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  1. Overcoming heat shock protein inhibition at critical temperature vital ...

    African Journals Online (AJOL)

    Our results show that the inhibition process is a functional variance of time and genetic variability characterized by differential down-regulation of housekeeping proteins (HKPs) of about 55.7 and 43.5 KD in some cultivars and complete inhibition of a prominent 19.9 KD HKP in Kufri Jyoti at all stressed time. Furthermore, the ...

  2. Combined PDGFR and HDAC Inhibition Overcomes PTEN Disruption in Chordoma

    OpenAIRE

    Lee, Dae-Hee; Zhang, Ying; Kassam, Amin B.; Park, Myung-Jin; Gardner, Paul; Prevedello, Daniel; Henry, Stephanie; Horbinski, Craig; Beumer, Jan H.; Tawbi, Hussein; Williams, Brian J.; Shaffrey, Mark E.; Egorin, Merrill J.; Abounader, Roger; Park, Deric M.

    2015-01-01

    Background The majority of chordomas show activation of the platelet-derived growth factor receptor (PDGFR). Based on in vitro intertumoral variation in response to recombinant PDGF protein and PDGFR inhibition, and variable tumor response to imatinib, we hypothesized that chordomas resistant to PDGFR inhibition may possess downstream activation of the pathway. Methods Molecular profiling was performed on 23 consecutive chordoma primary tissue specimens. Primary cultures established from 20 o...

  3. Combined PDGFR and HDAC Inhibition Overcomes PTEN Disruption in Chordoma.

    Directory of Open Access Journals (Sweden)

    Dae-Hee Lee

    Full Text Available The majority of chordomas show activation of the platelet-derived growth factor receptor (PDGFR. Based on in vitro intertumoral variation in response to recombinant PDGF protein and PDGFR inhibition, and variable tumor response to imatinib, we hypothesized that chordomas resistant to PDGFR inhibition may possess downstream activation of the pathway.Molecular profiling was performed on 23 consecutive chordoma primary tissue specimens. Primary cultures established from 20 of the 23 specimens, and chordoma cell lines, UCH-1 and UCH-2, were used for in vitro experiments.Loss of heterozygosity (LOH at the phosphatase and tensin homolog (PTEN locus was observed in 6 specimens (26%. PTEN disruption statistically correlated with increased Ki-67 proliferation index, an established marker of poor outcome for chordoma. Compared to wild type, PTEN deficient chordomas displayed increased proliferative rate, and responded less favorably to PDGFR inhibition. PTEN gene restoration abrogated this growth advantage. Chordomas are characterized by intratumoral hypoxia and local invasion, and histone deacetylase (HDAC inhibitors are capable of attenuating both hypoxic signaling and cell migration. The combination of PDGFR and HDAC inhibition effectively disrupted growth and invasion of PTEN deficient chordoma cells.Loss of heterozygosity of the PTEN gene seen in a subset of chordomas is associated with aggressive in vitro behavior and strongly correlates with increased Ki-67 proliferative index. Combined inhibition of PDGFR and HDAC attenuates proliferation and invasion in chordoma cells deficient for PTEN.

  4. Combined PDGFR and HDAC Inhibition Overcomes PTEN Disruption in Chordoma.

    Science.gov (United States)

    Lee, Dae-Hee; Zhang, Ying; Kassam, Amin B; Park, Myung-Jin; Gardner, Paul; Prevedello, Daniel; Henry, Stephanie; Horbinski, Craig; Beumer, Jan H; Tawbi, Hussein; Williams, Brian J; Shaffrey, Mark E; Egorin, Merrill J; Abounader, Roger; Park, Deric M

    2015-01-01

    The majority of chordomas show activation of the platelet-derived growth factor receptor (PDGFR). Based on in vitro intertumoral variation in response to recombinant PDGF protein and PDGFR inhibition, and variable tumor response to imatinib, we hypothesized that chordomas resistant to PDGFR inhibition may possess downstream activation of the pathway. Molecular profiling was performed on 23 consecutive chordoma primary tissue specimens. Primary cultures established from 20 of the 23 specimens, and chordoma cell lines, UCH-1 and UCH-2, were used for in vitro experiments. Loss of heterozygosity (LOH) at the phosphatase and tensin homolog (PTEN) locus was observed in 6 specimens (26%). PTEN disruption statistically correlated with increased Ki-67 proliferation index, an established marker of poor outcome for chordoma. Compared to wild type, PTEN deficient chordomas displayed increased proliferative rate, and responded less favorably to PDGFR inhibition. PTEN gene restoration abrogated this growth advantage. Chordomas are characterized by intratumoral hypoxia and local invasion, and histone deacetylase (HDAC) inhibitors are capable of attenuating both hypoxic signaling and cell migration. The combination of PDGFR and HDAC inhibition effectively disrupted growth and invasion of PTEN deficient chordoma cells. Loss of heterozygosity of the PTEN gene seen in a subset of chordomas is associated with aggressive in vitro behavior and strongly correlates with increased Ki-67 proliferative index. Combined inhibition of PDGFR and HDAC attenuates proliferation and invasion in chordoma cells deficient for PTEN.

  5. How Incest Offenders Overcome Internal Inhibitions through the Use of Cognitions and Cognitive Distortions.

    Science.gov (United States)

    Hartley, Carolyn Copps

    1998-01-01

    Explores cognitions incest offenders use to overcome their initial inhibitions against offending and to maintain their offending behavior once begun. Involves in-person interviews with caucasian male incest offenders in treatment. Discusses cognitions identified within the context of new theory on the role of cognitions in sexual offending. (MKA)

  6. Combined Pan-RAF and MEK Inhibition Overcomes Multiple Resistance Mechanisms to Selective RAF Inhibitors.

    Science.gov (United States)

    Whittaker, Steven R; Cowley, Glenn S; Wagner, Steve; Luo, Flora; Root, David E; Garraway, Levi A

    2015-12-01

    RAF and MEK inhibitors are effective in BRAF-mutant melanoma but not in BRAF-mutant colorectal cancer. To gain additional insights into this difference, we performed a genome-scale pooled shRNA enhancer screen in a BRAF-mutant, RAF inhibitor-resistant colorectal cancer cell line exposed to the selective RAF inhibitor PLX4720. We identified multiple genes along the receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) signaling axis that, when suppressed, either genetically or pharmacologically, sensitized cells to the selective RAF inhibitor through sustained inhibition of MAPK signaling. Strikingly, CRAF was a key mediator of resistance that could be overcome by the use of pan-RAF inhibitors in combination with a MEK inhibitor. Furthermore, the combination of pan-RAF and MEK inhibitors displayed strong synergy in melanoma and colorectal cancer cell lines with RAS-activating events such as RTK activation, KRAS mutation, or NF1 loss-of-function mutations. Combinations of selective RAF inhibitors, such as PLX4720 or dabrafenib, with MEK inhibitors did not incur such profound synergy, suggesting that inhibition of CRAF by pan-RAF inhibitors plays a key role in determining cellular response. Importantly, in contrast to the modest activity seen with single-agent treatment, dual pan-RAF and MEK inhibition results in the induction of apoptosis, greatly enhancing efficacy. Notably, combined pan-RAF and MEK inhibition can overcome intrinsic and acquired resistance to single-agent RAF/MEK inhibition, supporting dual pan-RAF and MEK inhibition as a novel therapeutic strategy for BRAF- and KRAS-mutant cancers. ©2015 American Association for Cancer Research.

  7. Micelle System Based on Molecular Economy Principle for Overcoming Multidrug Resistance and Inhibiting Metastasis.

    Science.gov (United States)

    Qi, Yan; Qin, Xianya; Yang, Conglian; Wu, Tingting; Qiao, Qi; Song, Qingle; Zhang, Zhiping

    2018-03-05

    The high mortality of cancer is mainly attributed to multidrug resistance (MDR) and metastasis. A simple micelle system was constructed here to codeliver doxorubicin (DOX), adjudin (ADD), and nitric oxide (NO) for overcoming MDR and inhibiting metastasis. It was devised based on the "molecular economy" principle as the micelle system was easy to fabricate and exhibited high drug loading efficiency, and importantly, each component of the micelles would exert one or more active functions. DOX acted as the main cell killing agent supplemented with ADD, NO, and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). MDR was overcome by synergistic effects of mitochondria inhibition agents, TPGS and ADD. A TPGS-based NO donor can be used as a drug carrier, and it can release NO to enhance drug accumulation and penetration in tumor, resulting in a positive cycle of drug delivery. This DOX-ADD conjugate self-assembly system demonstrated controlled drug release, increased cellular uptake and cytotoxicity, enhanced accumulation at tumor site, and improved in vivo metastasis inhibition of breast cancer. The micelles can fully take advantage of the functions of each component, and they provide a potential strategy for nanomedicine design and clinical cancer treatment.

  8. Inhibition of autophagy overcomes the nanotoxicity elicited by cadmium-based quantum dots.

    Science.gov (United States)

    Fan, Jiajun; Sun, Yun; Wang, Shaofei; Li, Yubin; Zeng, Xian; Cao, Zhonglian; Yang, Ping; Song, Ping; Wang, Ziyu; Xian, Zongshu; Gao, Hongjian; Chen, Qicheng; Cui, Daxiang; Ju, Dianwen

    2016-02-01

    Cadmium-based quantum dots (QDs) have shown their values in disease diagnosis, cellular and molecular tracking, small-animal imaging, and therapeutic drug delivery. However, the potential safety problems of QDs, mainly due to their nanotoxicities by unclear mechanisms, have greatly limited its applications. To reverse this situation, we investigated the underlying biological mechanisms of the toxicity of Quantum Dots CdTe/CdS 655 (QDs 655) in this work. QDs 655 was found to elicit nanotoxicity in vitro and in vivo. During the process, autophagy was activated, which was characterized by three main stages of autophagic flux including formation of autophagosomes, lysosomes fused with autophagosomes, and degradation of autophagosomes by lysosomes. Furthermore, the autophagic cell death was demonstrated in vitro under QDs 655 treatment while inhibition of autophagy by pharmacological inhibitors or genetic approaches could attenuate the toxicity induced by QDs 655 in vitro and in vivo. These results indicated that autophagic flux and autophagic cell death were triggered by QDs 655, which elucidated the critical role of autophagy in QDs 655 induced toxicity. Our data may suggest the approach to overcome the toxicity of QDs and other nanoparticles by autophagy inhibition. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. RITA plus 3-MA overcomes chemoresistance of head and neck cancer cells via dual inhibition of autophagy and antioxidant systems

    Directory of Open Access Journals (Sweden)

    Daiha Shin

    2017-10-01

    Condensed abstract: This study revealed a novel RITA resistant mechanism associated with the sustained induction of autophagy, p62 overexpression, and Keap1-Nrf2 antioxidant system activation. The combined treatment of RITA with the autophagy inhibitor 3-methyladenine overcomes RITA resistance via dual inhibition of autophagy and antioxidant systems in vitro and in vivo.

  10. By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma.

    Science.gov (United States)

    Li, Sainan; Dai, Weiqi; Mo, Wenhui; Li, Jingjing; Feng, Jiao; Wu, Liwei; Liu, Tong; Yu, Qiang; Xu, Shizan; Wang, Wenwen; Lu, Xiya; Zhang, Qinghui; Chen, Kan; Xia, Yujing; Lu, Jie; Zhou, Yingqun; Fan, Xiaoming; Xu, Ling; Guo, Chuanyong

    2017-12-15

    Hepatocellular carcinoma (HCC) is one of the few cancers with a continuous increase in incidence and mortality. Drug resistance is a major problem in the treatment of HCC. In this study, two sorafenib-resistant HCC cell lines and a nude mouse subcutaneously tumor model were used to explore the possible mechanisms leading to sorafenib resistance, and to investigate whether aspirin could increase the sensitivity of hepatoma cells to sorafenib. The combination of aspirin and sorafenib resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. High glycolysis and PFKFB3 overexpression occupied a dominant position in sorafenib resistance, and can be targeted and overcome by aspirin. Aspirin plus sorafenib induced apoptosis in tumors without inducing weight loss, hepatotoxicity or inflammation. Our results suggest that aspirin overcomes sorafenib resistance and their combination may be an effective treatment approach for HCC. © 2017 UICC.

  11. Nelfinavir augments proteasome inhibition by bortezomib in myeloma cells and overcomes bortezomib and carfilzomib resistance

    International Nuclear Information System (INIS)

    Kraus, M; Bader, J; Overkleeft, H; Driessen, C

    2013-01-01

    HIV protease inhibitors (HIV-PI) are oral drugs for HIV treatment. HIV-PI have antitumor activity via induction of ER-stress, inhibition of phospho-AKT (p-AKT) and the proteasome, suggesting antimyeloma activity. We characterize the effects of all approved HIV-PI on myeloma cells. HIV-PI were compared regarding cytotoxicity, proteasome activity, ER-stress induction and AKT phosphorylation using myeloma cells in vitro. Nelfinavir is the HIV-PI with highest cytotoxic activity against primary myeloma cells and with an IC 50 near therapeutic drug blood levels (8–14 μM), irrespective of bortezomib sensitivity. Only nelfinavir inhibited intracellular proteasome activity in situ at drug concentrations <40 μℳ. Ritonavir, saquinavir and lopinavir inhibited p-AKT comparable to nelfinavir, and showed similar synergistic cytotoxicity with bortezomib against bortezomib-sensitive cells. Nelfinavir had superior synergistic activity with bortezomib/carfilzomib in particular against bortezomib/carfilzomib-resistant myeloma cells. It inhibited not only the proteasomal β1/β5 active sites, similar to bortezomib/carfilzomib, but in addition the β2 proteasome activity not targeted by bortezomib/carfilzomib. Additional inhibition of β2 proteasome activity is known to sensitize cells for bortezomib and carfilzomib. Nelfinavir has unique proteasome inhibiting activity in particular on the bortezomib/carfilzomib-insensitive tryptic (β2) proteasome activity in intact myeloma cells, and is active against bortezomib/carfilzomib-resistant myeloma cells in vitro

  12. miR33 inhibition overcomes deleterious effects of diabetes mellitus on atherosclerosis plaque regression in mice.

    Science.gov (United States)

    Distel, Emilie; Barrett, Tessa J; Chung, Kellie; Girgis, Natasha M; Parathath, Saj; Essau, Christine C; Murphy, Andrew J; Moore, Kathryn J; Fisher, Edward A

    2014-10-10

    Diabetes mellitus increases cardiovascular disease risk in humans and remains elevated despite cholesterol-lowering therapy with statins. Consistent with this, in mouse models, diabetes mellitus impairs atherosclerosis plaque regression after aggressive cholesterol lowering. MicroRNA 33 (miR33) is a key negative regulator of the reverse cholesterol transport factors, ATP-binding cassette transporter A1 and high-density lipoprotein, which suggested that its inhibition may overcome this impairment. To assess the effects of miR33 inhibition on atherosclerosis regression in diabetic mice. Reversa mice, which are deficient in the low-density lipoprotein receptor and in which hypercholesterolemia is reversed by conditional inactivation of the microsomal triglyceride transfer protein gene, were placed on an atherogenic diet for 16 weeks, then either made diabetic by streptozotocin injection or kept normoglycemic. Lipid-lowering was induced by microsomal triglyceride transfer protein gene inactivation, and mice were treated with anti-miR33 or control oligonucleotides. Although regression was impaired in diabetic mice treated with control oligonucleotides, anti-miR33 treatment decreased plaque macrophage content and inflammatory gene expression in these mice. The decreased macrophage content in anti-miR33 treated diabetic mice was associated with a blunting of hyperglycemia-induced monocytosis and reduced monocyte recruitment to the plaque, which was traced to an inhibition of the proliferation of bone marrow monocyte precursors associated with the upregulation of their Abca1. miR33 inhibition overcomes deleterious effects of diabetes mellitus in atherosclerosis regression in mice, which suggests a therapeutic strategy in diabetic patients, who remain at elevated cardiovascular disease risk, despite plasma cholesterol lowering. © 2014 American Heart Association, Inc.

  13. Combined MEK and ERK inhibition overcomes therapy-mediated pathway reactivation in RAS mutant tumors.

    Science.gov (United States)

    Merchant, Mark; Moffat, John; Schaefer, Gabriele; Chan, Jocelyn; Wang, Xi; Orr, Christine; Cheng, Jason; Hunsaker, Thomas; Shao, Lily; Wang, Stephanie J; Wagle, Marie-Claire; Lin, Eva; Haverty, Peter M; Shahidi-Latham, Sheerin; Ngu, Hai; Solon, Margaret; Eastham-Anderson, Jeffrey; Koeppen, Hartmut; Huang, Shih-Min A; Schwarz, Jacob; Belvin, Marcia; Kirouac, Daniel; Junttila, Melissa R

    2017-01-01

    Mitogen-activated protein kinase (MAPK) pathway dysregulation is implicated in >30% of all cancers, rationalizing the development of RAF, MEK and ERK inhibitors. While BRAF and MEK inhibitors improve BRAF mutant melanoma patient outcomes, these inhibitors had limited success in other MAPK dysregulated tumors, with insufficient pathway suppression and likely pathway reactivation. In this study we show that inhibition of either MEK or ERK alone only transiently inhibits the MAPK pathway due to feedback reactivation. Simultaneous targeting of both MEK and ERK nodes results in deeper and more durable suppression of MAPK signaling that is not achievable with any dose of single agent, in tumors where feedback reactivation occurs. Strikingly, combined MEK and ERK inhibition is synergistic in RAS mutant models but only additive in BRAF mutant models where the RAF complex is dissociated from RAS and thus feedback productivity is disabled. We discovered that pathway reactivation in RAS mutant models occurs at the level of CRAF with combination treatment resulting in a markedly more active pool of CRAF. However, distinct from single node targeting, combining MEK and ERK inhibitor treatment effectively blocks the downstream signaling as assessed by transcriptional signatures and phospho-p90RSK. Importantly, these data reveal that MAPK pathway inhibitors whose activity is attenuated due to feedback reactivation can be rescued with sufficient inhibition by using a combination of MEK and ERK inhibitors. The MEK and ERK combination significantly suppresses MAPK pathway output and tumor growth in vivo to a greater extent than the maximum tolerated doses of single agents, and results in improved anti-tumor activity in multiple xenografts as well as in two Kras mutant genetically engineered mouse (GEM) models. Collectively, these data demonstrate that combined MEK and ERK inhibition is functionally unique, yielding greater than additive anti-tumor effects and elucidates a highly

  14. PP2A inhibition overcomes acquired resistance to HER2 targeted therapy.

    Science.gov (United States)

    McDermott, Martina Sj; Browne, Brigid C; Conlon, Neil T; O'Brien, Neil A; Slamon, Dennis J; Henry, Michael; Meleady, Paula; Clynes, Martin; Dowling, Paul; Crown, John; O'Donovan, Norma

    2014-06-24

    HER2 targeted therapies including trastuzumab and more recently lapatinib have significantly improved the prognosis for HER2 positive breast cancer patients. However, resistance to these agents is a significant clinical problem. Although several mechanisms have been proposed for resistance to trastuzumab, the mechanisms of lapatinib resistance remain largely unknown. In this study we generated new models of acquired resistance to HER2 targeted therapy and investigated mechanisms of resistance using phospho-proteomic profiling. Long-term continuous exposure of SKBR3 cells to low dose lapatinib established a cell line, SKBR3-L, which is resistant to both lapatinib and trastuzumab. Phospho-proteomic profiling and immunoblotting revealed significant alterations in phospho-proteins involved in key signaling pathways and molecular events. In particular, phosphorylation of eukaryotic elongation factor 2 (eEF2), which inactivates eEF2, was significantly decreased in SKBR3-L cells compared to the parental SKBR3 cells. SKBR3-L cells exhibited significantly increased activity of protein phosphatase 2A (PP2A), a phosphatase that dephosphorylates eEF2. SKBR3-L cells showed increased sensitivity to PP2A inhibition, with okadaic acid, compared to SKBR3 cells. PP2A inhibition significantly enhanced response to lapatinib in both the SKBR3 and SKBR3-L cells. Furthermore, treatment of SKBR3 parental cells with the PP2A activator, FTY720, decreased sensitivity to lapatinib. The alteration in eEF2 phosphorylation, PP2A activity and sensitivity to okadaic acid were also observed in a second HER2 positive cell line model of acquired lapatinib resistance, HCC1954-L. Our data suggests that decreased eEF2 phosphorylation, mediated by increased PP2A activity, contributes to resistance to HER2 inhibition and may provide novel targets for therapeutic intervention in HER2 positive breast cancer which is resistant to HER2 targeted therapies.

