Housman, Genevieve; Mills, Sarah; Tarara, Ross P.; Suzuki, Koichi; Cuozzo, Frank P.; Sauther, Michelle L.; Rosenberg, Michael S.; Stone, Anne C.

2018-01-01

Leprosy is caused by the bacterial pathogens Mycobacterium leprae and Mycobacterium lepromatosis. Apart from humans, animals such as nine-banded armadillos in the Americas and red squirrels in the British Isles are naturally infected with M. leprae. Natural leprosy has also been reported in certain nonhuman primates, but it is not known whether these occurrences are due to incidental infections by human M. leprae strains or by M. leprae strains specific to nonhuman primates. In this study, complete M. leprae genomes from three naturally infected nonhuman primates (a chimpanzee from Sierra Leone, a sooty mangabey from West Africa, and a cynomolgus macaque from The Philippines) were sequenced. Phylogenetic analyses showed that the cynomolgus macaque M. leprae strain is most closely related to a human M. leprae strain from New Caledonia, whereas the chimpanzee and sooty mangabey M. leprae strains belong to a human M. leprae lineage commonly found in West Africa. Additionally, samples from ring-tailed lemurs from the Bezà Mahafaly Special Reserve, Madagascar, and chimpanzees from Ngogo, Kibale National Park, Uganda, were screened using quantitative PCR assays, to assess the prevalence of M. leprae in wild nonhuman primates. However, these samples did not show evidence of M. leprae infection. Overall, this study adds genomic data for nonhuman primate M. leprae strains to the existing M. leprae literature and finds that this pathogen can be transmitted from humans to nonhuman primates as well as between nonhuman primate species. While the prevalence of natural leprosy in nonhuman primates is likely low, nevertheless, future studies should continue to explore the prevalence of leprosy-causing pathogens in the wild. PMID:29381722

Mycobacterium leprae genomes from naturally infected nonhuman primates.

PubMed

Honap, Tanvi P; Pfister, Luz-Andrea; Housman, Genevieve; Mills, Sarah; Tarara, Ross P; Suzuki, Koichi; Cuozzo, Frank P; Sauther, Michelle L; Rosenberg, Michael S; Stone, Anne C

2018-01-01

Leprosy is caused by the bacterial pathogens Mycobacterium leprae and Mycobacterium lepromatosis. Apart from humans, animals such as nine-banded armadillos in the Americas and red squirrels in the British Isles are naturally infected with M. leprae. Natural leprosy has also been reported in certain nonhuman primates, but it is not known whether these occurrences are due to incidental infections by human M. leprae strains or by M. leprae strains specific to nonhuman primates. In this study, complete M. leprae genomes from three naturally infected nonhuman primates (a chimpanzee from Sierra Leone, a sooty mangabey from West Africa, and a cynomolgus macaque from The Philippines) were sequenced. Phylogenetic analyses showed that the cynomolgus macaque M. leprae strain is most closely related to a human M. leprae strain from New Caledonia, whereas the chimpanzee and sooty mangabey M. leprae strains belong to a human M. leprae lineage commonly found in West Africa. Additionally, samples from ring-tailed lemurs from the Bezà Mahafaly Special Reserve, Madagascar, and chimpanzees from Ngogo, Kibale National Park, Uganda, were screened using quantitative PCR assays, to assess the prevalence of M. leprae in wild nonhuman primates. However, these samples did not show evidence of M. leprae infection. Overall, this study adds genomic data for nonhuman primate M. leprae strains to the existing M. leprae literature and finds that this pathogen can be transmitted from humans to nonhuman primates as well as between nonhuman primate species. While the prevalence of natural leprosy in nonhuman primates is likely low, nevertheless, future studies should continue to explore the prevalence of leprosy-causing pathogens in the wild.

Targeting KRAS-mutant non-small cell lung cancer with the Hsp90 inhibitor ganetespib.