  15. Inhibiting autophagy overcomes docetaxel resistance in castration-resistant prostate cancer cells.

    Science.gov (United States)

    Wang, Quan; He, Wei-Yang; Zeng, Yi-Zhou; Hossain, Arman; Gou, Xin

    2018-02-19

    This study investigates the docetaxel-resistant mechanism and explores the effect of tea polyphenols (TP) on autophagy and its related mechanism in human castration-resistant prostate cancer (CRPC) cell lines PC3 and DU145. Immunofluorescence assay and annexin V-FITC/PI double staining flow cytometry were used to analyze the apoptosis and autophagy of PC3 and DU145 cells. The expression of autophagy-related proteins was detected by western bolt. Docetaxel could induce autophagy and apoptosis, together with the expression increase in p-JNK, p-Bcl-2 and Beclin1. The level of autophagy was remarkably decreased, but apoptosis was increased after combining with TP. In addition, the expression of p-mTOR was increased after combining with TP. Docetaxel induces protective autophagy in CRPC cells by JNK pathway activation and then Bcl-2 phosphorylation and Beclin1 dissociation. TP activates mTOR pathway, which ultimately inhibits docetaxel-induced autophagy and improves therapeutic efficacy of docetaxel in CRPC cells.

  16. Inhibition of YAP function overcomes BRAF inhibitor resistance in melanoma cancer stem cells

    Science.gov (United States)

    Fisher, Matthew L.; Grun, Daniel; Adhikary, Gautam; Xu, Wen; Eckert, Richard L.

    2017-01-01

    Treating BRAF inhibitor-resistant melanoma is an important therapeutic goal. Thus, it is important to identify and target mechanisms of resistance to improve therapy. The YAP1 and TAZ proteins of the Hippo signaling pathway are important drivers of cancer cell survival, and are BRAF inhibitor resistant factors in melanoma. We examine the role of YAP1/TAZ in melanoma cancer stem cells (MCS cells). We demonstrate that YAP1, TAZ and TEAD (TEA domain transcription factor) levels are elevated in BRAF inhibitor resistant MCS cells and enhance cell survival, spheroid formation, matrigel invasion and tumor formation. Moreover, increased YAP1, TAZ and TEAD are associated with sustained ERK1/2 activity that is not suppressed by BRAF inhibitor. Xenograft studies show that treating BRAF inhibitor-resistant tumors with verteporfin, an agent that interferes with YAP1 function, reduces YAP1/TAZ level, restores BRAF inhibitor suppression of ERK1/2 signaling and reduces tumor growth. Verteporfin is highly effective as concentrations of verteporfin that do not impact tumor formation restore BRAF inhibitor suppression of tumor formation, suggesting that co-treatment with agents that inhibit YAP1 and BRAF(V600E) may be a viable therapy for cancer stem cell-derived BRAF inhibitor-resistant melanoma. PMID:29299145

  17. Improved PCR performance using template DNA from formalin-fixed and paraffin-embedded tissues by overcoming PCR inhibition.

    Directory of Open Access Journals (Sweden)

    Dimo Dietrich

    Full Text Available Formalin-fixed and paraffin-embedded (FFPE tissues represent a valuable source for biomarker studies and clinical routine diagnostics. However, they suffer from degradation of nucleic acids due to the fixation process. Since genetic and epigenetic studies usually require PCR amplification, this degradation hampers its use significantly, impairing PCR robustness or necessitating short amplicons. In routine laboratory medicine a highly robust PCR performance is mandatory for the clinical utility of genetic and epigenetic biomarkers. Therefore, methods to improve PCR performance using DNA from FFPE tissue are highly desired and of wider interest. The effect of template DNA derived from FFPE tissues on PCR performance was investigated by means of qPCR and conventional PCR using PCR fragments of different sizes. DNA fragmentation was analyzed via agarose gel electrophoresis. This study showed that poor PCR amplification was partly caused by inhibition of the DNA polymerase by fragmented DNA from FFPE tissue and not only due to the absence of intact template molecules of sufficient integrity. This PCR inhibition was successfully minimized by increasing the polymerase concentration, dNTP concentration and PCR elongation time thereby allowing for the robust amplification of larger amplicons. This was shown for genomic template DNA as well as for bisulfite-converted template DNA required for DNA methylation analyses. In conclusion, PCR using DNA from FFPE tissue suffers from inhibition which can be alleviated by adaptation of the PCR conditions, therefore allowing for a significant improvement of PCR performance with regard to variability and the generation of larger amplicons. The presented solutions to overcome this PCR inhibition are of tremendous value for clinical chemistry and laboratory medicine.

  18. Strategies for improving production performance of probiotic Pediococcus acidilactici viable cell by overcoming lactic acid inhibition.

    Science.gov (United States)

    Othman, Majdiah; Ariff, Arbakariya B; Wasoh, Helmi; Kapri, Mohd Rizal; Halim, Murni

    2017-11-27

    Lactic acid bacteria are industrially important microorganisms recognized for fermentative ability mostly in their probiotic benefits as well as lactic acid production for various applications. Fermentation conditions such as concentration of initial glucose in the culture, concentration of lactic acid accumulated in the culture, types of pH control strategy, types of aeration mode and different agitation speed had influenced the cultivation performance of batch fermentation of Pediococcus acidilactici. The maximum viable cell concentration obtained in constant fed-batch fermentation at a feeding rate of 0.015 L/h was 6.1 times higher with 1.6 times reduction in lactic acid accumulation compared to batch fermentation. Anion exchange resin, IRA 67 was found to have the highest selectivity towards lactic acid compared to other components studied. Fed-batch fermentation of P. acidilactici coupled with lactic acid removal system using IRA 67 resin showed 55.5 and 9.1 times of improvement in maximum viable cell concentration compared to fermentation without resin for batch and fed-batch mode respectively. The improvement of the P. acidilactici growth in the constant fed-batch fermentation indicated the use of minimal and simple process control equipment is an effective approach for reducing by-product inhibition. Further improvement in the cultivation performance of P. acidilactici in fed-bath fermentation with in situ addition of anion-exchange resin significantly helped to enhance the growth of P. acidilactici by reducing the inhibitory effect of lactic acid and thus increasing probiotic production.

  19. Inhibition of c-Myc overcomes cytotoxic drug resistance in acute myeloid leukemia cells by promoting differentiation.

    Directory of Open Access Journals (Sweden)

    Xiao-Na Pan

    Full Text Available Nowadays, drug resistance still represents a major obstacle to successful acute myeloid leukemia (AML treatment and the underlying mechanism is not fully elucidated. Here, we found that high expression of c-Myc was one of the cytogenetic characteristics in the drug-resistant leukemic cells. c-Myc over-expression in leukemic cells induced resistance to chemotherapeutic drugs, enhanced colony formation capacity and inhibited cell differentiation induced by all-trans retinoic acid (ATRA. Meanwhile, inhibition of c-Myc by shRNA or specific c-Myc inhibitor 10058-F4 rescued the sensitivity to cytotoxic drugs, restrained the colony formation ability and promoted differentiation. RT-PCR and western blotting analysis showed that down-regulation of C/EBPβ contributed to the poor differentiation state of leukemic cells induced by c-Myc over-expression. Importantly, over-expression of C/EBPβ could reverse c-Myc induced drug resistance. In primary AML cells, the c-Myc expression was negatively correlated with C/EBPβ. 10058-F4, displayed anti-proliferative activity and increased cellular differentiation with up-regulation of C/EBPβ in primary AML cells. Thus, our study indicated that c-Myc could be a novel target to overcome drug resistance, providing a new approach in AML therapy.

  20. Inhibition of β-Catenin to Overcome Endocrine Resistance in Tamoxifen-Resistant Breast Cancer Cell Line.

    Science.gov (United States)

    Won, Hye Sung; Lee, Kyung Mee; Oh, Ju Eon; Nam, Eun Mi; Lee, Kyoung Eun

    2016-01-01

    The β-catenin signaling is important in cell growth and differentiation and is frequently dysregulated in various cancers. The most well-known mechanism of endocrine resistance is cross-talk between the estrogen receptor (ER) and other growth factor signaling, such as phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway. In the present study, we investigated whether β-catenin could be a potential target to overcome endocrine resistance in breast cancer. We established tamoxifen-resistant (TamR) cell line via long-term exposure of MCF-7 breast cancer cells to gradually increasing concentrations of tamoxifen. The levels of protein expression and mRNA transcripts were determined using western blot analysis and real-time quantitative PCR. The transcriptional activity of β-catenin was measured using luciferase activity assay. TamR cells showed a mesenchymal phenotype, and exhibited a relatively decreased expression of ER and increased expression of human epidermal growth factor receptor 2 and the epidermal growth factor receptor. We confirmed that the expression and transcriptional activity of β-catenin were increased in TamR cells compared with control cells. The expression and transcriptional activity of β-catenin were inhibited by β-catenin small-molecule inhibitor, ICG-001 or β-catenin siRNA. The viability of TamR cells, which showed no change after treatment with tamoxifen, was reduced by ICG-001 or β-catenin siRNA. The combination of ICG-001 and mTOR inhibitor, rapamycin, yielded an additive effect on the inhibition of viability in TamR cells. These results suggest that β-catenin plays a role in tamoxifen-resistant breast cancer, and the inhibition of β-catenin may be a potential target in tamoxifen-resistant breast cancer.

  1. Inhibition of β-Catenin to Overcome Endocrine Resistance in Tamoxifen-Resistant Breast Cancer Cell Line.

    Directory of Open Access Journals (Sweden)

    Hye Sung Won

    Full Text Available The β-catenin signaling is important in cell growth and differentiation and is frequently dysregulated in various cancers. The most well-known mechanism of endocrine resistance is cross-talk between the estrogen receptor (ER and other growth factor signaling, such as phosphatidylinositol-3-kinase (PI3K/Akt and the mammalian target of rapamycin (mTOR signaling pathway. In the present study, we investigated whether β-catenin could be a potential target to overcome endocrine resistance in breast cancer.We established tamoxifen-resistant (TamR cell line via long-term exposure of MCF-7 breast cancer cells to gradually increasing concentrations of tamoxifen. The levels of protein expression and mRNA transcripts were determined using western blot analysis and real-time quantitative PCR. The transcriptional activity of β-catenin was measured using luciferase activity assay.TamR cells showed a mesenchymal phenotype, and exhibited a relatively decreased expression of ER and increased expression of human epidermal growth factor receptor 2 and the epidermal growth factor receptor. We confirmed that the expression and transcriptional activity of β-catenin were increased in TamR cells compared with control cells. The expression and transcriptional activity of β-catenin were inhibited by β-catenin small-molecule inhibitor, ICG-001 or β-catenin siRNA. The viability of TamR cells, which showed no change after treatment with tamoxifen, was reduced by ICG-001 or β-catenin siRNA. The combination of ICG-001 and mTOR inhibitor, rapamycin, yielded an additive effect on the inhibition of viability in TamR cells.These results suggest that β-catenin plays a role in tamoxifen-resistant breast cancer, and the inhibition of β-catenin may be a potential target in tamoxifen-resistant breast cancer.

  2. Intracellular expression of IRF9 Stat fusion protein overcomes the defective Jak-Stat signaling and inhibits HCV RNA replication

    Directory of Open Access Journals (Sweden)

    Balart Luis A

    2010-10-01

    Full Text Available Abstract Interferon alpha (IFN-α binds to a cell surface receptor that activates the Jak-Stat signaling pathway. A critical component of this pathway is the translocation of interferon stimulated gene factor 3 (a complex of three proteins Stat1, Stat2 and IRF9 to the nucleus to activate antiviral genes. A stable sub-genomic replicon cell line resistant to IFN-α was developed in which the nuclear translocation of Stat1 and Stat2 proteins was prevented due to the lack of phosphorylation; whereas the nuclear translocation of IRF9 protein was not affected. In this study, we sought to overcome defective Jak-Stat signaling and to induce an antiviral state in the IFN-α resistant replicon cell line by developing a chimera IRF9 protein fused with the trans activating domain (TAD of either a Stat1 (IRF9-S1C or Stat2 (IRF9-S2C protein. We show here that intracellular expression of fusion proteins using the plasmid constructs of either IRF9-S1C or IRF9-S2C, in the IFN-α resistant cells, resulted in an increase in Interferon Stimulated Response Element (ISRE luciferase promoter activity and significantly induced HLA-1 surface expression. Moreover, we show that transient transfection of IRF9-S1C or IRF9-S2C plasmid constructs into IFN-α resistant replicon cells containing sub-genomic HCV1b and HCV2a viruses resulted in an inhibition of viral replication and viral protein expression independent of IFN-α treatment. The results of this study indicate that the recombinant fusion proteins of IRF9-S1C, IRF9-S2C alone, or in combination, have potent antiviral properties against the HCV in an IFN-α resistant cell line with a defective Jak-Stat signaling.

  3. Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism-Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer.

    Science.gov (United States)

    Tanimoto, Azusa; Takeuchi, Shinji; Arai, Sachiko; Fukuda, Koji; Yamada, Tadaaki; Roca, Xavier; Ong, S Tiong; Yano, Seiji

    2017-06-15

    Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non-small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism. Experimental Design: We used EGFR -mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of osimertinib in vitro and in vivo Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR. Results: EGFR -mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to osimertinib in a polymorphism dosage-dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion-positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with osimertinib could regress tumors in EGFR -mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR -T790M mutations. Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treating EGFR -mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139-49. ©2016 AACR . ©2016 American Association for Cancer Research.

  4. A new real-time PCR method to overcome significant quantitative inaccuracy due to slight amplification inhibition

    Directory of Open Access Journals (Sweden)

    Stocchi Laura

    2008-07-01

    Full Text Available Abstract Background Real-time PCR analysis is a sensitive DNA quantification technique that has recently gained considerable attention in biotechnology, microbiology and molecular diagnostics. Although, the cycle-threshold (Ct method is the present "gold standard", it is far from being a standard assay. Uniform reaction efficiency among samples is the most important assumption of this method. Nevertheless, some authors have reported that it may not be correct and a slight PCR efficiency decrease of about 4% could result in an error of up to 400% using the Ct method. This reaction efficiency decrease may be caused by inhibiting agents used during nucleic acid extraction or copurified from the biological sample. We propose a new method (Cy0 that does not require the assumption of equal reaction efficiency between unknowns and standard curve. Results The Cy0 method is based on the fit of Richards' equation to real-time PCR data by nonlinear regression in order to obtain the best fit estimators of reaction parameters. Subsequently, these parameters were used to calculate the Cy0 value that minimizes the dependence of its value on PCR kinetic. The Ct, second derivative (Cp, sigmoidal curve fitting method (SCF and Cy0 methods were compared using two criteria: precision and accuracy. Our results demonstrated that, in optimal amplification conditions, these four methods are equally precise and accurate. However, when PCR efficiency was slightly decreased, diluting amplification mix quantity or adding a biological inhibitor such as IgG, the SCF, Ct and Cp methods were markedly impaired while the Cy0 method gave significantly more accurate and precise results. Conclusion Our results demonstrate that Cy0 represents a significant improvement over the standard methods for obtaining a reliable and precise nucleic acid quantification even in sub-optimal amplification conditions overcoming the underestimation caused by the presence of some PCR inhibitors.

  5. Combined ALK and MDM2 inhibition increases antitumor activity and overcomes resistance in humanALKmutant neuroblastoma cell lines and xenograft models.

    Science.gov (United States)

    Wang, Hui Qin; Halilovic, Ensar; Li, Xiaoyan; Liang, Jinsheng; Cao, Yichen; Rakiec, Daniel P; Ruddy, David A; Jeay, Sebastien; Wuerthner, Jens U; Timple, Noelito; Kasibhatla, Shailaja; Li, Nanxin; Williams, Juliet A; Sellers, William R; Huang, Alan; Li, Fang

    2017-04-20

    The efficacy of ALK inhibitors in patients with ALK -mutant neuroblastoma is limited, highlighting the need to improve their effectiveness in these patients. To this end, we sought to develop a combination strategy to enhance the antitumor activity of ALK inhibitor monotherapy in human neuroblastoma cell lines and xenograft models expressing activated ALK. Herein, we report that combined inhibition of ALK and MDM2 induced a complementary set of anti-proliferative and pro-apoptotic proteins. Consequently, this combination treatment synergistically inhibited proliferation of TP53 wild-type neuroblastoma cells harboring ALK amplification or mutations in vitro, and resulted in complete and durable responses in neuroblastoma xenografts derived from these cells. We further demonstrate that concurrent inhibition of MDM2 and ALK was able to overcome ceritinib resistance conferred by MYCN upregulation in vitro and in vivo. Together, combined inhibition of ALK and MDM2 may provide an effective treatment for TP53 wild-type neuroblastoma with ALK aberrations.

  6. BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe.

    Science.gov (United States)

    Bai, Zhaoshi; Gao, Meiqi; Zhang, Huijuan; Guan, Qi; Xu, Jingwen; Li, Yao; Qi, Huan; Li, Zhengqiang; Zuo, Daiying; Zhang, Weige; Wu, Yingliang

    2017-08-28

    Multidrug resistance (MDR) interferes with the efficiency of chemotherapy. Therefore, developing novel anti-cancer agents that can overcome MDR is necessary. Here, we screened a series of colchicine binding site inhibitors (CBSIs) and found that 5-(3, 4, 5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl) imidazol (BZML) displayed potent cytotoxic activity against both A549 and A549/Taxol cells. We further explored the underlying mechanisms and found that BZML caused mitosis phase arrest by inhibiting tubulin polymerization in A549 and A549/Taxol cells. Importantly, BZML was a poor substrate for P-glycoprotein (P-gp) and inhibited P-gp function by decreasing P-gp expression at the protein and mRNA levels. Cell morphology changes and the expression of cycle- or apoptosis-related proteins indicated that BZML mainly drove A549/Taxol cells to die by mitotic catastrophe (MC), a p53-independent apoptotic-like cell death, whereas induced A549 cells to die by apoptosis. Taken together, our data suggest that BZML is a novel colchicine binding site inhibitor and overcomes MDR in A549/Taxol cells by inhibiting P-gp function and inducing MC. Our study also offers a new strategy to solve the problem of apoptosis-resistance. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Overcoming challenges

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    Full Text Available ... section Back to section menu It's Only Natural Planning ahead Breastfeeding and baby basics Making breastfeeding work ... It's Only Natural Overcoming challenges It's Only Natural Planning ahead Addressing breastfeeding myths Overcoming challenges Common questions ...