PubMed

Acquaviva, Jaime; Smith, Donald L; Sang, Jim; Friedland, Julie C; He, Suqin; Sequeira, Manuel; Zhang, Chaohua; Wada, Yumiko; Proia, David A

2012-12-01

Mutant KRAS is a feature of more than 25% of non-small cell lung cancers (NSCLC) and represents one of the most prevalent oncogenic drivers in this disease. NSCLC tumors with oncogenic KRAS respond poorly to current therapies, necessitating the pursuit of new treatment strategies. Targeted inhibition of the molecular chaperone Hsp90 results in the coordinated blockade of multiple oncogenic signaling pathways in tumor cells and has thus emerged as an attractive avenue for therapeutic intervention in human malignancies. Here, we examined the activity of ganetespib, a small-molecule inhibitor of Hsp90 currently in clinical trials for NSCLCs in a panel of lung cancer cell lines harboring a diverse spectrum of KRAS mutations. In vitro, ganetespib was potently cytotoxic in all lines, with concomitant destabilization of KRAS signaling effectors. Combinations of low-dose ganetespib with MEK or PI3K/mTOR inhibitors resulted in superior cytotoxic activity than single agents alone in a subset of mutant KRAS cells, and the antitumor efficacy of ganetespib was potentiated by cotreatment with the PI3K/mTOR inhibitor BEZ235 in A549 xenografts in vivo. At the molecular level, ganetespib suppressed activating feedback signaling loops that occurred in response to MEK and PI3K/mTOR inhibition, although this activity was not the sole determinant of combinatorial benefit. In addition, ganetespib sensitized mutant KRAS NSCLC cells to standard-of-care chemotherapeutics of the antimitotic, topoisomerase inhibitor, and alkylating agent classes. Taken together, these data underscore the promise of ganetespib as a single-agent or combination treatment in KRAS-driven lung tumors.

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 %.

A Novel Oncolytic Herpes Simplex Virus that Synergizes with Phosphatidylinositol 3-Kinase/Akt Pathway Inhibitors to Target Glioblastoma Stem Cells

PubMed Central

Kanai, Ryuichi; Wakimoto, Hiroaki; Martuza, Robert L.; Rabkin, Samuel D.

2011-01-01

Purpose To develop a new oncolytic herpes simplex virus (oHSV) for glioblastoma therapy that will be effective in glioblastoma stem cells (GSCs), an important and untargeted component of glioblastoma. One approach to enhance oHSV efficacy is by combination with other therapeutic modalities. Experimental design MG18L, containing a US3 deletion and an inactivating LacZ insertion in UL39, was constructed for the treatment of brain tumors. Safety was evaluated after intracerebral injection in HSV-susceptible mice. The efficacy of MG18L in human GSCs and glioma cell lines in vitro was compared to other oHSVs, alone or in combination with PI3K/Akt inhibitors (LY294002, triciribine, GDC-0941, BEZ235). Cytotoxic interactions between MG18L and PI3K/Akt inhibitors were determined using Chou-Talalay analysis. In vivo efficacy studies were performed using a clinically relevant mouse model of GSC-derived glioblastoma. Results MG18L was severely neuroattenuated in mice, replicated well in GSCs, and had anti-glioblastoma activity in vivo. PI3K/Akt inhibitors displayed significant but variable anti-proliferative activities in GSCs, while their combination with MG18L synergized in killing GSCs and glioma lines, but not human astrocytes, through enhanced induction of apoptosis. Importantly, synergy was independent of inhibitor sensitivity. In vivo, the combination of MG18L and LY294002 significantly prolonged survival of mice, as compared to either agent alone, achieving 50% long-term survival in glioblastoma-bearing mice. Conclusions This study establishes a novel therapeutic strategy: oHSV manipulation of critical oncogenic pathways to sensitize cancer cells to molecularly-targeted drugs. MG18L is a promising agent for the treatment of glioblastoma, being especially effective when combined with PI3K/Akt pathway-targeted agents. PMID:21505062

Enhancement of the anti-tumor activity of FGFR1 inhibition in squamous cell lung cancer by targeting downstream signaling involved in glucose metabolism