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

    Directory of Open Access Journals (Sweden)

    Minyong Kang

    2017-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Zhen-Wei Zou

    2018-06-01

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

  10. Small-molecule inhibition of HIV pre-mRNA splicing as a novel antiretroviral therapy to overcome drug resistance.

    Directory of Open Access Journals (Sweden)

    Nadia Bakkour

    2007-10-01

    Full Text Available The development of multidrug-resistant viruses compromises antiretroviral therapy efficacy and limits therapeutic options. Therefore, it is an ongoing task to identify new targets for antiretroviral therapy and to develop new drugs. Here, we show that an indole derivative (IDC16 that interferes with exonic splicing enhancer activity of the SR protein splicing factor SF2/ASF suppresses the production of key viral proteins, thereby compromising subsequent synthesis of full-length HIV-1 pre-mRNA and assembly of infectious particles. IDC16 inhibits replication of macrophage- and T cell-tropic laboratory strains, clinical isolates, and strains with high-level resistance to inhibitors of viral protease and reverse transcriptase. Importantly, drug treatment of primary blood cells did not alter splicing profiles of endogenous genes involved in cell cycle transition and apoptosis. Thus, human splicing factors represent novel and promising drug targets for the development of antiretroviral therapies, particularly for the inhibition of multidrug-resistant viruses.

  11. Nitric Oxide Synthase Gene Transfer Overcomes the Inhibition of Wound Healing by Sulfur Mustard in a Human Keratinocyte In Vitro Model

    Science.gov (United States)

    Ishida, Hiroshi; Ray, Radharaman; Amnuaysirikul, Jack; Ishida, Keiko; Ray, Prabhati

    2012-01-01

    Sulfur mustard (SM) is a chemical warfare agent that causes extensive skin injury. Previously we reported that SM exposure resulted in suppression of inducible nitric oxide synthase (iNOS) expression to inhibit the healing of scratch wounds in a cultured normal human epidermal keratinocyte (NHEK) model. Based on this finding, the present study was to use adenovirus-mediated gene transfer of iNOS to restore the nitric oxide (NO) supply depleted by exposure to SM and to evaluate the effect of NO on wound healing inhibited by SM in NHEKs. The effect of the iNOS gene transfer on iNOS protein expression and NO generation were monitored by Western blot and flow cytometry, respectively. Wound healing with or without the iNOS gene transfer after SM exposure was assessed by light and confocal microscopy. The iNOS gene transfer via adenovirus resulted in overexpression of the iNOS and an increase in NO production regardless of SM exposure in the NHEK model. The gene transfer was also effective in overcoming the inhibition of wound healing due to SM exposure leading to the promotion of wound closure. The findings in this study suggest that the iNOS gene transfer is a promising therapeutic strategy for SM-induced skin injury. PMID:23762631

  12. The targeted inhibition of mitochondrial Hsp90 overcomes the apoptosis resistance conferred by Bcl-2 in Hep3B cells via necroptosis

    International Nuclear Information System (INIS)

    Yan, Chunlan; Oh, Joon Seok; Yoo, Seung Hee; Lee, Jee Suk; Yoon, Young Geol; Oh, Yoo Jin; Jang, Min Seok; Lee, Sang Yeob; Yang, Jun; Lee, Sang Hwa; Kim, Hye Young; Yoo, Young Hyun

    2013-01-01

    Previous studies have reported that a Gamitrinib variant containing triphenylphosphonium (G-TPP) binds to mitochondrial Hsp90 and rapidly inhibits its activity, thus inducing the apoptotic pathway in the cells. Accordingly, G-TPP shows a potential as a promising drug for the treatment of cancer. A cell can die from different types of cell death such as apoptosis, necrosis, necroptosis, and autophagic cell death. In this study, we further investigated the mechanisms and modes of cell death in the G-TPP-treated Hep3B and U937 cell lines. We discovered that G-TPP kills the U937 cells through the apoptotic pathway and the overexpression of Bcl-2 significantly inhibits U937 cell death to G-TPP. We further discovered that G-TPP kills the Hep3B cells by activating necroptosis in combination with the partial activation of caspase-dependent apoptosis. Importantly, G-TPP overcomes the apoptosis resistance conferred by Bcl-2 in Hep3B cells via necroptosis. We also observed that G-TPP induces compensatory autophagy in the Hep3B cell line. We further found that whereas there is a Bcl-2-Beclin 1 interaction in response to G-TPP, silencing the beclin 1 gene failed to block LC3-II accumulation in the Hep3B cells, indicating that G-TPP triggers Beclin 1-independent protective autophagy in Hep3B cells. Taken together, these data reveal that G-TPP induces cell death through a combination of death pathways, including necroptosis and apoptosis, and overcomes the apoptosis resistance conferred by Bcl-2 in Hep3B cells via necroptosis. These findings are important for the therapeutic exploitation of necroptosis as an alternative cell death program to bypass the resistance to apoptosis. Highlights: ► G-TPP binds to mitochondrial Hsp90. ► G-TPP induces apoptosis in U937 human leukemia cancer cells. ► G-TPP induces combination of death pathways in Hep3B cell. ► G-TPP overcomes the resistance conferred by Bcl-2 in Hep3B cells via necroptosis. ► G-TPP triggers Beclin 1-independent

  13. Overcoming challenges

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    Full Text Available ... into your life Breastfeeding in daily life: At home and in public Laws that support breastfeeding 10 ... and jobs View all pages in this section Home It's Only Natural Overcoming challenges It's Only Natural ...

  14. Overcoming challenges

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    Full Text Available ... and mission Leadership Programs and activities In your community Funding opportunities Internships and jobs View all pages ... breastfeeding myths Breastfeeding myths in the African-American community Incredible facts about babies, breastmilk, and breastfeeding Overcoming ...

  15. Overcoming challenges

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    Full Text Available ... receive Breastfeeding email updates Enter email Submit Overcoming challenges Breastfeeding has a long list of benefits for ... getting started. Hear how moms overcame common nursing challenges and stayed committed to breastfeeding. Common questions about ...

  16. Overcoming challenges

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    Full Text Available ... Disease and Stroke HIV and AIDS Mental Health Pain Pregnancy Reproductive Health Sexual Health Sexually Transmitted Infections ... breastfeeding Overcoming challenges Common questions about breastfeeding and pain Breastfeeding checklist: How to get a good latch ...

  17. Overcoming challenges

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    Full Text Available ... Contact Us Blog Popular topics Vision and mission Leadership Programs and activities In your community Funding opportunities Internships and jobs View all pages in this section Home It's Only Natural Overcoming challenges It's Only Natural Planning ahead Addressing breastfeeding myths ...

  18. Overcoming resistance to mitochondrial apoptosis by BZML-induced mitotic catastrophe is enhanced by inhibition of autophagy in A549/Taxol cells.

    Science.gov (United States)

    Bai, Zhaoshi; Gao, Meiqi; Xu, Xiaobo; Zhang, Huijuan; Xu, Jingwen; Guan, Qi; Wang, Qing; Du, Jianan; Li, Zhengqiang; Zuo, Daiying; Zhang, Weige; Wu, Yingliang

    2018-03-01

    Our previous in vitro study showed that 5-(3, 4, 5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl) imidazol (BZML) is a novel colchicine binding site inhibitor with potent anti-cancer activity against apoptosis resistance in A549/Taxol cells through mitotic catastrophe (MC). However, the mechanisms underlying apoptosis resistance in A549/Taxol cells remain unknown. To clarify these mechanisms, in the present study, we investigated the molecular mechanisms of apoptosis and autophagy, which are closely associated with MC in BZML-treated A549 and A549/Taxol cells. Xenograft NSCLC models induced by A549 and A549/Taxol cells were used to evaluate the efficacy of BZML in vivo. The activation of the mitochondrial apoptotic pathway was assessed using JC-1 staining, Annexin V-FITC/PI double-staining, a caspase-9 fluorescence metric assay kit and western blot. The different functional forms of autophagy were distinguished by determining the impact of autophagy inhibition on drug sensitivity. Our data showed that BZML also exhibited desirable anti-cancer activity against drug-resistant NSCLC in vivo. Moreover, BZML caused ROS generation and MMP loss followed by the release of cytochrome c from mitochondria to cytosol in both A549 and A549/Taxol cells. However, the ROS-mediated apoptotic pathway involving the mitochondria that is induced by BZML was only fully activated in A549 cells but not in A549/Taxol cells. Importantly, we found that autophagy acted as a non-protective type of autophagy during BZML-induced apoptosis in A549 cells, whereas it acted as a type of cytoprotective autophagy against BZML-induced MC in A549/Taxol cells. Our data suggest that the anti-apoptosis property of A549/Taxol cells originates from a defect in activation of the mitochondrial apoptotic pathway, and autophagy inhibitors can potentiate BZML-induced MC to overcome resistance to mitochondrial apoptosis. © 2018 John Wiley & Sons Ltd.

  19. Inhibition of p70S6K1 Activation by Pdcd4 Overcomes the Resistance to an IGF-1R/IR Inhibitor in Colon Carcinoma Cells.

    Science.gov (United States)

    Zhang, Yan; Wang, Qing; Chen, Li; Yang, Hsin-Sheng

    2015-03-01

    Agents targeting insulin-like growth factor 1 receptor (IGF-1R) are being actively examined in clinical trials. Although there has been some initial success of single-agent targeting IGF-1R, attempts in later studies failed because of resistance. This study aimed to understand the effects of programmed cell death 4 (Pdcd4) on the chemosensitivity of the IGF-1R inhibitor OSI-906 in colorectal cancer cells and the mechanism underlying this impact. Using OSI-906-resistant and -sensitive colorectal cancer cells, we found that the Pdcd4 level directly correlates with cell chemosensitivity to OSI-906. In addition, tumors derived from Pdcd4 knockdown cells resist the growth inhibitory effect of OSI-906 in a colorectal cancer xenograft mouse model. Moreover, Pdcd4 enhances the antiproliferative effect of OSI-906 in resistant cells through suppression of p70S6K1 activation. Knockdown of p70S6K1, but not p70S6K2, significantly increases the chemosensitivity of OSI-906 in cultured colorectal cancer cells. Furthermore, the combination of OSI-906 and PF-4708671, a p70S6K1 inhibitor, efficiently suppresses the growth of OSI-906-resistant colon tumor cells in vitro and in vivo. Taken together, activation of p70S6K1 that is inhibited by Pdcd4 is essential for resistance to the IGF-1R inhibitor in colon tumor cells, and the combinational treatment of OSI-906 and PF-4708671 results in enhanced antiproliferation effects in colorectal cancer cells in vitro and in vivo, providing a novel venue to overcome the resistance to the IGF-1R inhibitor in treating colorectal cancer. ©2015 American Association for Cancer Research.

  20. Overcoming prejudice.

    Science.gov (United States)

    Da Silva, J M; Correa, J; Terto, V

    1998-02-01

    People of African descent comprise a large proportion of Brazil's population. While racism exists in the country, it is commonly denied. Most Afro-Brazilians live in poor areas, with poor health care services, sanitation, schools, and transport. Since HIV is linked to poverty, Afro-Brazilians are more affected by HIV than is the overall population. Although Afro-Brazilians contribute to Brazil's culture, they do not benefit from that contribution. Recognizing this considerable social problem, Project Araye was created in 1996 to address issues of race and HIV. Building upon religious and cultural traditions, the project is staffed by Afro-Brazilians who are knowledgeable in both health issues and Afro-Brazilian culture. Project Araye supports a wide range of diverse community leaders in linking sexual health and HIV with other health concerns which affect Afro-Brazilians such as sickle-cell anemia, diabetes, and leprosy. One important challenge has been overcoming the target population's denial of HIV and encouraging Afro-Brazilians to accept that HIV also affects them. Community leaders include religious leaders, rap musicians, artists, and other people respected by various communities. Activities include visits to samba dance schools, Umbanda and Candomble temples, and street youth groups to provide HIV-related information.

  1. AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance

    Energy Technology Data Exchange (ETDEWEB)

    O’Hare, Thomas; Shakespeare, William C.; Zhu, Xiaotian; Eide, Christopher A.; Rivera, Victor M.; Wang, Frank; Adrian, Lauren T.; Zhou, Tianjun; Huang, Wei-Sheng; Xu, Qihong; Metcalf, III, Chester A.; Tyner, Jeffrey W.; Loriaux, Marc M.; Corbin, Amie S.; Wardwell, Scott; Ning, Yaoyu; Keats, Jeffrey A.; Wang, Yihan; Sundaramoorthi, Raji; Thomas, Mathew; Zhou, Dong; Snodgrass, Joseph; Commodore, Lois; Sawyer, Tomi K.; Dalgarno, David C.; Deininger, Michael W.N.; Druker, Brian J.; Clackson, Tim; (OHSU- Cancer Instit.); (ARIAD)

    2010-09-07

    Inhibition of BCR-ABL by imatinib induces durable responses in many patients with chronic myeloid leukemia (CML), but resistance attributable to kinase domain mutations can lead to relapse and a switch to second-line therapy with nilotinib or dasatinib. Despite three approved therapeutic options, the cross-resistant BCR-ABL{sup T315I} mutation and compound mutants selected on sequential inhibitor therapy remain major clinical challenges. We report design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants. AP24534 inhibited all tested BCR-ABL mutants in cellular and biochemical assays, suppressed BCR-ABL{sup T315I}-driven tumor growth in mice, and completely abrogated resistance in cell-based mutagenesis screens. Our work supports clinical evaluation of AP24534 as a pan-BCR-ABL inhibitor for treatment of CML.

  2. Prasugrel but not high dose clopidogrel overcomes the lansoprazole neutralizing effect of P2Y12 inhibition: Results of the randomized DOSAPI study.

    Science.gov (United States)

    Collet, Jean-Philippe; Hulot, Jean-Sébastien; Abtan, Jérémie; Anzaha, Ghalia; Kerneis, Mathieu; Silvain, Johanne; Cayla, Guillaume; O'Connor, Stephen A; Barthélémy, Olivier; Beygui, Farzin; Galier, Sophie; Brugier, Delphine; Stanek, Eric J; Charland, Scott L; Gallois, Vanessa; Montalescot, Gilles

    2014-09-01

    The potential negative metabolic interaction between proton pump inhibitors and clopidogrel is an unsolved issue. We hypothesized that doubling the clopidogrel maintenance dose (150 mg) would be less effective than switching to prasugrel 10 mg maintenance dose (MD) to overcome this negative interaction. In a randomized study with a factorial design, 82 stable coronary artery disease patients treated with 75 mg clopidogrel MD and aspirin were assigned to receive in a double blind fashion lansoprazole (30 mg/day) or placebo and to receive in an open fashion 150 mg clopidogrel MD or 10 mg prasugrel MD. The primary endpoint was the relative change in residual platelet reactivity over the 14-day study period [(RPA14day-RPAbaseline)/RPAbaseline]. The effect of doubling the clopidogrel MD on relative change in RPA was neutralized by lansoprazole (-53.6±48.4% versus +0.8±53.7% without and with lansoprazole, respectively, p = 0.02) whereas 10 mg of prasugrel MD dramatically reduced RPA irrespective of lansoprazole co-administration (-81.8 %±24.8% vs. -72.9%±32.9% without and with lansoprazole, respectively, p = NS). Lansoprazole exposure was the only parameter with a significant interaction with RPA among subgroups. The higher platelet inhibitory effect obtained by doubling the clopidogrel MD was totally neutralized by the co-administration of lansoprazole. This drug interaction was not observed with prasugrel 10 mg.

  3. Doxorubicin Conjugated to Immunomodulatory Anticancer Lactoferrin Displays Improved Cytotoxicity Overcoming Prostate Cancer Chemo resistance and Inhibits Tumour Development in TRAMP Mice.

    Science.gov (United States)

    Shankaranarayanan, Jayanth Suryanarayanan; Kanwar, Jagat R; Al-Juhaishi, Afrah Jalil Abd; Kanwar, Rupinder K

    2016-08-31

    Advanced, metastatic, castration resistant and chemo-resistant prostate cancer has triggered change in the drug development landscape against prostate cancer. Bovine lactoferrin (bLf) is currently attracting attention in clinics for its anti-cancer properties and proven safety profile. bLf internalises into cancer cells via receptor mediated endocytosis, boosts immunity and complements chemotherapy. We employed bLf as an excellent functional carrier protein for delivering doxorubicin (Dox) into DU145 cells, CD44+/EpCAM+ double positive enriched DU145 3D prostaspheres and drug resistant ADR1000-DU145 cells, thus circumventing Dox efflux, to overcome chemo-resistance. Successful bLf-Dox conjugation with iron free or iron saturated bLf forms did not affect the integrity and functionality of bLf and Dox. bLf-Dox internalised into DU145 cells within 6 h, enhanced nuclear Dox retention up to 24 h, and proved significantly effective (p resistance.

  4. Inhibition of ABCB1 (MDR1 expression by an siRNA nanoparticulate delivery system to overcome drug resistance in osteosarcoma.

    Directory of Open Access Journals (Sweden)

    Michiro Susa

    2010-05-01

    Full Text Available The use of neo-adjuvant chemotherapy in treating osteosarcoma has improved patients' average 5 year survival rate from 20% to 70% in the past 30 years. However, for patients who progress after chemotherapy, its effectiveness diminishes due to the emergence of multi-drug resistance (MDR after prolonged therapy.In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure resulting from MDR, we designed and evaluated a novel drug delivery system for MDR1 siRNA delivery. Novel biocompatible, lipid-modified dextran-based polymeric nanoparticles were used as the platform for MDR1 siRNA delivery; and the efficacy of combination therapy with this system was evaluated. In this study, multi-drug resistant osteosarcoma cell lines (KHOS(R2 and U-2OS(R2 were treated with the MDR1 siRNA nanocarriers and MDR1 protein (P-gp expression, drug retention, and immunofluoresence were analyzed. Combination therapy of the MDR1 siRNA loaded nanocarriers with increasing concentrations of doxorubicin was also analyzed. We observed that MDR1 siRNA loaded dextran nanoparticles efficiently suppresses P-gp expression in the drug resistant osteosarcoma cell lines. The results also demonstrated that this approach may be capable of reversing drug resistance by increasing the amount of drug accumulation in MDR cell lines.Lipid-modified dextran-based polymeric nanoparticles are a promising platform for siRNA delivery. Nanocarriers loaded with MDR1 siRNA are a potential treatment strategy for reversing MDR in osteosarcoma.

  5. Chk1/2 inhibition overcomes the cisplatin resistance of head and neck cancer cells secondary to the loss of functional p53

    Science.gov (United States)

    Gadhikar, Mayur A.; Sciuto, Maria Rita; Alves, Marcus Vinicius Ortega; Pickering, Curtis R.; Osman, Abdullah A.; Neskey, David M.; Zhao, Mei; Fitzgerald, Alison L.; Myers, Jeffrey N.; Frederick, Mitchell J

    2014-01-01

    Despite the use of multimodality therapy employing cisplatin to treat patients with advanced stage head and neck squamous cell carcinoma (HNSCC), there is an unacceptably high rate of treatment failure. TP53 is the most commonly mutated gene in HNSCC, and the impact of p53 mutation on response to cisplatin treatment is poorly understood. Here we show unambiguously that wild type TP53 (wtp53) is associated with sensitivity of HNSCC cells to cisplatin treatment while mutation or loss of TP53 is associated with cisplatin resistance. We also demonstrate that senescence is the major cellular response to cisplatin in wtp53 HNSCC cells and that cisplatin resistance in p53 null or mutant TP53 cells is due to their lack of senescence. Given the dependence on Chk1/2 kinases to mediate the DNA damage response in p53 deficient cells, there is potential to exploit this to therapeutic advantage through targeted inhibition of the Chk1/2 kinases. Treatment of p53 deficient HNSCC cells with the Chk inhibitor AZD7762 sensitizes them to cisplatin through induction of mitotic cell death. This is the first report demonstrating the ability of a Chk kinase inhibitor to sensitize TP53-deficient HNSCC to cisplatin in a synthetic lethal manner, which has significance given the frequency of TP53 mutations in this disease and because cisplatin has become part of standard therapy for aggressive HNSCC tumors. These pre-clinical data provide evidence that a personalized approach to the treatment of HNSCC based on Chk inhibition in p53 mutant tumors may be feasible. PMID:23839309

  6. [Overexpression of Keap1 inhibits the cell proliferation and metastasis and overcomes the drug resistance in human lung cancer A549 cells].

    Science.gov (United States)

    Weng, X; Yan, Y Y; Tong, Y H; Fan, Y; Zeng, J M; Wang, L L; Lin, N M

    2016-06-23

    To investigate the effect of Keap1-Nrf2 pathway on cell proliferation, metastasis and drug resistance of human lung cancer A549 cell line. A549-Keap1 cell line, constantly expressing wild type Keap1, was established by lentiviral transfection. Real-time RT-PCR and western blot were used to determine the expression of Nrf2 and its target gene in A549 cells. Sulforhodamine B (SRB) assay, flow cytometry, colony formation assay, transwell assay, and cell wound-healing assay were performed to explore the effect of wild type Keap1 expression on the proliferation, invasion, migration and drug resistance of A549 cells. Over-expressed Keap1 decreased the expression of Nrf2 protein and the mRNA level of its downstream target genes and inhibited the ability of cell proliferation and clone formation of A549 cells. Keap1 overexpression induced G0/G1 phase arrest. The percentage of A549-Keap1 cells in G0/G1 phase was significantly higher than that of A549-GFP cells (80.2±5.9)% vs. (67.1±0.9%)(PA549-Keap1 cells (156.33±17.37), the number of invasive A549-GFP cells was significantly higher (306.67±22.19) in a high power field. Keap1 overexpression significantly enhanced the sensitivity of A549 cells to carboplatin and gemcitabine (PA549-Keap1 and A549-GFP cells were (52.1±3.3) μmol/L and (107.8±12.9) μmol/L, respectively. The IC50s of gemcitabine in A549-Keap1 and A549-GFP cells were (6.8±1.2) μmol/L and (9.9±0.5) μmol/L, respectively. Keap1 overexpression significantly inhibits the expression of Nrf2 and its downstream target genes, suppresses tumor cell proliferation and metastasis, and enhances the sensitivity of A549 cells to anticancer drugs.

  7. JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias.

    Science.gov (United States)

    Delgado-Martin, C; Meyer, L K; Huang, B J; Shimano, K A; Zinter, M S; Nguyen, J V; Smith, G A; Taunton, J; Winter, S S; Roderick, J R; Kelliher, M A; Horton, T M; Wood, B L; Teachey, D T; Hermiston, M L

    2017-12-01

    While outcomes for children with T-cell acute lymphoblastic leukemia (T-ALL) have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid (GC) resistance is more common than resistance to other chemotherapies at relapse. In addition, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor (ETP) T-ALLs as well as in a subset of non-ETP T-ALLs. GC-resistant non-ETP T-ALLs are characterized by strong induction of JAK/STAT signaling in response to interleukin-7 (IL7) stimulation. Removing IL7 or inhibiting JAK/STAT signaling sensitizes these T-ALLs, and a subset of ETP T-ALLs, to GCs. The combination of the GC dexamethasone and the JAK1/2 inhibitor ruxolitinib altered the balance between pro- and anti-apoptotic factors in samples with IL7-dependent GC resistance, but not in samples with IL7-independent GC resistance. Together, these data suggest that the addition of ruxolitinib or other inhibitors of IL7 receptor/JAK/STAT signaling may enhance the efficacy of GCs in a biologically defined subset of T-ALL.

  8. Bitter Melon (Momordica charantia) Extract Inhibits Tumorigenicity and Overcomes Cisplatin-Resistance in Ovarian Cancer Cells Through Targeting AMPK Signaling Cascade.

    Science.gov (United States)

    Yung, Mingo M H; Ross, Fiona A; Hardie, D Grahame; Leung, Thomas H Y; Zhan, Jinbiao; Ngan, Hextan Y S; Chan, David W

    2016-09-01

    Objective Acquired chemoresistance is a major obstacle in the clinical management of ovarian cancer. Therefore, searching for alternative therapeutic modalities is urgently needed. Bitter melon (Momordica charantia) is a traditional dietary fruit, but its extract also shows potential medicinal values in human diabetes and cancers. Here, we sought to investigate the extract of bitter melon (BME) in antitumorigenic and cisplatin-induced cytotoxicity in ovarian cancer cells. Three varieties of bitter melon were used to prepare the BME. Ovarian cancer cell lines, human immortalized epithelial ovarian cells (HOSEs), and nude mice were used to evaluate the cell cytotoxicity, cisplatin resistance, and tumor inhibitory effect of BME. The molecular mechanism of BME was examined by Western blotting. Cotreatment with BME and cisplatin markedly attenuated tumor growth in vitro and in vivo in a mouse xenograft model, whereas there was no observable toxicity in HOSEs or in nude mice in vivo Interestingly, the antitumorigenic effects of BME varied with different varieties of bitter melon, suggesting that the amount of antitumorigenic substances may vary. Studies of the molecular mechanism demonstrated that BME activates AMP-activated protein kinase (AMPK) in an AMP-independent but CaMKK (Ca(2+)/calmodulin-dependent protein kinase)-dependent manner, exerting anticancer effects through activation of AMPK and suppression of the mTOR/p70S6K and/or the AKT/ERK/FOXM1 (Forkhead Box M1) signaling cascade. BME functions as a natural AMPK activator in the inhibition of ovarian cancer cell growth and might be useful as a supplement to improve the efficacy of cisplatin-based chemotherapy in ovarian cancer. © The Author(s) 2015.

  9. Overcoming job stress

    Science.gov (United States)

    ... medlineplus.gov/ency/patientinstructions/000884.htm Overcoming job stress To use the sharing features on this page, ... stay healthy and feel better. Causes of Job Stress Although the cause of job stress is different ...

  10. Overcoming: a concept analysis.

    Science.gov (United States)

    Brush, Barbara L; Kirk, Keri; Gultekin, Laura; Baiardi, Janet M

    2011-01-01

    Nurses often work with individuals and populations striving to improve or maintain the quality of their lives. Many, struggling from complex health and social problems, are challenged to surmount barriers to achieve this goal. The growing number of homeless families in the United States represent one such cohort. To develop an operational definition of overcoming and explicate its meaning, attributes, and characteristics as it relates to homeless families. Using the concept analysis method described by Walker and Avant, along with an extensive literature review, and sample cases pertaining to family homelessness, we delineated the defining attributes, antecedents, consequences, and empirical referents of the concept, overcoming. The results of this concept analysis, particularly the relationship of overcoming to family homelessness, provide guidance for further conceptualization and empirical testing, as well as for clinical practice. © 2011 Wiley Periodicals, Inc.

  11. Overcoming Faculty Resistance.

    Science.gov (United States)

    Gaff, Jerry G.

    1978-01-01

    Teaching improvement and institutional renewal efforts often face pessimism about change, if not suspicion and resistance, but faculty teams can overcome these problems through an action-oriented but low-profile "organic" approach. The need for personal invitations by colleagues is shown. (Author/LBH)

  12. Overcoming Fossilized English.

    Science.gov (United States)

    Graham, Janet G.

    Causes of language fossilization and ways to overcome it are considered. Fossilization is the relatively permanent incorporation of incorrect linguistic forms into a person's second language competence. The discussion is focused on fossilization of incorrect syntactical rules, based on experiences with learners of English as a second language at…

  13. How Artists Overcome Creative Blocks.

    Science.gov (United States)

    Hirst, Barbara

    1992-01-01

    Six practicing artists were interviewed about how they overcome creative blocks. Their responses indicated that feelings of self-doubt, fear, and depression accompany blocks but that relaxing and working on new directions and playing ideas off a supportive person helped to overcome such blocks. (DB)

  14. A copper chelate induces apoptosis and overcomes multidrug resistance in T-cell acute lymphoblastic leukemia through redox imbalance and inhibition of EGFR/PI3K/Akt expression.

    Science.gov (United States)

    Banerjee, Kaushik; Das, Satyajit; Sarkar, Avijit; Chatterjee, Mitali; Biswas, Jaydip; Choudhuri, Soumitra Kumar

    2016-12-01

    T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive form of cancer and the therapeutic outcome for T-ALL patients remains poor. Thus innovative therapeutic strategies with less toxic drugs are of immense need. Moreover combinational effect of redox imbalance with modulated EGFR/PI3K/Akt axis in T-ALL is still elusive. To explore more effective drugs we developed and characterized 5-SMAG, Cu-5-SMAG and Cu-OBPHA complexes by different spectroscopic methods and revealed that introduction of methoxy group and copper to the previously synthesized Schiff base ligand, NG can efficiently target leukemia by sparing the normal cells and overcomes MDR in T-ALL through induction of caspase3 dependent apoptosis as assessed by MTT, Cell-cycle, Annexin-V and caspase3 activation assay. However the ligand 5-SMAG fails to exert significant cytotoxicity. Moreover introduction of copper does not increase the efficacy of the drug molecule as Cu-OBPHA fails to exert significant effect compared to Cu-5-SMAG. Moreover Cu-5-SMAG targets T-ALL cells more than Cu-OBPHA because Cu-5-SMAG generates greater extent of redox imbalance compared to Cu-OBPHA and when this redox imbalance is reduced by application of NAC and PEG-Catalase, highest abrogation of apoptosis is observed following Cu-5-SMAG treatment In addition, Cu-5-SMAG significantly down-regulates the activation and expression of EGFR1, Akt and PI3K in drug-resistant T-ALL cells. Furthermore Cu-5-SMAG significantly increases the life-span of doxorubicin resistant and sensitive Ehrlich ascites carcinoma bearing Swiss albino mice without inducing any significant systemic toxicity compared to 5-SMAG and Cu-OBPHA treatment. Therefore typical architect of Cu-5-SMAG made it a promising new anti-leukemic agent irrespective of the MDR phenotype. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  15. Overcoming Multidrug Resistance in Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Karobi Moitra

    2015-01-01

    Full Text Available The principle mechanism of protection of stem cells is through the expression of ATP-binding cassette (ABC transporters. These transporters serve as the guardians of the stem cell population in the body. Unfortunately these very same ABC efflux pumps afford protection to cancer stem cells in tumors, shielding them from the adverse effects of chemotherapy. A number of strategies to circumvent the function of these transporters in cancer stem cells are currently under investigation. These strategies include the development of competitive and allosteric modulators, nanoparticle mediated delivery of inhibitors, targeted transcriptional regulation of ABC transporters, miRNA mediated inhibition, and targeting of signaling pathways that modulate ABC transporters. The role of ABC transporters in cancer stem cells will be explored in this paper and strategies aimed at overcoming drug resistance caused by these particular transporters will also be discussed.

  16. ABCG2 inhibition as a therapeutic approach for overcoming ...

    Indian Academy of Sciences (India)

    2016-02-16

    Feb 16, 2016 ... Breast cancer resistance protein (BCRP, ABCP or MXR)/ATP-binding cassette subfamily G member 2 (ABCG2) was characterized as a multidrug resistance efflux transporter in 1998. ABCG2 physiologically acts as a part of a self- defence mechanism for the organism; it enhances eliminating of toxic ...

  17. Overcoming heat shock protein inhibition at critical temperature vital ...

    African Journals Online (AJOL)

    Bengyella

    2012-06-12

    Jun 12, 2012 ... (http://cpri.ernet.in/varieties.html). The prevailing temperature increase during potato farming seasons is more threatening when heat-stress coincides with senescence stages of growth. Heat stress proteins (HSPs) expression and related cognates are geared to protect cells or organisms from harmful stress.

  18. ABCG2 inhibition as a therapeutic approach for overcoming ...

    Indian Academy of Sciences (India)

    Breast cancer resistance protein (BCRP, ABCP or MXR) / ATP-binding cassette subfamily G member 2 (ABCG2) was characterized as a multidrug resistance efflux transporter in 1998. ABCG2 physiologically acts as a part of a self-defense mechanism for the organism; it enhances eliminating of toxic xenobiotic substances ...

  19. ABCG2 Inhibition as a Therapeutic Approach for Overcoming ...

    Indian Academy of Sciences (India)

    Breast cancer resistance protein (BCRP, ABCP or MXR) / ATP-binding cassette subfamily G member 2 (ABCG2) was characterized as a multidrug resistance efflux transporter in 1998. ABCG2 physiologically acts as a part of a self-defense mechanism for the organism; it enhances eliminating of toxic xenobiotic substances ...

  20. Family skills for overcoming adversity

    Directory of Open Access Journals (Sweden)

    Mónica Patricia Ardila Hernández

    2013-12-01

    Full Text Available This section draws on research four families in displacement in Tunja Boyacá step of this research is to present the problem of displacement from another different look that has embargoed regarding this topic. Critical reflection was raised from resilient approach Parsons theory in order to understand families immersed in this conflict as change agents capable of adapting to a new system and overcome adversity. Within this scheme is used to obtain qualitative research of the following categories : adaptation to the new social context risk factors present in families and protective factors.

  1. Overcoming "the Valley of Death".

    Science.gov (United States)

    McIntyre, Robin A

    2014-01-01

    On a global level there are major challenges arising from climate change, resource use and changing age demographics. These issues have created a global marketplace for novel innovative products and solutions which can help to combat and overcome these challenges which have created significant commercial opportunities for companies, particularly for small and medium size enterprises or SMEs. Companies most likely to take advantage of these opportunities will be those which can innovate in a timely manner. Innovation significantly contributes to higher productivity and economic growth, and is core to a company's competitiveness within often challenging marketplaces. However, many factors can stifle innovation. Companies can struggle to identify finance for early-stage development, the returns can be difficult to predict, and the innovation 'landscape' is often complex and unclear. This brief review describes some of the main issues with commercialising innovative ideas and provides guidance with respect to the often complicated funding landscape both on a National and European level.

  2. Antibiotic stewardship: overcoming implementation barriers.

    Science.gov (United States)

    Bal, Abhijit M; Gould, Ian M

    2011-08-01

    Antimicrobial stewardship is now recognized as a formal strategy for curbing the upward trend in antibiotic resistance. Literature on antimicrobial stewardship has focused on areas of strategic importance and operational delivery. A number of barriers have been recognized in the implementation of successful programs. These include lack of physician participation, lack of diagnostic facility, absence of formal mechanism of data collection, variation between countries, and lack of cooperative strategies. In this review, we suggest strategies to overcome these barriers. In the last few years, it has been recognized that an executive program is necessary for successful implementation of strategies to control the growing antibiotic resistance. Efforts have been made at higher levels of government through organizations such as the European Centre for Disease Prevention and Control. The need for community healthcare involvement has also been recognized. At a local level, strategies to promote cooperation between various committees (e.g. infection control and antimicrobial management teams) have been proposed and adopting antibiotic care bundles as part of patient safety and healthcare is being explored. We suggest that executive level planning, local cooperation, sustained education, emphasis on de-escalation, and use of care bundles could stem the tide of growing resistance.

  3. Overcoming Incommensurability Through Intercultural Dialogue

    Directory of Open Access Journals (Sweden)

    Paul Healy

    2013-07-01

    Full Text Available Is universalism necessarily ethnocentric? Are there inevitably incommensurable differences between diverse cultures and traditions? While these questions may appear highly theoretical at first sight, they inevitably have significant practical consequences as witnessed by the prominent contemporary discourse about a “clash of civilizations”, on the one hand, and by the challenges confronting multiculturalism, on the other. As these debates attest, the foregoing questions are truly significant because, if there is no genuine possibility of overcoming incommensurability by finding and building on common ground, the future looks bleak for intercultural relations, both internally and externally. In revisiting pivotal issues at the heart of the Winchean rationality debates, and in drawing some selective comparisons with the Kuhnian incommensurability debates which came to the fore at a similar time, this paper draws on core hermeneutic insights to vindicate the tenability of a dialogical approach to the problem of intercultural communication and understanding. This approach, it is contended, can give difference its due to the extent of stimulating a genuine and productive process of intercultural learning, in a manner that truly navigates between the Scylla of an ethnocentric universalism and the Charybdis of a self-sealing relativism, and thereby not only averts a destructive cultural stand-off or clash, but facilitates the emergence of a well-grounded “fusion of horizons”.

  4. Heating plant overcomes coal crisis

    International Nuclear Information System (INIS)

    Sobinkovic, B.

    2006-01-01

    At the last moment Kosice managed to overcome the threat of a more than 30-percent heating price increase. The biggest local heat producer, Teplaren Kosice, is running out of coal supplies. The only alternative would be gas, which is far more expensive. The reason for this situation was a dispute of the heating plant with one of its suppliers, Kimex. Some days ago, the dispute was settled and the heating plant is now expecting the first wagon loads of coal to arrive. These are eagerly awaited, as its supplies will not last for more than a month. It all started with a public tender for a coal supplier. Teplaren Kosice (TEKO) announced the tender for the delivery of 120,000 tons of coal in June. Kimex, one of the traditional and biggest suppliers, was disqualified in the course of the tender. The winners of the tender were Slovenergo, Bratislava and S-Plus Trade, Vranov nad Toplou. TEKO signed contracts with them but a district court in Kosice prohibited the company from purchasing coal from these contractors. Kimex filed a complaint claiming that it was disqualified unlawfully. Based on this the court issued a preliminary ruling prohibiting the purchase of coal from the winners of the tender. The heating plant had to wait for the final verdict. The problem was then solved by the company's new Board of Directors, who were appointed in mid October who managed to sign new contracts with the two winners and Kimex. The new contracts cover the purchase of 150-thousand tons of coal, which is 30,000 more than in the original tender specification. Each company will supply one third. (authors)

  5. Exploiting nanotechnology to overcome tumor drug resistance: Challenges and opportunities.

    Science.gov (United States)

    Kirtane, Ameya R; Kalscheuer, Stephen M; Panyam, Jayanth

    2013-11-01

    Tumor cells develop resistance to chemotherapeutic drugs through multiple mechanisms. Overexpression of efflux transporters is an important source of drug resistance. Efflux transporters such as P-glycoprotein reduce intracellular drug accumulation and compromise drug efficacy. Various nanoparticle-based approaches have been investigated to overcome efflux-mediated resistance. These include the use of formulation excipients that inhibit transporter activity and co-delivery of the anticancer drug with a specific inhibitor of transporter function or expression. However, the effectiveness of nanoparticles can be diminished by poor transport in the tumor tissue. Hence, adjunct therapies that improve the intratumoral distribution of nanoparticles may be vital to the successful application of nanotechnology to overcome tumor drug resistance. This review discusses the mechanisms of tumor drug resistance and highlights the opportunities and challenges in the use of nanoparticles to improve the efficacy of anticancer drugs against resistant tumors. © 2013.