PubMed Central

Fumarola, Claudia; Cretella, Daniele; La Monica, Silvia; Bonelli, Mara A.; Alfieri, Roberta; Caffarra, Cristina; Quaini, Federico; Madeddu, Denise; Falco, Angela; Cavazzoni, Andrea; Digiacomo, Graziana; Mazzaschi, Giulia; Vivo, Valentina; Barocelli, Elisabetta; Tiseo, Marcello; Petronini, Pier Giorgio; Ardizzoni, Andrea

2017-01-01

Fibroblast Growth Factor Receptor (FGFR) signaling is a complex pathway which controls several processes, including cell proliferation, survival, migration, and metabolism. FGFR1 signaling is frequently deregulated via amplification/over-expression in NSCLC of squamous histotype (SQCLC), however its inhibition has not been successfully translated in clinical setting. We determined whether targeting downstream signaling implicated in FGFR1 effects on glucose metabolism potentiates the anti-tumor activity of FGFR1 inhibition in SQCLC. In FGFR1 amplified/over-expressing SQCLC cell lines, FGF2-mediated stimulation of FGFR1 under serum-deprivation activated both MAPK and AKT/mTOR pathways and increased glucose uptake, glycolysis, and lactate production, through AKT/mTOR-dependent HIF-1α accumulation and up-regulation of GLUT-1 glucose transporter. These effects were hindered by PD173074 and NVP-BGJ398, selective FGFR inhibitors, as well as by dovitinib, a multi-kinase inhibitor. Glucose metabolism was hampered by the FGFR inhibitors also under hypoxic conditions, with consequent inhibition of cell proliferation and viability. In presence of serum, glucose metabolism was impaired only in cell models in which FGFR1 inhibition was associated with AKT/mTOR down-regulation. When the activation of the AKT/mTOR pathway persisted despite FGFR1 down-regulation, the efficacy of NVP-BGJ398 could be significantly improved by the combination with NVP-BEZ235 or other inhibitors of this signaling cascade, both in vitro and in xenotransplanted nude mice. Collectively our results indicate that inhibition of FGFR1 signaling impacts on cancer cell growth also by affecting glucose energy metabolism. In addition, this study strongly suggests that the therapeutic efficacy of FGFR1 targeting molecules in SQCLC may be implemented by combined treatments tackling on glucose metabolism. PMID:29190880

Tumor vessel normalization by the PI3K inhibitor HS-173 enhances drug delivery.

PubMed

Kim, Soo Jung; Jung, Kyung Hee; Son, Mi Kwon; Park, Jung Hee; Yan, Hong Hua; Fang, Zhenghuan; Kang, Yeo Wool; Han, Boreum; Lim, Joo Han; Hong, Soon-Sun

2017-09-10

Tumor vessels are leaky and immature, which causes poor oxygen and nutrient supply to tumor vessels and results in cancer cell metastasis to distant organs. This instability of tumor blood vessels also makes it difficult for anticancer drugs to penetrate and reach tumors. Numerous tumor vessel normalization approaches have been investigated for improving drug delivery into tumors. In this study, we investigated whether phosphoinositide 3-kinase (PI3K) inhibitors are able to improve vascular structure and function over the prolonged period necessary to achieve effective vessel normalization. The PI3K inhibitors, HS-173 and BEZ235 potently suppressed tumor growth and hypoxia, and increased tumor apoptosis in animal models. PI3K inhibitors also induced a regular, flat monolayer of endothelial cells (ECs) in vessels, improving stability of vessel structure, and normalized tumor vessels by increasing vascular maturity, pericyte coverage, basement membrane thickness, and tight-junctions. These effects resulted in a decrease in tumor vessel tortuosity and vessel thinning, and improved vessel function and blood flow. The tumor vessel stabilization effect of the PI3K inhibitor HS-173 also decreased the number of metastatic lung nodules in vivo metastasis model. Furthermore, HS-173 improved the delivery of doxorubicin into the tumor region, enhancing its anticancer effects. Mechanistic studies suggested that PI3K inhibitor HS-173-induced vessel normalization reflected changes in endothelial Notch signaling. Taken together, our findings indicate that vessel normalization by PI3K inhibitors restrained tumor growth and metastasis while improving chemotherapy by enhancing drug delivery into the tumor, suggesting that HS-173 may have a therapeutic value as an enhancer or an anticancer drug. Copyright © 2017 Elsevier B.V. All rights reserved.