  6. The role of photodynamic therapy in overcoming cancer drug resistance

    Science.gov (United States)

    Spring, Bryan Q.; Rizvi, Imran; Xu, Nan; Hasan, Tayyaba

    2015-01-01

    Many modalities of cancer therapy induce mechanisms of treatment resistance and escape pathways during chronic treatments, including photodynamic therapy (PDT). It is conceivable that resistance induced by one treatment might be overcome by another treatment. Emerging evidence suggests that the unique mechanisms of tumor cell and microenvironment damage produced by PDT could be utilized to overcome cancer drug resistance, to mitigate the compensatory induction of survival pathways and even to re-sensitize resistant cells to standard therapies. Approaches that capture the unique features of PDT, therefore, offer promising factors for increasing the efficacy of a broad range of therapeutic modalities. Here, we highlight key preclinical findings utilizing PDT to overcome classical drug resistance or escape pathways and thus enhance the efficacy of many pharmaceuticals, possibly explaining the clinical observations of the PDT response to otherwise treatment-resistant diseases. With the development of nanotechnology, it is possible that light activation may be used not only to damage and sensitize tumors but also to enable controlled drug release to inhibit escape pathways that may lead to resistance or cell proliferation. PMID:25856800

  7. Overcoming Anarchy in the Advanced Language Class.

    Science.gov (United States)

    Gutierrez, John R.

    1990-01-01

    The coordination, articulation, and implementation of informed teaching techniques and objectives will help to overcome the anarchy and confusion that characterize higher education advanced-level foreign language classes, and will begin to produce a pool of highly competent foreign language speakers and writers. (33 references) (CB)

  8. Overcoming Violence through Local Institutions: A Comparative ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Overcoming Violence through Local Institutions: A Comparative Study of Households and Communities in Colombia. Violent conflicts have lasting effects on social norms, institutions, and governance at the local level. Two conditions must take place for societies to sustain an end to large-scale violence: -the nature of ...

  9. Communication in diabetes management: overcoming the challenges

    African Journals Online (AJOL)

    2011-08-24

    Aug 24, 2011 ... Review Article: Communication in diabetes management: overcoming the challenges. 52. 2012 Volume 17 No 1. JEMDSA ... the importance of recognising good communication as being pivotal to optimum patient .... communication techniques may be termed “soft skills” when compared to the detection and ...

  10. Overcoming Xenophobia: Learning to Accept Differences.

    Science.gov (United States)

    Baker, Judith A.

    1990-01-01

    Quality health education requires that health educators engage in the professional and personal development necessary to overcome xenophobia when working with special populations (obese, elderly, indigent, minorities, etc.). This article describes strategies employed in a university community health education class to help students overcome…

  11. Learning communities and overcoming poverty in Brazil

    Directory of Open Access Journals (Sweden)

    Tatiana Santos Pitanga

    2015-09-01

    Full Text Available Object: Brazil has implemented social programs to meet the Millennium Development Goals of reducing poverty and inequality. Despite the good results still there are ghettos and educational and social inequalities. Moreover Learning Communities are responding to these needs by promoting education based on successful actions scientifically proven of which promote educational change and social inclusion. The aim of this article is to highlight the characteristics of Learning Communities that allow overcoming poverty, and in this perspective, explain the implementation of the Learning Communities in Brazil and how, in this way, it is creating the conditions for effective overcoming give poverty and inequality in this country.Design / methodology: This article is based on documentary analysis of reports of the INCLUD-ED - the project on school education more scientific resources has been funded by the European Union, United Nations / ECLAC, Brazilian public agencies and websites of official institutions that promote Learning Communities in Brazil. Brazilian Institute of Geography and Statistics are also collected.Contributions and results: It highlights successful actions that contribute to overcoming poverty and social exclusion. Such actions are based on dialogic learning, democratic management and the formation of heterogeneous groups. It is observed that in Brazil are carrying out such actions and the ongoing expansion of the project in the country is creating the conditions for effective poverty reduction.Added value: This article reveals specific elements of overcoming poverty through education.

  12. Successful Writing: Five Roadblocks to Overcome

    Science.gov (United States)

    King, Kathleen P.

    2013-01-01

    This article provides essential strategies to be more successful in one of the major roles in academia: writing. Most academics struggle with roadblocks in their writing process. We are forever battling to complete research articles, manuscripts, grant proposals or other documents. The strategies and perspective shared here help overcome several…

  13. Overcoming the Limitations of Learning Objects

    Science.gov (United States)

    Wiley, David; Waters, Sandie; Dawson, Deonne; Lambert, Brent; Barclay, Matthew; Wade, David; Nelson, Laurie

    2004-01-01

    There are a number of issues that face individuals who would use learning objects for instructional purposes. These issues include problems with decontextualization, enabling meaningful reusability, and overcoming biases toward didactic approaches in the use of learning objects. We discuss these problems in some detail, and present a project-based…

  14. Bacterial resistance to silver nanoparticles and how to overcome it.

    Science.gov (United States)

    Panáček, Aleš; Kvítek, Libor; Smékalová, Monika; Večeřová, Renata; Kolář, Milan; Röderová, Magdalena; Dyčka, Filip; Šebela, Marek; Prucek, Robert; Tomanec, Ondřej; Zbořil, Radek

    2018-01-01

    Silver nanoparticles have already been successfully applied in various biomedical and antimicrobial technologies and products used in everyday life. Although bacterial resistance to antibiotics has been extensively discussed in the literature, the possible development of resistance to silver nanoparticles has not been fully explored. We report that the Gram-negative bacteria Escherichia coli 013, Pseudomonas aeruginosa CCM 3955 and E. coli CCM 3954 can develop resistance to silver nanoparticles after repeated exposure. The resistance stems from the production of the adhesive flagellum protein flagellin, which triggers the aggregation of the nanoparticles. This resistance evolves without any genetic changes; only phenotypic change is needed to reduce the nanoparticles' colloidal stability and thus eliminate their antibacterial activity. The resistance mechanism cannot be overcome by additional stabilization of silver nanoparticles using surfactants or polymers. It is, however, strongly suppressed by inhibiting flagellin production with pomegranate rind extract.

  15. Bacterial resistance to silver nanoparticles and how to overcome it

    Science.gov (United States)

    Panáček, Aleš; Kvítek, Libor; Smékalová, Monika; Večeřová, Renata; Kolář, Milan; Röderová, Magdalena; Dyčka, Filip; Šebela, Marek; Prucek, Robert; Tomanec, Ondřej; Zbořil, Radek

    2018-01-01

    Silver nanoparticles have already been successfully applied in various biomedical and antimicrobial technologies and products used in everyday life. Although bacterial resistance to antibiotics has been extensively discussed in the literature, the possible development of resistance to silver nanoparticles has not been fully explored. We report that the Gram-negative bacteria Escherichia coli 013, Pseudomonas aeruginosa CCM 3955 and E. coli CCM 3954 can develop resistance to silver nanoparticles after repeated exposure. The resistance stems from the production of the adhesive flagellum protein flagellin, which triggers the aggregation of the nanoparticles. This resistance evolves without any genetic changes; only phenotypic change is needed to reduce the nanoparticles' colloidal stability and thus eliminate their antibacterial activity. The resistance mechanism cannot be overcome by additional stabilization of silver nanoparticles using surfactants or polymers. It is, however, strongly suppressed by inhibiting flagellin production with pomegranate rind extract.

  16. Vav1-phospholipase C-γ1 (Vav1-PLC-γ1) Pathway Initiated by T Cell Antigen Receptor (TCRγδ) Activation Is Required to Overcome Inhibition by Ubiquitin Ligase Cbl-b during γδT Cell Cytotoxicity*

    Science.gov (United States)

    Yin, Shanshan; Zhang, Jianmin; Mao, Yujia; Hu, Yu; Cui, Lianxian; Kang, Ning; He, Wei

    2013-01-01

    T cell antigen receptor γδ (TCRγδ) and natural killer group 2, member D (NKG2D) are two crucial receptors for γδT cell cytotoxicity. Compelling evidences suggest that γδT cell cytotoxicity is TCRγδ-dependent and can be co-stimulated by NKG2D. However, the molecular mechanism of underlying TCRγδ-dependent activation of γδT cells remains unclear. In this study we demonstrated that TCRγδ but not NKG2D engagement induced lytic granule polarization and promoted γδT cell cytotoxicity. TCRγδ activation alone was sufficient to trigger Vav1-dependent phospholipase C-γ1 signaling, resulting in lytic granule polarization and effective killing, whereas NKG2D engagement alone failed to trigger cytotoxicity-related signaling to overcome the inhibitory effect of Cbl-b; therefore, NKG2D engagement alone could not induce effective killing. However, NKG2D ligation augmented the activation of γδT cell cytotoxicity through the Vav1-phospholipase C-γ1 pathway. Vav1 overexpression or Cbl-b knockdown not only enhanced TCRγδ activation-initiated killing but also enabled NKG2D activation alone to induce γδT cell cytotoxicity. Taken together, our results suggest that the activation of γδT cell cytotoxicity requires a strong activation signal to overcome the inhibitory effect of Cbl-b. Our finding provides new insights into the molecular mechanisms underlying the initiation of γδT cell cytotoxicity and likely implications for optimizing γδT cell-based cancer immunotherapy. PMID:23897818

  17. YOUTH UNEMPLOYMENT: CAUSES AND MEASURES TO OVERCOME

    OpenAIRE

    Milena Velikova

    2016-01-01

    The article examines the main causes of youth unemployment in Bulgaria and possible measures to overcome it, putting emphasis on active policy of the state. Difficulties encountered by young people in finding suitable employment derive primarily from the low level of education, vocational training, insufficient or inaccurate professional orientation and lack of work experience. In this connection it is necessary to create opportunities for young people to receive appropriate training to assis...

  18. Fortification: overcoming technical and practical barriers.

    Science.gov (United States)

    Hurrell, Richard F

    2002-04-01

    The main barriers to successful iron fortification are the following: 1) finding an iron compound that is adequately absorbed but causes no sensory changes to the food vehicle; and 2) overcoming the inhibitory effect on iron absorption of dietary components such as phytic acid, phenolic compounds and calcium. These barriers have been successfully overcome with some food vehicles but not with others. Iron-fortified fish sauce, soy sauce, curry powder, sugar, dried milk, infant formula and cereal based complementary foods have been demonstrated to improve iron status in targeted populations. The reasons for this success include the use of soluble iron such as ferrous sulfate, the addition of ascorbic acid as an absorption enhancer or the use of NaFeEDTA to overcome the negative effect of phytic acid. In contrast, at the present time, it is not possible to guarantee a similar successful fortification of cereal flours or salt. There is considerable doubt that the elemental iron powders currently used to fortify cereal flours are adequately absorbed, and there is an urgent need to investigate their potential for improving iron status. Better absorbed alternative compounds for cereal fortification include encapsulated ferrous sulfate and NaFeEDTA, which, unlike ferrous sulfate, do not provoke fat oxidation of cereals during storage. Encapsulated compounds also offer a possibility to fortify low grade salt without causing off-colors or iodine loss. Finally, a new and useful additional approach to ensuring adequate iron absorption from cereal based complementary foods is the complete degradation of phytic acid with added phytases or by activating native cereal phytases.

  19. How to Overcome Poverty Traps by Education

    OpenAIRE

    Siemers, Lars-Hinrich Rudolf

    2004-01-01

    The thesis addresses the question of how poverty can be overcome by education. The starting point is the following type of poverty trap: poverty forces parents to send their children to work to secure the survival of the household. Due to child labor, children do not attend school and do not form human capital. When these children are adult, the lack of education causes them being as poor as their parents have been. This produces a vicious circle that has to be broken. In an OLG growth mode...

  20. YOUTH UNEMPLOYMENT: CAUSES AND MEASURES TO OVERCOME

    Directory of Open Access Journals (Sweden)

    Milena Velikova

    2016-12-01

    Full Text Available The article examines the main causes of youth unemployment in Bulgaria and possible measures to overcome it, putting emphasis on active policy of the state. Difficulties encountered by young people in finding suitable employment derive primarily from the low level of education, vocational training, insufficient or inaccurate professional orientation and lack of work experience. In this connection it is necessary to create opportunities for young people to receive appropriate training to assist them in finding employment, the provision of post-employment and integration into society.

  1. Overcoming resistance to β-lactam antibiotics.

    Science.gov (United States)

    Worthington, Roberta J; Melander, Christian

    2013-05-03

    β-Lactam antibiotics are one of the most important antibiotic classes but are plagued by problems of resistance, and the development of new β-lactam antibiotics through side-chain modification of existing β-lactam classes is not keeping pace with resistance development. In this JOCSynopsis, we summarize small molecule strategies to overcome resistance to β-lactam antibiotics. These approaches include the development of β-lactamase inhibitors and compounds that interfere with the ability of the bacteria to sense an antibiotic threat and activate their resistance mechanisms.

  2. Overcoming some limitations of imprecise reliability models

    DEFF Research Database (Denmark)

    Kozine, Igor; Krymsky, Victor

    2011-01-01

    The application of imprecise reliability models is often hindered by the rapid growth in imprecision that occurs when many components constitute a system and by the fact that time to failure is bounded from above. The latter results in the necessity to explicitly introduce an upper bound on time...... to failure which is in reality a rather arbitrary value. The practical meaning of the models of this kind is brought to question. We suggest an approach that overcomes the issue of having to impose an upper bound on time to failure and makes the calculated lower and upper reliability measures more precise...

  3. Overcoming Knowledge Gaps in Postmerger Integration

    DEFF Research Database (Denmark)

    Alaranta, Maria Eliisa; Martela, Eero

    2012-01-01

    best facilitate overcoming the gaps in experiential knowledge in these dynamic hybrid organizational situations. We study a case of integration of software-maintenance processes after a megamerger. In the first phase of the integration, the company combined best features of existing knowledge systems......Over 50% of mergers and acquisitions (M&As) fail, mainly because of integration problems. In such integrations, much of the experiential (learning-by-doing) knowledge critical for running the business becomes redundant or is lost. However, we know virtually nothing about what type of mechanisms...... of change, integrating information systems, leadership, joint collaboration, acquiring knowledge externally, and relocating personnel....

  4. Overcome IMF crisis with idea and invention

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yeon Jung

    1998-01-15

    This book introduces the invention as a tool to overcome IMF crisis. These are the titles of the way to create invention and idea : what is idea? everyone can create something, have a confidence, this is patent, replace or change something, invention is not logical, challenge the normal law, throw away stereotype, movement of idea, original imagination, there are a lot of solutions, there is no expert, have a positive thought, why does inventor invent? necessity is invention of mother, three stage of idea and invention and imitation for invention.

  5. Overcoming Challenges in Engineering the Genetic Code.

    Science.gov (United States)

    Lajoie, M J; Söll, D; Church, G M

    2016-02-27

    Withstanding 3.5 billion years of genetic drift, the canonical genetic code remains such a fundamental foundation for the complexity of life that it is highly conserved across all three phylogenetic domains. Genome engineering technologies are now making it possible to rationally change the genetic code, offering resistance to viruses, genetic isolation from horizontal gene transfer, and prevention of environmental escape by genetically modified organisms. We discuss the biochemical, genetic, and technological challenges that must be overcome in order to engineer the genetic code. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Reshaping transport operations to overcome new challenges

    International Nuclear Information System (INIS)

    Harari, F.; Blachet, L.

    2004-01-01

    After more than 30 years of Spent Fuel Nuclear Fuel (SFN) and High Level Waste (HLW) casks shipments to and from the COGEMA reprocessing factories in LA HAGUE, COGEMA LOGISTICS has demonstrated a unique outstanding performance in transportation for the benefit of its international customers and has integrated all feed-back from past successful operations. While maintaining the highest safety and security records, the last 5 years have been a major challenge to overcome the increase in transport throughputs, regulatory requirements, specific customer demands and new environmental approach (both COGEMA-La Hague and COGEMA LOGISTICS have been certified ISO14001 since 2003). Improvements in procedures, equipments, controls, inspection and organization have been undertaken. Additional important logistics means such as cranes, lifting devices, spreaders were put in operations in the dedicated workshop of our road and maritime facilities as well as in our rail terminals. Thus COGEMA LOGISTICS has developed and improved important logistics means in the Cherbourg area for the loading and unloading operations of heavy casks (i.e. whose weight is between 25 and 120 tons) among three modes of freight (road, railway or maritime transportation). In Valognes, which is currently the most important railway terminal in the world for the transfer of nuclear materials, about 1200 transfers of heavy casks were performed in 2003. New transport equipment and assets were integrated successfully to answer the new requirements for the best interest of our customers. This paper will provide information about equipments and management system developed to overcome these challenges

  7. Overcoming maladaptive plasticity through plastic compensation

    Directory of Open Access Journals (Sweden)

    Matthew R.J. MORRIS, Sean M. ROGERS

    2013-08-01

    Full Text Available Most species evolve within fluctuating environments, and have developed adaptations to meet the challenges posed by environmental heterogeneity. One such adaptation is phenotypic plasticity, or the ability of a single genotype to produce multiple environmentally-induced phenotypes. Yet, not all plasticity is adaptive. Despite the renewed interest in adaptive phenotypic plasticity and its consequences for evolution, much less is known about maladaptive plasticity. However, maladaptive plasticity is likely an important driver of phenotypic similarity among populations living in different environments. This paper traces four strategies for overcoming maladaptive plasticity that result in phenotypic similarity, two of which involve genetic changes (standing genetic variation, genetic compensation and two of which do not (standing epigenetic variation, plastic compensation. Plastic compensation is defined as adaptive plasticity overcoming maladaptive plasticity. In particular, plastic compensation may increase the likelihood of genetic compensation by facilitating population persistence. We provide key terms to disentangle these aspects of phenotypic plasticity and introduce examples to reinforce the potential importance of plastic compensation for understanding evolutionary change [Current Zoology 59 (4: 526–536, 2013].

  8. Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer.