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

PubMed Central

ROGERS-BROADWAY, KARLY-RAI; CHUDASAMA, DIMPLE; PADOS, GEORGE; TSOLAKIDIS, DIMITRIS; GOUMENOU, ANASTASIA; HALL, MARCIA; KARTERIS, EMMANOUIL

2016-01-01

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. PMID:27211906

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

PubMed Central

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

2013-01-01

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

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

PubMed

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

2012-10-01

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

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

NASA Image and Video Library

2014-05-07

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

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

NASA Image and Video Library

2014-05-07

The March 29, 2014, X-class flare appears as a bright light on the upper right in this image from SDO, showing light in the 304 Angstrom wavelength. This wavelength shows material on the sun in what's called the transition region, where the chromosphere transitions into the upper solar atmosphere, the corona. Some light of the flare is clearly visible, but the flare appears brighter in other images that show hotter temperature material. Credit: NASA/SDO/AIA -- On March 29, 2014 the sun released an X-class flare. It was observed by NASA's Interface Region Imaging Spectrograph, or IRIS; NASA's Solar Dynamics Observatory, or SDO; NASA's Reuven Ramaty High Energy Solar Spectroscopic Imager, or RHESSI; the Japanese Aerospace Exploration Agency's Hinode; and the National Solar Observatory's Dunn Solar Telescope located at Sacramento Peak in New Mexico. To have a record of such an intense flare from so many observatories is unprecedented. Such research can help scientists better understand what catalyst sets off these large explosions on the sun. Perhaps we may even some day be able to predict their onset and forewarn of the radio blackouts solar flares can cause near Earth - blackouts that can interfere with airplane, ship and military communications. Read more: 1.usa.gov/1kMDQbO Join our Google+ Hangout on May 8 at 2:30pm EST: go.nasa.gov/1mwbBEZ NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer.

PubMed

Humphries, Matthew P; Sundara Rajan, Sreekumar; Droop, Alastair; Suleman, Charlotte A B; Carbone, Carmine; Nilsson, Cecilia; Honarpisheh, Hedieh; Cserni, Gabor; Dent, Jo; Fulford, Laura; Jordan, Lee B; Jones, J Louise; Kanthan, Rani; Litwiniuk, Maria; Di Benedetto, Anna; Mottolese, Marcella; Provenzano, Elena; Shousha, Sami; Stephens, Mark; Walker, Rosemary A; Kulka, Janina; Ellis, Ian O; Jeffery, Margaret; Thygesen, Helene H; Cappelletti, Vera; Daidone, Maria G; Hedenfalk, Ingrid A; Fjällskog, Marie-Louise; Melisi, Davide; Stead, Lucy F; Shaaban, Abeer M; Speirs, Valerie

2017-05-15

Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar. Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico Biomarkers were immunohistochemically assessed in 697 MBCs ( n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor. Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed ( P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival. Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required. Clin Cancer Res; 23(10); 2575-83. ©2016 AACR . ©2016 American Association for Cancer Research.

In vitro multifaceted activities of a specific group of novel phosphatidylinositol 3-kinase inhibitors on hotspot mutant PIK3CA.