    Science.gov (United States)

    Roh, Jong-Lyel; Kim, Eun Hye; Jang, Hye Jin; Park, Jin Young; Shin, Daiha

    2016-10-10

    Inhibition of key molecules related to ferroptosis, cystine/glutamate antiporter and glutathione peroxidase, may induce eradication of chemotherapy/radiotherapy-resistant cancer cells. The present study investigated whether ferroptosis could overcome head and neck cancer (HNC) resistance to cisplatin treatment. Three cisplatin-resistant HNC cell lines (AMC-HN3R, -HN4R, and -HN9R) and their parental lines were used. The effects of cystine and glutamate alteration and pharmacological and genetic inhibition of cystine/glutamate antiporter were assessed by measuring viability, death, reactive oxygen species production, protein expression, and preclinical mouse tumor xenograft models. Conditioned media with no cystine or glutamine excess induced ferroptosis of both cisplatin-sensitive and -resistant HNC cells without any apparent changes to necrosis and apoptosis markers. The cystine/glutamate antiporter inhibitors erastin and sulfasalazine inhibited HNC cell growth and accumulated lipid reactive oxygen species, thereby inducing ferroptosis. Genetic silencing of cystine/glutamate antiporter with siRNA or shRNA treatment also induced effective ferroptotic cell death of resistant HNC cells and enhanced the cisplatin cytotoxicity of resistant HNC cells. Pharmacological and genetic inhibition of cystine/glutamate antiporter significantly sensitized resistant HNC cells to cisplatin in vitro and in vivo. Pharmacological and genetic inhibition of cystine/glutamate antiporter overcomes the cisplatin resistance of HNC cells by inducing ferroptosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Overcoming the isolation of disadvantaged housing areas

    DEFF Research Database (Denmark)

    Stender, Marie; Bech-Danielsen, Claus

    Disadvantaged social housing areas in Denmark are currently subject to more thorough physical refurbishments, aiming to overcome the isolated character of the housing estates. The ambition is to attract new users and residents by opening up the borders of the area and establish attractive, new...... penthouse flats, new urban functions within the area or spectacular new public spaces near it. In this paper the social impact of such transformations are analysed and discussed based on case-studies in 3 Danish areas. The analysis shows that especially everyday-route strategies adding new public functions...... within the area can pave can the way for integration with the surroundings. The applicability of such strategies is however highly dependent on context, location and existing image. Social distance may sustain though physical borders are removed, yet, the negative image of the areas can in itself call...

  10. Innovative Strategies to Overcome Biofilm Resistance

    Directory of Open Access Journals (Sweden)

    Aleksandra Taraszkiewicz

    2013-01-01

    Full Text Available We review the recent literature concerning the efficiency of antimicrobial photodynamic inactivation toward various microbial species in planktonic and biofilm cultures. The review is mainly focused on biofilm-growing microrganisms because this form of growth poses a threat to chronically infected or immunocompromised patients and is difficult to eradicate from medical devices. We discuss the biofilm formation process and mechanisms of its increased resistance to various antimicrobials. We present, based on data in the literature, strategies for overcoming the problem of biofilm resistance. Factors that have potential for use in increasing the efficiency of the killing of biofilm-forming bacteria include plant extracts, enzymes that disturb the biofilm structure, and other nonenzymatic molecules. We propose combining antimicrobial photodynamic therapy with various antimicrobial and antibiofilm approaches to obtain a synergistic effect to permit efficient microbial growth control at low photosensitizer doses.

  11. Overcoming Obstacles to Drug Repositioning in Japan

    Directory of Open Access Journals (Sweden)

    Yuhei Nishimura

    2017-10-01

    Full Text Available Drug repositioning (DR is the process of identifying new indications for existing drugs. DR usually focuses on drugs that have cleared phase-I safety trials but has yet to show efficacy for the intended indication. Therefore, DR can probably skip the preclinical and phase-I study, which can reduce the cost throughout drug development. However, the expensive phase-II/III trials are required to establish efficacy. The obstacles to DR include identification of new indications with a high success rate in clinical studies, obtaining funding for clinical studies, patent protection, and approval systems. To tackle these obstacles, various approaches have been applied to DR worldwide. In this perspective, we provide representative examples of DR and discuss the ongoing efforts to overcome obstacles to DR in Japan.

  12. Overcoming Obstacles to Drug Repositioning in Japan.

    Science.gov (United States)

    Nishimura, Yuhei; Tagawa, Masaaki; Ito, Hideki; Tsuruma, Kazuhiro; Hara, Hideaki

    2017-01-01

    Drug repositioning (DR) is the process of identifying new indications for existing drugs. DR usually focuses on drugs that have cleared phase-I safety trials but has yet to show efficacy for the intended indication. Therefore, DR can probably skip the preclinical and phase-I study, which can reduce the cost throughout drug development. However, the expensive phase-II/III trials are required to establish efficacy. The obstacles to DR include identification of new indications with a high success rate in clinical studies, obtaining funding for clinical studies, patent protection, and approval systems. To tackle these obstacles, various approaches have been applied to DR worldwide. In this perspective, we provide representative examples of DR and discuss the ongoing efforts to overcome obstacles to DR in Japan.

  13. Innovative strategies to overcome biofilm resistance.

    Science.gov (United States)

    Taraszkiewicz, Aleksandra; Fila, Grzegorz; Grinholc, Mariusz; Nakonieczna, Joanna

    2013-01-01

    We review the recent literature concerning the efficiency of antimicrobial photodynamic inactivation toward various microbial species in planktonic and biofilm cultures. The review is mainly focused on biofilm-growing microrganisms because this form of growth poses a threat to chronically infected or immunocompromised patients and is difficult to eradicate from medical devices. We discuss the biofilm formation process and mechanisms of its increased resistance to various antimicrobials. We present, based on data in the literature, strategies for overcoming the problem of biofilm resistance. Factors that have potential for use in increasing the efficiency of the killing of biofilm-forming bacteria include plant extracts, enzymes that disturb the biofilm structure, and other nonenzymatic molecules. We propose combining antimicrobial photodynamic therapy with various antimicrobial and antibiofilm approaches to obtain a synergistic effect to permit efficient microbial growth control at low photosensitizer doses.

  14. Overcoming Students' Misconceptions in Earth Science Education

    Science.gov (United States)

    Kirkby, K. C.; Finley, F. N.; Morin, P. J.; Chen, A. P.

    2006-12-01

    The University of Minnesota's Introductory Geology Program recently began to develop and use geologic concept surveys. Designed to measure changes in student knowledge and confidence through the semester, these surveys clearly demonstrate the remarkable tenacity of students' prior knowledge and misconceptions in surviving or resisting course instruction, unless instruction is specifically designed to counteract those misconceptions. Students do not simply absorb new information and knowledge, but interpret it in light of their previous understanding of how things work. They use this previous understanding to interpret, revise and often dismiss new information presented in class. This filtering process is one of the most important, if often overlooked, barriers to effective instruction. The present study demonstrates that classroom `interventions', targeted to specific misconceptions can overcome this barrier. Once students believe that their previous understanding is incorrect or incomplete and inadequately explains phenomena, they are more likely to understand, accept and use a new interpretation in subsequent explanations. These ideas are well known in education departments, but are less well established in the earth science field. Compared to physics and mathematics, earth science education also suffers from a relative lack of research on students' prior knowledge and misconceptions, the basis on which successful `interventions' rely. The present study presents a suite of common earth science misconceptions and demonstrates the effectiveness of targeted `interventions' in overcoming them, compared to traditional instruction methods. The results clearly demonstrate the importance of instructors knowing what knowledge or concepts students bring to their courses, as well as the remarkable effort still needed to identify and document students' perceptions of how the Earth works. This work is sponsored in part by the Fund for the Improvement of Postsecondary

  15. Overcoming fixation with repeated memory suppression.

    Science.gov (United States)

    Angello, Genna; Storm, Benjamin C; Smith, Steven M

    2015-01-01

    Fixation (blocks to memories or ideas) can be alleviated not only by encouraging productive work towards a solution, but, as the present experiments show, by reducing counterproductive work. Two experiments examined relief from fixation in a word-fragment completion task. Blockers, orthographically similar negative primes (e.g., ANALOGY), blocked solutions to word fragments (e.g., A_L_ _GY) in both experiments. After priming, but before the fragment completion test, participants repeatedly suppressed half of the blockers using the Think/No-Think paradigm, which results in memory inhibition. Inhibiting blockers did not alleviate fixation in Experiment 1 when conscious recollection of negative primes was not encouraged on the fragment completion test. In Experiment 2, however, when participants were encouraged to remember negative primes at fragment completion, relief from fixation was observed. Repeated suppression may nullify fixation effects, and promote creative thinking, particularly when fixation is caused by conscious recollection of counterproductive information.

  16. Cooperative networks overcoming defectors by social influence

    Science.gov (United States)

    Gomez Portillo, Ignacio

    2014-01-01

    We address the cooperation problem in structured populations by considering the prisoner’s dilemma game as a metaphor of the social interactions between individuals with imitation capacity. We present a new strategy update rule called democratic weighted update where the individual’s behavior is socially influenced by each one of their neighbors. In particular, the capacity of an individual to socially influence other ones is proportional to its accumulated payoff. When in a neighborhood there are cooperators and defectors, the focal player is contradictorily influenced by them and, therefore, the effective social influence is given by the difference of the accumulated payoff of each strategy in its neighborhood. First, by considering the growing process of the network and neglecting mutations, we show the evolution of highly cooperative systems. Then, we broadly show that the social influence allows to overcome the emergence of defectors into highly cooperative systems. In this way, we conclude that in a structured system formed by a growing process, the cooperation evolves if the individuals have an imitation capacity socially influenced by each one of their neighbors. Therefore, here we present a theoretical solution of the cooperation problem among genetically unrelated individuals.

  17. Overcoming soil compaction in surface mine reclamation

    International Nuclear Information System (INIS)

    Sweigard, R.J.

    1991-01-01

    Rubber-tyred soil reconstruction equipment causes compaction of soil and means surface mine operators cannot satisfy crop yield standards defined by the Surface Mining Control and Reclamation Act. Soil compaction can be overcome by either modifying the reconstruction process or alleviating the problem, for example by deep tillage, once it occurs. The Dept. of Mining Engineering at the Institute of Mining and Minerals Research is conducting a laboratory investigation into a method of injecting low density porous organic material into a bin containing soil at the same time as the soil is ripped. This should prevent voids collapsing when subjected to forces from farm equipment and natural sources. Soil analyses are performed before and after the injection. Ripping and injection with ground pecan shells had a residual effect on nuclear bulk density compared to the initially compacted case and also showed an improvement in hydraulic conductivity. Work is in progress on modifying the system to handle other injection material and should lead on to field tests on a prototype involving both soil analysis and crop yield determination. 1 fig

  18. Developing an intervention to overcome procrastination.

    Science.gov (United States)

    Otermin-Cristeta, Solange; Hautzinger, Martin

    2018-01-01

    The main goal of this study was the development of a reliable intervention to overcome general procrastination orientated to college students, designed to be used in practical clinical work. The workshops involved six meetings based on behavioral and cognitive techniques, paradox intervention, and psychoeducation. 175 students participated voluntarily. Their procrastination levels were measured in a pretest, post-test, and a 3-month follow-up. After the first interview, the participants were randomly divided into three groups (Intervention A, Intervention B, and a control group with no intervention). There was a significant improvement after the intervention. After 3 months, the average score was still significantly lower than in the pretest, whereas the score of the control group remained unchanged. The participants in Workshop A scored significantly lower in the post-test than the ones in Workshop B. After 3 months, the participants in Workshop B scored significantly lower in the follow up. So both interventions resulted to be effective in reducing procrastination sustainably.

  19. Overponderabilia: Overcoming Overthinking When Studying "Ourselves"

    Directory of Open Access Journals (Sweden)

    Kasper Tang Vangkilde

    2016-05-01

    Full Text Available This article discusses a key methodological difficulty in conducting qualitative research close to home: the issue of overthinking. Whereas MALINOWSKI's concern regarding imponderabilia, i.e., the risk of not thinking about the subtle phenomena of everyday life, has long haunted ethnographers and qualitative researchers, not least those working "at home," we highlight an issue of overponderabilia, i.e., the risk of overthinking seemingly familiar statements and practices of the people studied. How do we, as qualitative researchers, study very well-known phenomena such as science, bureaucracy, management etc. without reading our own ideas and understandings into the deceptively familiar concepts and accounts of our research subjects? Pondering this issue is inevitably a central concern for the increasing number of qualitative researchers who study people who apparently talk, think and work in a way which is similar to their own. While previous answers or solutions to this issue first and foremost emphasize various means of reflexivity, this article presents the method of "mutual participatory observation" as a particular way of overcoming overthinking: a method which in situ invites our research subjects into our thinking. Thus, in the pursuit of an ever enhanced understanding, qualitative research becomes not so much a reflexive deciphering as an active debate; that is, a mutual induction of the differences between the qualitative researcher and the research subjects. URN: http://nbn-resolving.de/urn:nbn:de:0114-fqs1602281

  20. Mid-Atlantic Wind - Overcoming the Challenges

    Energy Technology Data Exchange (ETDEWEB)

    Daniel F. Ancona III; Kathryn E. George; Richard P. Bowers; Dr. Lynn Sparling; Bruce Buckheit; Daniel LoBue

    2012-05-31

    This study, supported by the US Department of Energy, Wind Powering America Program, Maryland Department of Natural Resources and Chesapeake Bay Foundation, analyzed barriers to wind energy development in the Mid-Atlantic region along with options for overcoming or mitigating them. The Mid-Atlantic States including Delaware, Maryland, North Carolina and Virginia, have excellent wind energy potential and growing demand for electricity, but only two utility-scale projects have been installed to date. Reasons for this apathetic development of wind resources were analyzed and quantified for four markets. Specific applications are: 1) Appalachian mountain ridgeline sites, 2) on coastal plains and peninsulas, 3) at shallow water sites in Delaware and Chesapeake Bays, Albemarle and Pamlico Sounds, and 4) at deeper water sites off the Atlantic coast. Each market has distinctly different opportunities and barriers. The primary barriers to wind development described in this report can be grouped into four categories; state policy and regulatory issues, wind resource technical uncertainty, economic viability, and public interest in environmental issues. The properties of these typologies are not mutually independent and do interact. The report concluded that there are no insurmountable barriers to land-based wind energy projects and they could be economically viable today. Likewise potential sites in sheltered shallow waters in regional bay and sounds have been largely overlooked but could be viable currently. Offshore ocean-based applications face higher costs and technical and wind resource uncertainties. The ongoing research and development program, revision of state incentive policies, additional wind measurement efforts, transmission system expansion, environmental baseline studies and outreach to private developers and stakeholders are needed to reduce barriers to wind energy development.

  1. Mid-Atlantic Wind - Overcoming the Challenges

    Energy Technology Data Exchange (ETDEWEB)

    Daniel F. Ancona III; Kathryn E. George; Lynn Sparling; Bruce C. Buckheit; Daniel LoBue; and Richard P. Bowers

    2012-06-29

    This study, supported by the US Department of Energy, Wind Powering America Program, Maryland Department of Natural Resources and Chesapeake Bay Foundation, analyzed barriers to wind energy development in the Mid-Atlantic region along with options for overcoming or mitigating them. The Mid-Atlantic States including Delaware, Maryland, North Carolina and Virginia, have excellent wind energy potential and growing demand for electricity, but only two utility-scale projects have been installed to date. Reasons for this apathetic development of wind resources were analyzed and quantified for four markets. Specific applications are: 1) Appalachian mountain ridgeline sites, 2) on coastal plains and peninsulas, 3) at shallow water sites in Delaware and Chesapeake Bays, Albemarle and Pamlico Sounds, and 4) at deeper water sites off the Atlantic coast. Each market has distinctly different opportunities and barriers. The primary barriers to wind development described in this report can be grouped into four categories; state policy and regulatory issues, wind resource technical uncertainty, economic viability, and public interest in environmental issues. The properties of these typologies are not mutually independent and do interact. The report concluded that there are no insurmountable barriers to land-based wind energy projects and they could be economically viable today. Likewise potential sites in sheltered shallow waters in regional bay and sounds have been largely overlooked but could be viable currently. Offshore ocean-based applications face higher costs and technical and wind resource uncertainties. The ongoing research and development program, revision of state incentive policies, additional wind measurement efforts, transmission system expansion, environmental baseline studies and outreach to private developers and stakeholders are needed to reduce barriers to wind energy development.

  2. Overcoming Immune Dysregulation with Immunoengineered Nanobiomaterials.

    Science.gov (United States)

    Scott, Evan A; Karabin, Nicholas B; Augsornworawat, Punn

    2017-06-21

    The immune system is governed by an immensely complex network of cells and both intracellular and extracellular molecular factors. It must respond to an ever-growing number of biochemical and biophysical inputs by eliciting appropriate and specific responses in order to maintain homeostasis. But as with any complex system, a plethora of false positives and false negatives can occur to generate dysregulated responses. Dysregulated immune responses are essential components of diverse inflammation-driven pathologies, including cancer, heart disease, and autoimmune disorders. Nanoscale biomaterials (i.e., nanobiomaterials) have emerged as highly customizable platforms that can be engineered to interact with and direct immune responses, holding potential for the design of novel and targeted approaches to redirect or inhibit inflammation. Here, we present recent developments of nanobiomaterials that were rationally designed to target and modulate inflammatory cells and biochemical pathways for the treatment of immune dysregulation.

  3. Targeted multidrug delivery system to overcome chemoresistance in breast cancer

    Directory of Open Access Journals (Sweden)

    Tang Y

    2017-01-01

    Full Text Available Yuan Tang,1 Fariborz Soroush,1 Zhaohui Tong,2 Mohammad F Kiani,1 Bin Wang1,3 1Department of Mechanical Engineering, Temple University, Philadelphia, PA, 2Department of Agricultural and Biological Engineering, University of Florida, Gainesville, FL, 3Department of Biomedical Engineering, Widener University, Chester, PA, USA Abstract: Chemotherapy has been widely used in breast cancer patients to reduce tumor size. However, most anticancer agents cannot differentiate between cancerous and normal cells, resulting in severe systemic toxicity. In addition, acquired drug resistance during the chemotherapy treatment further decreases treatment efficacy. With the proper treatment strategy, nanodrug carriers, such as liposomes/immunoliposomes, may be able to reduce undesired side effects of chemotherapy, to overcome the acquired multidrug resistance, and to further improve the treatment efficacy. In this study, a novel combinational targeted drug delivery system was developed by encapsulating antiangiogenesis drug bevacizumab into liposomes and encapsulating chemotherapy drug doxorubicin (DOX into immunoliposomes where the human epidermal growth factor receptor 2 (HER2 antibody was used as a targeting ligand. This novel combinational system was tested in vitro using a HER2 positive and multidrug resistant breast cancer cell line (BT-474/MDR, and in vivo using a xenograft mouse tumor model. In vitro cell culture experiments show that immunoliposome delivery led to a high cell nucleus accumulation of DOX, whereas free DOX was observed mostly near the cell membrane and in cytoplasm due to the action of P-gp. Combining liposomal bevacizumab with immunoliposomal DOX achieved the best tumor growth inhibition and the lowest toxicity. Tumor size decreased steadily within a 60-day observation period indicating a potential synergistic effect between DOX and bevacizumab through the targeted delivery. Our findings clearly indicate that tumor growth was significantly

  4. Overcoming natural replication barriers: differential helicase requirements.

    Science.gov (United States)

    Anand, Ranjith P; Shah, Kartik A; Niu, Hengyao; Sung, Patrick; Mirkin, Sergei M; Freudenreich, Catherine H

    2012-02-01

    DNA sequences that form secondary structures or bind protein complexes are known barriers to replication and potential inducers of genome instability. In order to determine which helicases facilitate DNA replication across these barriers, we analyzed fork progression through them in wild-type and mutant yeast cells, using 2-dimensional gel-electrophoretic analysis of the replication intermediates. We show that the Srs2 protein facilitates replication of hairpin-forming CGG/CCG repeats and prevents chromosome fragility at the repeat, whereas it does not affect replication of G-quadruplex forming sequences or a protein-bound repeat. Srs2 helicase activity is required for hairpin unwinding and fork progression. Also, the PCNA binding domain of Srs2 is required for its in vivo role of replication through hairpins. In contrast, the absence of Sgs1 or Pif1 helicases did not inhibit replication through structural barriers, though Pif1 did facilitate replication of a telomeric protein barrier. Interestingly, replication through a protein barrier but not a DNA structure barrier was modulated by nucleotide pool levels, illuminating a different mechanism by which cells can regulate fork progression through protein-mediated stall sites. Our analyses reveal fundamental differences in the replication of DNA structural versus protein barriers, with Srs2 helicase activity exclusively required for fork progression through hairpin structures.

  5. A SYSTEMIC VISION OF BIOLOGY: OVERCOMING LINEARITY

    Directory of Open Access Journals (Sweden)

    M. Mayer

    2005-07-01

    were used to build  a hipermedia  material.  This  technology  permit  overcomes a linear  communication, improving the  comprehension  of the network perspective.   The teachers  speeches revealed  their  conceptual  con- structions along the  course,  showed the development of the  competences  in identify  interconnection points  in the flow and chemical cycling of energy, compatible  with a systemic view of life.

  6. Fear of Public Speaking: How Can I Overcome It?

    Science.gov (United States)

    ... I overcome it? How can I overcome my fear of public speaking? Answers from Craig N. Sawchuk, Ph.D., L.P. Fear of public speaking is a common form of ... It can range from slight nervousness to paralyzing fear and panic. Many people with this fear avoid ...

  7. PP2A inhibition overcomes acquired resistance to HER2 targeted therapy

    OpenAIRE

    McDermott, Martina SJ; Browne, Brigid C; Conlon, Neil T; O’Brien, Neil A; Slamon, Dennis J; Henry, Michael; Meleady, Paula; Clynes, Martin; Dowling, Paul; Crown, John; O’Donovan, Norma

    2014-01-01

    Background: HER2 targeted therapies including trastuzumab and more recently lapatinib have significantly improved the prognosis for HER2 positive breast cancer patients. However, resistance to these agents is a significant clinical problem. Although several mechanisms have been proposed for resistance to trastuzumab, the mechanisms of lapatinib resistance remain largely unknown. In this study we generated new models of acquired resistance to HER2 targeted therapy and investigated ...

  8. Addition of AT(1) blocker fails to overcome resistance to ACE inhibition in adriamycin nephrosis

    NARCIS (Netherlands)

    Bos, H; Henning, RH; Tiebosch, ATMG; de Jong, PE; de Zeeuw, D; Navis, G

    Background. Angiotensin-converting enzyme (ACE) inhibitors provide renoprotection, but there is considerable interindividual variability in therapeutic efficacy, with residual proteinuria and progressive renal function loss in many individuals. This requires additional strategies to optimize therapy

  9. Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling.

    Science.gov (United States)

    Jensen, Liselotte E

    2017-08-15

    Pathogens deploy immune evasion strategies to successfully establish infections within their hosts. Naturally, the host responds by acquiring mechanisms to counter these strategies. There is increasing evidence that the three interleukin-36 (IL-36) cytokines, IL-36α, IL-36β and IL-36γ, play important roles in host immunity. With a focus on the skin as a target for microbial and viral invasion, the current knowledge of IL-36 functions is reviewed. Furthermore, the hypothesis that the IL-36s have evolved to counteract virulence factors is presented using viruses as an example. The IL-36s are related to IL-1α, IL-1β, IL-18, and IL-33. Numerous viruses affecting the skin have developed immune evasion strategies that neutralize IL-1α, IL-1β, or IL-18 signaling or combinations of these pathways. Through small differences in activation mechanisms and receptor utilization, it is possible that IL-36 signaling may proceed unhindered in the presence of these viral inhibitors. Thus, one physiological function of the IL-36s may be to counteract microbial immune evasion. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  10. Overcoming IGF1R/IR Resistance Through Inhibition of MEK Signaling in Colorectal Cancer Models

    Science.gov (United States)

    Flanigan, Sara A.; Pitts, Todd M.; Newton, Timothy P.; Kulikowski, Gillian N.; Tan, Aik Choon; McManus, Martine C.; Spreafico, Anna; Kachaeva, Maria I.; Selby, Heather M.; Tentler, John J.; Eckhardt, S. Gail; Leong, Stephen

    2013-01-01

    Purpose Results from clinical trials involving resistance to molecularly targeted therapies have revealed the importance of rational single agent and combination treatment strategies. In this study, we tested the efficacy of a type 1 insulin-like growth factor receptor (IGF1R)/insulin receptor (IR) tyrosine kinase inhibitor (TKI), OSI-906, in combination with a MEK 1/2 inhibitor based on evidence that the MAPK pathway was upregulated in colorectal cancer (CRC) cell lines that were resistant to OSI-906. Experimental Design The antiproliferative effects of OSI-906 and the MEK 1/2 inhibitor U0126, were analyzed both as single agents and in combination in 13 CRC cell lines in vitro. Apoptosis, downstream effector proteins, and cell cycle were also assessed. Additionally, the efficacy of OSI-906 combined with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886), was evaluated in vivo using human CRC xenograft models. Results The combination of OSI-906 and U0126 resulted in synergistic effects in 11 out of 13 CRC cell lines tested. This synergy was variably associated with apoptosis or cell cycle arrest in addition to molecular effects on pro-survival pathways. The synergy was also reflected in the in vivo xenograft studies following treatment with the combination of OSI-906 and selumetinib. Conclusions Results from this study demonstrate synergistic antiproliferative effects in response to the combination of OSI-906 with a MEK 1/2 inhibitor in CRC cell line models both in vitro and in vivo, which supports the rational combination of OSI-906 with a MEK inhibitor in patients with CRC. PMID:24045180

  11. The multiple strategies of an insect herbivore to overcome plant cyanogenic glucoside defence

    DEFF Research Database (Denmark)

    Pentzold, Stefan; Zagrobelny, Mika; Roelsgaard, Pernille Sølvhøj

    2014-01-01

    during feeding and digestion are unknown. We show that CNglc-sequestering Zygaena filipendulae larvae combine behavioural, morphological, physiological and biochemical strategies at different time points during feeding and digestion to avoid toxic hydrolysis of the CNglcs present in their Lotus food......, a highly alkaline midgut lumen inhibited the activity of ingested plant b-glucosidases significantly. Moreover, insect b-glucosidases from the saliva and gut tissue did not hydrolyse the CNglcs present in Lotus. The strategies disclosed may also be used by other insect species to overcome CNglc-based plant...

  12. Overcoming Residents Opportunity Apathy in Danish Social Housing Democracy

    DEFF Research Database (Denmark)

    Bertelsen, Olav W.

    2014-01-01

    In this paper, I discuss how various technologies can support democratic collaboration in the social housing sector in Denmark, and help overcome opportunity apathy. I exemplify the discussion with an ongoing process of strategy development, in a Danish housing organization....

  13. Strategies to overcome myelotoxic therapy for the treatment of ...

    African Journals Online (AJOL)

    Strategies to overcome myelotoxic therapy for the treatment of Burkitt's and AIDS- related non-Hodgkin's lymphoma. R Rochford, G Feuer, J Orem, C Banura, E Katongole-Mbidde, WO Mwanda, A Moormann, WJ Harrington, SC Remick ...

  14. Overcoming the shortage of transplantable organs: ethical and psychological aspects.

    Science.gov (United States)

    Quante, Michael; Wiedebusch, Silvia

    2007-03-02

    The main ethical problem of organ transplantation is the shortage of transplantable organs. The substitute strategies currently under discussion endanger frust in transplantion medicine and thereby increase the problem. Thus ethically preferable alternatives to overcome the shortage are suggested.

  15. The facilitation by church leaders in overcoming resistance to change.

    OpenAIRE

    2008-01-01

    Little has been done to address the issue of how to overcome resistance to change in a change effort in the church world. “How to overcome resistance to change?” is a question that requires serious consideration among church leaders. Church leaders continue to act in ways that produce resistance to change and ultimately failed change efforts. These actions on the part of church leaders often strengthen and reinforce the sources of resistance to change, making it very difficult for change to b...

  16. Book Review Overcoming Body Image Disturbance: A Programme ...

    African Journals Online (AJOL)

    Book Review Overcoming Body Image Disturbance: A Programme for People with Eating Disorders By Lorraine Bell and Jenny Rushforth (2008). Carla Dukas. Abstract. Routledge, London Paperback, ISBN 978-0-415-42330-4, ZAR 393 160 pages40. Journal of Child and Adolescent Mental Health 2008, 20(2): 133–134.

  17. Midwives unable to overcome language barriers in prenatal care

    NARCIS (Netherlands)

    M.P. Fransen (Mirjam); H.I.J. Wildschut (Hajo); J.P. Mackenbach (Johan); E.A.P. Steegers (Eric); M.L.E. Essink-Bot (Marie-Louise)

    2012-01-01

    textabstractBackground: The present study aims to explore to what extent midwives experience barriers in providing information about prenatal screening for Down syndrome to women from diverse ethnic backgrounds, and to assess their competences to overcome these barriers. Methods: Midwives from 24

  18. Addressing and overcoming barriers for energy savings in business

    DEFF Research Database (Denmark)

    Dirckinck-Holmfeld, Kasper

    of the local authorities, evaluating the specific concept applied, highlighting the specific barriers and constraints encountered during the project so far, as well as how the local authorities can help the companies overcome these. With this paper, the author intent to provide some inspiration for other local...

  19. Using problem-solving instruction to overcome high school ...

    African Journals Online (AJOL)

    kofi.mereku

    African Journal of Educational Studies in Mathematics and Sciences Vol. 13, 2017. 33. Using problem-solving instruction to overcome high school chemistry students' difficulties with stoichiometric problems. S. 1Mandina & C. E. 2Ochonogor. Abstract. The study sought to find out the difficulties encountered by high school ...

  20. Using problem-solving instruction to overcome high school ...

    African Journals Online (AJOL)

    Using problem-solving instruction to overcome high school chemistry students' difficulties with stoichiometric problems. ... African Journal of Educational Studies in Mathematics and Sciences ... The study sought to find out the difficulties encountered by high school chemistry students when solving stoichiometric problems.

  1. Towards overcoming poor readership and building reading culture ...

    African Journals Online (AJOL)

    Towards overcoming poor readership and building reading culture of in schools. ... Gender and Behaviour ... The paper is based on a longitudinal project which set out to build a culture of reading among high school learners in De Vos Malan in King William's Town District in the Eastern Cape Province of South Africa.

  2. Evaluation of different methods to overcome in vitro seed dormancy ...

    African Journals Online (AJOL)

    SAM

    2014-09-03

    Sep 3, 2014 ... Seeds from yellow passion fruit (Passiflora edulis Sims) present dormancy imposed by the seed-coat. The present study aimed to evaluate some methods to overcome dormancy of seeds from P. edulis grown under in vitro conditions. The experimental design was completely randomized in factorial scheme ...

  3. Evaluation of different methods to overcome in vitro seed dormancy ...

    African Journals Online (AJOL)

    Seeds from yellow passion fruit (Passiflora edulis Sims) present dormancy imposed by the seed-coat. The present study aimed to evaluate some methods to overcome dormancy of seeds from P. edulis grown under in vitro conditions. The experimental design was completely randomized in factorial scheme (15 scarification ...

  4. Cross-Cultural Encounters as a Way of Overcoming Xenophobia.

    Science.gov (United States)

    Scheunpflug, Annette

    1997-01-01

    Examines the educational potential of cross-cultural travel to overcome xenophobia, stating that international encounters must not be a replacement for dealing with the conditions that create societal prejudice. Asserts that a precondition for change in a person's perception of foreign peoples and cultures lies in the alteration of that person's…

  5. Technology Adoption in Higher Education: Overcoming Anxiety through Faculty Bootcamp

    Science.gov (United States)

    Johnson, Terri; Wisniewski, Mary Ann; Kuhlemeyer, Greg; Isaacs, Gerald; Krzykowski, Jamie

    2012-01-01

    The reluctance to design and teach online courses in higher education is often attributed to technology anxiety in faculty. This article documents a faculty development model that has successfully helped faculty overcome this obstacle. "Bootcamps," faculty development programs held at Carroll University in Waukesha, WI, were specifically and…

  6. How insects overcome two-component plant chemical defence

    DEFF Research Database (Denmark)

    Pentzold, Stefan; Zagrobelny, Mika; Rook, Frederik

    2014-01-01

    are alkaloid, benzoxazinoid, cyanogenic and iridoid glucosides as well as glucosinolates and salicinoids. Conversely, many insects have evolved a diversity of counteradaptations to overcome this type of constitutive chemical defence. Here we discuss that such counter-adaptations occur at different time points...

  7. Six world-class research teams to investigate overcoming ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    2017-10-26

    Six world-class research teams to investigate overcoming therapeutic resistance in high fatality cancers. October 26, 2017. Together with our partners the Canadian Institutes of Health Research, the Azrieli Foundation and the Israel Science Foundation we are pleased to announce the recipients of the Joint Canada-Israel ...

  8. Overcoming Destitution through Literacy: A Case of the Disabled ...

    African Journals Online (AJOL)

    This paper describes an experimental literacy programme for the disabled, set up in Kano (1), Nigeria between 1989 and 1990. The programme's objective was to help the destitutes to overcome some of their socio-economic drawbacks. The pro gramme took off with the enrolment of 450 people. At the end of the ...

  9. Overcoming family planning challenges in Africa: toward meeting ...

    African Journals Online (AJOL)

    Overcoming family planning challenges in Africa: toward meeting unmet need and scaling up service delivery. Andrzej Kulczycki. Abstract. No Abstract. Full Text: EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT · AJOL African Journals Online. HOW TO USE AJOL.

  10. Overcoming Branding Barriers in Nonprofit, Private Colleges and Universities

    Science.gov (United States)

    Chyr, Fred

    2017-01-01

    Purpose: The purpose of this Delphi study was to explore the views of experts in the field of nonprofit private colleges and universities in the United States to define branding and identify current barriers to branding, to discover how those barriers can be overcome, and to determine what barriers to branding are likely to occur 5 years in the…

  11. Consumer and Employer Strategies for Overcoming Employment Barriers. Technical Report.

    Science.gov (United States)

    Crudden, Adele; Williams, Wendy; McBroom, Lynn W.; Moore, J. Elton

    This report on strategies for overcoming employment barriers for persons with visual impairments summarizes comments and suggestions of 7 focus groups comprised of either consumers (n=49) or employers (n=19). The report first reviews the literature concerning employment barriers and how consumers in previous studies suggested these barriers be…

  12. A thematic analysis of how prisoners overcome suicidality.

    Science.gov (United States)

    Reading, Lucy; Bowen, Erica

    2014-01-01

    The purpose of this paper is to explore the perceptions, beliefs and abilities that support adult male prisoners in overcoming suicidality. Semi-structured interviews were conducted with eight male life sentenced prisoners in a Category B prison. Thematic analysis was used to analyse the data and interpret how prisoners have overcome suicidality. Findings - Five overarching themes were identified; sense of self, presence of meaning, connectedness, shift of perspective and re-establishing control. The themes were closely interconnected and revealed novel insights into the variables that supported prisoners to overcome suicidality. The themes were drawn from a specific prisoner population, which may not be representative of the wider prison population. Additionally, the sole focus on suicidality may be an oversimplification of self-destructive behaviours and could have affected the factors identified. The results highlight the need to refine suicide prevention strategies in prisons; in the assessment of suicide risk, the improvement of supportive regimes and the development of psychological interventions. This research is the first to qualitatively examine the factors involved in overcoming suicide in adult male prisoners. The research is of value to researchers and practitioners alike, as it extends previous research in prison populations and suggests avenues for the development of suicide prevention strategies.

  13. Six world-class research teams to investigate overcoming ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Six world-class research teams to investigate overcoming therapeutic resistance in high fatality cancers. 26 octobre 2017. Together with our partners the Canadian Institutes of Health Research, the Azrieli Foundation and the Israel Science Foundation we are pleased to announce the recipients of the Joint Canada-Israel ...

  14. Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy

    Directory of Open Access Journals (Sweden)

    Laura Pisarsky

    2016-05-01

    Full Text Available Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis. Gene expression profiling of tumor cells reveals metabolic reprogramming toward anaerobic glycolysis. Indeed, combinatorial treatment with a glycolysis inhibitor (3PO efficiently inhibits tumor growth. Moreover, tumors establish metabolic symbiosis, illustrated by the differential expression of MCT1 and MCT4, monocarboxylate transporters active in lactate exchange in glycolytic tumors. Accordingly, genetic ablation of MCT4 expression overcomes adaptive resistance against anti-angiogenic therapy. Hence, targeting metabolic symbiosis may be an attractive avenue to avoid resistance development to anti-angiogenic therapy in patients.

  15. Strategies to overcome resistance to epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer.

    Science.gov (United States)

    Jeong, Woo-Jeong; Cha, Pu-Hyeon; Choi, Kang-Yell

    2014-08-07

    Administration of monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) such as cetuximab and panitumumab in combination with conventional chemotherapy substantially prolongs survival of patients with metastatic colorectal cancer (mCRC). However, the efficacy of these mAbs is limited due to genetic variation among patients, in particular K-ras mutations. The discovery of K-ras mutation as a predictor of non-responsiveness to EGFR mAb therapy has caused a major change in the treatment of mCRC. Drugs that inhibit transformation caused by oncogenic alterations of Ras and its downstream components such as BRAF, MEK and AKT seem to be promising cancer therapeutics as single agents or when given with EGFR inhibitors. Although multiple therapeutic strategies to overcome EGFR mAb-resistance are under investigation, our understanding of their mode of action is limited. Rational drug development based on stringent preclinical data, biomarker validation, and proper selection of patients is of paramount importance in the treatment of mCRC. In this review, we will discuss diverse approaches to overcome the problem of resistance to existing anti-EGFR therapies and potential future directions for cancer therapies related to the mutational status of genes associated with EGFR-Ras-ERK and PI3K signalings.

  16. Novel nanostructured enoxaparin sodium-PLGA hybrid carriers overcome tumor multidrug resistance of doxorubicin hydrochloride.