PubMed

Kong, Dexin; Yamori, Takao; Yamazaki, Kanami; Dan, Shingo

2014-12-01

As accumulating evidences suggest close involvement of phosphatidylinositol 3-kinase (PI3K) in cancer, novel PI3K inhibitors such as ZSTK474, GDC-0941, NVP-BEZ235 and BKM-120 have been developed for cancer therapy. A high frequency of hotspot mutations known as E542K, E545K and H1047R in the PIK3CA gene, which encodes the catalytic subunit of PI3Kα, has been found in various types of human cancers. The hotspot PIK3CA mutations also lead to resistance to therapeutics targeting epidermal growth factor receptor (EGFR), further suggesting that inhibition of hotspot mutant PIK3CA be required for a PI3K inhibitor as anticancer drug candidate. To investigate the activity of the novel PI3K inhibitors on the hotspot mutant PIK3CA, we determined the inhibition against the respective recombinant mutant PI3Kαs by biochemical assay. We further examined the activity at cellular background by determining the effect on phosphorylation of Akt (Ser473), and that on the growth of cancer cells. In addition, apoptosis and autophagy in cells with or without hotspot PIK3CA mutation induced by the four inhibitors were investigated. Our results indicated that each inhibitor exhibit comparable activity on the hotspot mutant PI3Kα to that on the wild type, which was further demonstrated by the cell-based assays. No clear correlation was shown between the PIK3CA genetic status and the sensitivity for apoptosis or autophagy induction. Interestingly, among the 4 PI3K inhibitors, BKM-120 is the weakest in PI3K inhibitory potency, but induces most potent apoptosis, suggesting that BKM-120 might have a unique mode of action. Our result shows that the PI3K inhibitors exhibit potent activity on both hotspot mutant and wild type PI3Kα, suggesting they might be used to treat patients with or without PIK3CA mutation when approved.

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

NASA Image and Video Library

2014-05-07

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

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

Power estimation on functional level for programmable processors

NASA Astrophysics Data System (ADS)

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

2004-05-01

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

Surgical site infection among patients after colorectal cancer surgery.

PubMed

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

2017-02-28

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

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

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

NASA Astrophysics Data System (ADS)

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

2013-12-01

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

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

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

Registration of untypical 3D objects in Polish cadastre - do we need 3D cadastre? / Rejestracja nietypowych obiektów 3D w polskim katastrze - czy istnieje potrzeba wdrożenia katastru 3D?

NASA Astrophysics Data System (ADS)

Marcin, Karabin

2012-11-01

Polish cadastral system consists of two registers: cadastre and land register. The cadastre register data on cadastral objects (land, buildings and premises) in particular location (in a two-dimensional coordinate system) and their attributes as well as data about the owners. The land register contains data concerned ownerships and other rights to the property. Registration of a land parcel without spatial objects located on the surface is not problematic. Registration of buildings and premises in typical cases is not a problem either. The situation becomes more complicated in cases of multiple use of space above the parcel and with more complex construction of the buildings. The paper presents rules concerning the registration of various untypical 3D objects located within the city of Warsaw. The analysis of the data concerning those objects registered in the cadastre and land register is presented in the paper. And this is the next part of the author's detailed research. The aim of this paper is to answer the question if we really need 3D cadastre in Poland. Polski system katastralny składa się z dwóch rejestrów: ewidencji gruntów i budynków (katastru nieruchomosci) oraz ksiąg wieczystych. W ewidencji gruntów i budynków (katastrze nieruchomości) rejestrowane są dane o położeniu (w dwuwymiarowym układzie współrzędnych), atrybuty oraz dane o właścicielach obiektów katastralnych (działek, budynków i lokali), w księgach wieczystych oprócz danych właścicielskich, inne prawa do nieruchomości. Rejestracja działki bez obiektów przestrzennych położonych na jej powierzchni nie stanowi problemu. Także rejestracja budynków i lokali w typowych przypadkach nie stanowi trudności. Sytuacja staje się bardziej skomplikowana w przypadku wielokrotnego użytkowania przestrzeni powyzej lub poniżej powierzchni działki oraz w przypadku budynków o złożonej konstrukcji. W artykule przedstawiono zasady związane z rejestracją nietypowych obiektów 3

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.

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

NASA Astrophysics Data System (ADS)

Brensons, I.; Polukoshko, S.

2013-10-01

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

The Effect of Temperature of Rocks on Microclimatic Conditions in Long Gate Roads and Galleries in Coal Mines

NASA Astrophysics Data System (ADS)

Cygankiewicz, Janusz; Knechtel, Józef

2014-03-01

uwzględniono tylko człon reprezentujący ruch ciepła w skałach. Badane wyrobisko podzielono na odcinki o długości 50 m. Korzystając z metody różnic skończonych dla każdego z odcinków wyznaczono temperaturę ociosu, a następnie temperaturę i strumień entalpii powietrza. W odniesieniu do wyrobisk kamiennych rozważania przeprowadzono dla wariantu z technologicznymi źródłami ciepła oraz bez takich źródeł. Dla chodników węglowych przedstawiono nowy sposób określenia ciepła utleniania węgla, na podstawie wyników badań J. Cygankiewicza (2012a, 2012b). Korzystając z wyników badań J. Drzewieckiego i J. Smołki (1994), uwzględniono wpływ spękań górotworu na przenoszenie ciepła do powietrza w wyrobisku.

Airborne laser-spark for ambient desorption/ionisation.

PubMed

Bierstedt, Andreas; Riedel, Jens

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

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

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

NASA Astrophysics Data System (ADS)

Nowak, Bernard; Życzkowski, Piotr

2013-12-01

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

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

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.

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

Determining Acceptable Explosive Charge Mass Under Different Geological Conditions / Problematyka Wyznaczania Dopuszczalnych Ładunków Mw W Zróżnicowanych Warunkach Geologicznych

NASA Astrophysics Data System (ADS)

Pyra, Józef; Sołtys, Anna; Winzer, Jan; Dworzak, Michał; Biessikirski, Andrzej

2015-09-01

ę ograniczenie całkowitej masy ładunków materiału wybuchowego odpalanego w całej serii oraz mas przypadających na pojedynczy stopień opóźnienia. Podejście takie stanowi w ostateczności jeden ze sposobów minimalizowania niekorzystnego oddziaływania drgań na obiekty budowlane znajdujące się w bezpośrednim otoczeniu kopalni. Metodyka wyznaczania dopuszczalnych mas ładunków MW dla danych warunków górniczo-geologicznych, mimo że w sposób szczegółowy opisana w literaturze fachowej oraz znajdująca szerokie zastosowanie, niekiedy musi zostać zmodyfikowana w zależności od odmiennej struktury masywu skalnego, warunków topograficznych oraz urbanizacyjnych. Zróżnicowana budowa geologiczna złoża oraz struktur geologicznych na których posadowione zostały chronione obiekty budowlane determinuje strukturę częstotliwościową i sposób propagowanych drgań. Istotą w takim przypadkach staje się określenie progu szkodliwości drgań, który pozwoli na bezpieczne prowadzenie robót bez możliwości wystąpienia uszkodzeń na obiektach chronionych zlokalizowanych w otoczeniu kopalń. Dodatkowo jak przedstawiono w artykule może dochodzić do sytuacji gdzie wykonywanie robót strzałowych w jednym miejscu wyrobiska może powodować zupełnie odmienną propagację drgań w różnych kierunkach. Rozpatrując powyższe względy oraz uwzględniając, że często ma się do czynienia z bardzo bliską zabudowę znajdującą się w otoczeniu kopalni niekiedy zachodzi konieczność wyznaczenia dwóch lub więcej równań propagacji drgań parasejsmicznych. Postępowanie takie prowadzi w konsekwencji do wyznaczenia różnych, często odmiennych, dopuszczalnych mas ładunków MW, których detonacja nie powinna powodować niekorzystnego wpływu na obiekty budowlane. Zależności te są zmienne w funkcji miejsca wykonywania robót strzałowych, a tym samym kwestia ta stanowi ważne zagadnienie z punktu widzenia przedsiębiorcy, którego głównym celem jest maksymalizacja

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

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

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

PubMed

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

1997-01-12

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

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