    Science.gov (United States)

    Wang, Jia; Wu, Lei; Kou, Longfa; Xu, Meng; Sun, Jin; Wang, Yongjun; Fu, Qiang; Zhang, Peng; He, Zhonggui

    2016-11-20

    Novel enoxaparin sodium-PLGA hybrid nanocarries (EPNs) were successfully designed for sustained delivery of hydrophilic cationic doxorubicin hydrochloride (DOX) and to overcome multidrug resistance (MDR). By incorporation of the negative polymer of enoxaparin sodium (ES), DOX was highly encapsulated into EPNs with an encapsulation efficiency of 92.49%, and ES effectively inhibited the proliferation of HUVEC cell lines. The in vivo pharmacokinetics study after intravenous injection indicated that DOX-loaded EPNs (DOX-EPNs) exhibited a higher area under the curve (AUC) and a longer half-life (t 1/2 ) in comparison with DOX solution (DOX-Sol). The biodistribution study demonstrated that DOX-EPNs increased the DOX level in plasma and decreased the accumulation of DOX in liver and spleen. Compared with DOX-Sol, DOX-EPNs increased the cytotoxicity in P-gp over-expressing MCF-7/Adr cells, attributed to the higher intracellular efficiency of DOX produced by the EPNs. DOX-EPNs entered into resistant tumor cells by multiple endocytosis pathways, which resulted in overcoming the multidrug resistance of MCF-7/Adr cells by escaping the efflux induced by P-gp transporters. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Identification and characterization of SSE15206, a microtubule depolymerizing agent that overcomes multidrug resistance

    KAUST Repository

    Manzoor, Safia

    2018-02-13

    Microtubules are highly dynamic structures that form spindle fibres during mitosis and are one of the most validated cancer targets. The success of drugs targeting microtubules, however, is often limited by the development of multidrug resistance. Here we describe the discovery and characterization of SSE15206, a pyrazolinethioamide derivative [3-phenyl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide] that has potent antiproliferative activities in cancer cell lines of different origins and overcomes resistance to microtubule-targeting agents. Treatment of cells with SSE15206 causes aberrant mitosis resulting in G2/M arrest due to incomplete spindle formation, a phenotype often associated with drugs that interfere with microtubule dynamics. SSE15206 inhibits microtubule polymerization both in biochemical and cellular assays by binding to colchicine site in tubulin as shown by docking and competition studies. Prolonged treatment of cells with the compound results in apoptotic cell death [increased Poly (ADP-ribose) polymerase cleavage and Annexin V/PI staining] accompanied by p53 induction. More importantly, we demonstrate that SSE15206 is able to overcome resistance to chemotherapeutic drugs in different cancer cell lines including multidrug-resistant KB-V1 and A2780-Pac-Res cell lines overexpressing MDR-1, making it a promising hit for the lead optimization studies to target multidrug resistance.

  18. CD44-engineered mesoporous silica nanoparticles for overcoming multidrug resistance in breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xin; Liu, Ying; Wang, Shouju; Shi, Donghong [Department of Radiology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); Zhou, Xianguang [National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing 210016 (China); Wang, Chunyan; Wu, Jiang; Zeng, Zhiyong; Li, Yanjun; Sun, Jing [Department of Radiology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); Wang, Jiandong [Department of Pathology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); Zhang, Longjiang [Department of Radiology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); Teng, Zhaogang, E-mail: tzg@fudan.edu.cn [Department of Radiology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093 (China); Lu, Guangming, E-mail: cjr.luguangming@vip.163.com [Department of Radiology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093 (China)

    2015-03-30

    Graphical abstract: - Highlights: • CD44-engineered mesoporous silica nanoparticles are synthesized. • The mechanism of CD44-engineered mesoporous silica nanoparticles is revealed. • This new delivery system increased the drug accumulation in vitro and in vivo. • This new delivery system offers an effective approach to treat multidrug resistance. - Abstract: Multidrug resistance is a major impediment for the successful chemotherapy in breast cancer. CD44 is over-expressed in multidrug resistant human breast cancer cells. CD44 monoclonal antibody exhibits anticancer potential by inhibiting proliferation and regulating P-glycoprotein-mediated drug efflux activity in multidrug resistant cells. Thereby, CD44 monoclonal antibody in combination with chemotherapeutic drug might be result in enhancing chemosensitivity and overcoming multidrug resistance. The purpose of this study is to investigate the effects of the CD44 monoclonal antibody functionalized mesoporous silica nanoparticles containing doxorubicin on human breast resistant cancer MCF-7 cells. The data showed that CD44-modified mesoporous silica nanoparticles increased cytotoxicity and enhanced the downregulation of P-glycoprotein in comparison to CD44 antibody. Moreover, CD44-engineered mesoporous silica nanoparticles provided active target, which promoted more cellular uptake of DOX in the resistant cells and more retention of DOX in tumor tissues than unengineered counterpart. Animal studies of the resistant breast cancer xenografts demonstrated that CD44-engineered drug delivery system remarkably induced apoptosis and inhibited the tumor growth. Our results indicated that the CD44-engineered mesoporous silica nanoparticle-based drug delivery system offers an effective approach to overcome multidrug resistance in human breast cancer.

  19. Conjugation of platinum(IV) complexes with chlorambucil to overcome cisplatin resistance via a "joint action" mode toward DNA.

    Science.gov (United States)

    Qin, Xiaodong; Fang, Lei; Chen, Feihong; Gou, Shaohua

    2017-09-08

    Two platinum(IV) complexes were designed and prepared by conjugation of cisplatin and oxaliplatin units with a DNA-damaging agent, chlorambucil, respectively. By taking a joint action to enhance the damage of DNA, the conjugates displayed potent antitumor activity against all the tested cancer cell lines comparable to cisplatin and oxaliplatin, and notably could overcome cisplatin resistance at certain degree. Complex 4, a hybrid of cisplatin and chlorambucil, arrested the cell cycle at the S and G2 phases, distinctive from those of cisplatin and oxaliplatin. Apoptosis studies revealed that complex 4 could induce cell apoptosis significantly in both SGC7901 and SGC7901/CDDP cells. Moreover, further investigation indicated that complex 4 suppressed the drug resistance by the improvement of the platinum uptake and the inhibition of PRAP-1 protein. These results show that the "joint action" on DNA is an effective strategy to overcome cisplatin resistance. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  20. Overcoming obstacles against effective solar lighting interventions in South Asia

    International Nuclear Information System (INIS)

    Wong, Sam

    2012-01-01

    Basing on our devised World Bank’s ‘Design Principles’ for effective renewable energy projects in developing countries and an in-depth analysis of our two solar lighting projects in Bangladesh and India, this paper explores three key obstacles that constrain poor people from obtaining solar lighting: financial exclusion, weak governance, and passive NGO and customer participation. The low take-up rate has a social and psychological impact. This paper recommends creating easy access to credit, establishing a robust complaint system, and developing strategic partnership to overcome the obstacles. - Research Highlights: ► To provide a critical analysis of the World Bank's 'Design Principles' for renewable energy policies in developing countries. ► To explain why some solar lighting projects do not work and how the barriers can be overcome. ► To highlight the roles of poverty, governance and technical support in solar lighting design.

  1. Namaste (counterbalancing technique: Overcoming warping in costal cartilage

    Directory of Open Access Journals (Sweden)

    Kapil S Agrawal

    2015-01-01

    Full Text Available Background: Indian noses are broader and lack projection as compared to other populations, hence very often need augmentation, that too by large volume. Costal cartilage remains the material of choice in large volume augmentations and repair of complex primary and secondary nasal deformities. One major disadvantage of costal cartilage grafts (CCG which offsets all other advantages is the tendency to warp and become distorted over a period of time. We propose a simple technique to overcome this menace of warping. Materials and Methods: We present the data of 51 patients of rhinoplasty done using CCG with counterbalancing technique over a period of 4 years. Results: No evidence of warping was found in any patient up to a maximum follow-up period of 4 years. Conclusion: Counterbalancing is a useful technique to overcome the problem of warping. It gives liberty to utilize even unbalanced cartilage safely to provide desired shape and use the cartilage without any wastage.

  2. Targeted cancer therapy; nanotechnology approaches for overcoming drug resistance.

    Science.gov (United States)

    Gao, Yan; Shen, Jacson K; Milane, Lara; Hornicek, Francis J; Amiji, Mansoor M; Duan, Zhenfeng

    2015-01-01

    Recent advances in cancer molecular biology have resulted in parallel and unprecedented progress in the development of targeted cancer therapy. Targeted therapy can provide higher efficacy and lower toxicity than conventional chemotherapy for cancer. However, like traditional chemotherapy, molecularly targeted cancer therapy also faces the challenge of drug resistance. Multiple mechanisms are responsible for chemotherapy resistance in tumors, including over-expression of efflux transporters, somatic alterations of drug targets, deregulation of apoptosis, and numerous pharmacokinetic issues. Nanotechnology based approaches are proving to be efficacious in overcoming drug resistance in cancer. Combination of targeted therapies with nanotechnology approaches is a promising strategy to overcome targeted therapy drug resistance in cancer treatment. This review discusses the mechanisms of targeted drug resistance in cancer and discusses nanotechnology approaches to circumvent this resistance.

  3. Emerging role of mammalian autophagy in ketogenesis to overcome starvation

    OpenAIRE

    Takagi, Ayano; Kume, Shinji; Maegawa, Hiroshi; Uzu, Takashi

    2016-01-01

    Autophagy is essential for the survival of lower organisms under conditions of nutrient depletion. However, whether autophagy plays a physiological role in mammals experiencing starvation is unknown. Ketogenesis is critical for overcoming starvation in mammals. We recently revealed that hepatic and renal autophagy are involved in starvation-induced ketogenesis, by utilizing tissue-specific autophagy-deficient mouse models. The liver is the principal organ to regulate ketogenesis, and a defici...

  4. Overcoming Blockages to Collective Innovation in Digital Infrastructures

    DEFF Research Database (Denmark)

    Rukanova, Boriana; Reuver, Mark; Henningsson, Stefan

    2017-01-01

    Decentralized digital technologies increasingly enable multiple organizations to co-create digital infrastructures. However, collective innovation processes often come to a stand-still because of conflicting interests and business models. While existing research suggests various factors that block...... and develop a conceptual framework based on collective action theory. We evaluate the framework through a longitudinal case study on mobile payment infrastructure development. We find various reconfiguration processes that organizations use to overcome blockages of collective innovation. Theoretically...

  5. Debate on science and technology promotion for overcoming economic crisis

    International Nuclear Information System (INIS)

    1990-05-01

    This book records debate point and topic presentation of debate on science and technology promotion for overcoming economic difficulties which lists opening greeting, topic presentation such as innovation of national science technology system, sufficient supply and demand of science and engineering personnel, invigoration of technology research of corporation and general debate. This debate was held by the Policy Board of democratic and liberal party on 22 May 1990 in Press center.

  6. The Regional Supply of Venture Capital - Can Syndication overcome Bottlenecks?

    OpenAIRE

    Fritsch, Michael; Schilder, Dirk

    2010-01-01

    We investigate whether the supply of venture capital (VC) is driven by spatial proximity between a VC company and the portfolio firm. Our analysis is based on information about VC investments in Germany between 2004 and 2009. We find that possible problems caused by the geographic distance to a portfolio firm seem to be overcome by syndication of investments with one of the VC firms located close to the investment. Our analysis does, however, suggest that short geographic distance between an ...

  7. Overcoming Autophagy to Induce Apoptosis in Castration Resistant Prostate Cancer

    Science.gov (United States)

    2015-10-01

    AWARD NUMBER: W81XWH-12-1-0529 TITLE: Overcoming Autophagy to Induce Apoptosis in Castration Resistant Prostate Cancer PRINCIPAL...survival mechanism and led cells to undergo apoptosis . Survival mechanisms elicited by CRPC C4-2B cells when treated with Enza may be blocked by...Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer

  8. Engaging basic scientists in translational research: identifying opportunities, overcoming obstacles

    Science.gov (United States)

    2012-01-01

    This report is based on the Federation of American Societies for Experimental Biology’s symposium, “Engaging basic Scientists in Translational Research: Identifying Opportunities, Overcoming Obstacles,” held in Chevy Chase, MD, March 24–25, 2011. Meeting participants examined the benefits of engaging basic scientists in translational research, the challenges to their participation in translational research, and the roles that research institutions, funding organizations, professional societies, and scientific publishers can play to address these challenges. PMID:22500917

  9. [Embodied narratives of overcoming: A pathway towards recovery?

    Science.gov (United States)

    Magalhães Dahl, Catarina; Mitkiewicz de Souza, Flávia; Marcos Lovisi, Giovanni; Susser, Ezra; Tavares Cavalcanti, Maria

    2017-11-01

    Narratives play a fundamental role in the recovery of persons with schizophrenia, mainly from the paradigmatic change engendered by the recovery movement. Rather than a methodological tool or a byproduct of recovery, narratives are integral components of this process. This article aims to analyze overcoming narratives, in the light of the corporeality paradigm, based on an emblematic case of a peer support worker. This is a qualitative study carried out in the context of a randomized clinical trial, and it is based on one in-depth interview and focus groups for the construction of the narrative. Thematic analysis was carried out and the following categories were identifed: sense of self and embodiment; experience of time and space; relationship with others; illness experience and overcoming. The embodied narratives of overcoming constitute in the register of a non-linear temporality, and it is based on a dialectical and dialogic process of construction/reconstruction of the sense of self and of the body itself. We propose that embodied narratives are considered as a methodological principle for narrative analysis on recovery, as well as an intrinsic dimension of the recovery journey; that is, as the center of gravity of the process of construction / reconstruction of the sense of self, embodiment and the sense of belonging to the world.

  10. [Heinrich von Kleist--crisis and creative overcoming].

    Science.gov (United States)

    Schlimme, J

    2001-07-01

    Heinrich von Kleist's life was shaken repeatedly by negative life-events, finally he committed suicide in his last life-crisis (1811). His work was mostly understood as descriptions of negative life-events and failed-being. In this article it will be shown that in at least two "crises" Kleist's work can be understood as a creative overcome of those. Kleist shows in his "Essay to Find a Sure Way to Happiness" (1799) his way of solving his "Soldier-Crisis" (1798), a depressive episode. In "The Broken Jug" (1802 - 1805) he shows the implications of a philosophical problem experienced in his "Kant-Crisis" (1801) and offers chances to overcome this particular crisis, which still seems to be an actual problem of ourselves. Though his crises must be understood as depressive episodes, at least the "Kant-Crisis" with its connections to philosophical and artistical matters seems to be more complicated than a simple depressive syndrome. Kleist formulates his basic life-experience, to be repeatedly shaken by "crises" respectively depressive episodes and the necessity to overcome each in a new way of living.

  11. Inhibition Efficiency in Highly Proficient Bilinguals and Simultaneous Interpreters: Evidence from Language Switching and Stroop Tasks.

    Science.gov (United States)

    Aparicio, Xavier; Heidlmayr, Karin; Isel, Frédéric

    2017-12-01

    The present behavioral study aimed to examine the impact of language control expertise on two domain-general control processes, i.e. active inhibition of competing representations and overcoming of inhibition. We compared how Simultaneous Interpreters (SI) and Highly Proficient Bilinguals-two groups assumed to differ in language control capacity-performed executive tasks involving specific inhibition processes. In Experiment 1 (language decision task), both active and overcoming of inhibition processes are involved, while in Experiment 2 (bilingual Stroop task) only interference suppression is supposed to be required. The results of Experiment 1 showed a language switching effect only for the highly proficient bilinguals, potentially because overcoming of inhibition requires more cognitive resources than in SI. Nevertheless, both groups performed similarly on the Stroop task in Experiment 2, which suggests that active inhibition may work similarly in both groups. These contrasting results suggest that overcoming of inhibition may be harder to master than active inhibition. Taken together, these data indicate that some executive control processes may be less sensitive to the degree of expertise in bilingual language control than others. Our findings lend support to psycholinguistic models of bilingualism postulating a higher-order mechanism regulating language activation.

  12. INHIBITION IN SPEAKING PERFORMANCE

    Directory of Open Access Journals (Sweden)

    Isna Humaera

    2015-09-01

    Full Text Available The most common problem encountered by the learner in the language acquisition process is learner inhibition. Inhibition refers to a temperamental tendency to display wariness, fearfulness, or restrain in response to unfamiliar people, objects, and situations. There are some factors that cause inhibition, such as lack of motivation, shyness, self-confidence, self-esteem, and language ego. There are also levels of inhibition, it refers to kinds of inhibition and caused of inhibition itself. Teacher can support their students to reduce their inhibition effect by many ways, one of them by creating good classroom management including establishing good rapport between teacher and learners.

  13. Strategies Used by Prehospital Providers to Overcome Language Barriers.

    Science.gov (United States)

    Tate, Ramsey C; Hodkinson, Peter W; Meehan-Coussee, Kelly; Cooperstein, Noah

    2016-01-01

    Language barriers are commonly encountered in the prehospital setting but there is a paucity of research on how prehospital providers address language discordance. We sought to identify the communication strategies, and the limitations of those strategies, used by emergency medical services (EMS) providers when confronted with language barriers in a variety of linguistic and cultural contexts. EMS providers were queried regarding communication strategies to overcome language barriers as part of an international, multi-site, sequential explanatory, qualitative-predominant, mixed methods study of prehospital language barriers. A survey of EMS telecommunicators was administered at dispatch centers in New Mexico (United States) and Western Cape (South Africa). Semi-structured qualitative interviews of EMS field providers were conducted at agencies who respond to calls from participating dispatch centers. Survey data included quantitative data on demographics and communication strategies used to overcome language barriers as well as qualitative free-text responses on the limitations of strategies. Interviews elicited narratives of encounters with language-discordant patients and the strategies used to communicate. Data from the surveys and interviews were integrated at the point of analysis. 125 telecommunicators (overall response rate of 84.5%) and a purposive sample of 27 field providers participated in the study. The characteristics of participants varied between countries and between agencies, consistent with variations in participating agencies' hiring and training practices. Telecommunicators identified 3rd-party telephonic interpreter services as the single most effective strategy when available, but also described time delays and frustration with interpreter communications that leads them to preferentially try other strategies. In the field, all providers reported using similar strategies, relying heavily on bystanders, multilingual coworkers, and non

  14. Re-Vitalizing Worthiness: A theory of overcoming suicidality

    Directory of Open Access Journals (Sweden)

    Evelyn Gordon, RPN, Reg. Fam. Ther. & Sup. (FTAI, MSc, Ph.D.

    2011-06-01

    Full Text Available Rates of suicide and suicidality have risen in many countries in recent years and in Ireland this trend has been particularly evident among young men (NOSP, 2005, focusing attention on how best to respond to this group. Although mental health professionals have been identified as a key group to respond to the suicidal person, it has been suggested that they are ill-prepared for working in this area (Maltsberger & Goldblatt, 1996; Ting et al., 2006; Cutcliffe & Stevenson, 2007. This study aimed to address these issues by developing a theoretical understanding of suicidality among young men to inform professional practice. Using Classic Grounded Theory (Glaser & Strauss, 1967, in-depth one-to-one interviews were conducted with 17 young men who had been suicidal and had been in contact with the mental health services. The substantive theory that emerged, re-vitalizing worthiness in overcoming suicidality, describes the psychosocial process that young men go through to resolve their main concern, which centres on their painful pull between life and death. Overcoming suicidality involves moving from a death orientation to a life orientation while incorporating the inevitability of death into their new sense of being. This transition entails identity re-configuration whereby young men emerge as individuals of value who are deserving of life. The process is influenced significantly by personal insights and interpersonal interactions that influence their suicide trajectories and life pathways. The theory contributes to the fields of suicidology and mental health by providing a theoretical understanding of overcoming suicidality and identifying professional and social practices that facilitate and impede this process.

  15. Overcoming design fixation through education and creativity methods

    DEFF Research Database (Denmark)

    Howard, T. J.; Maier, A. M.; Onarheim, B.

    2013-01-01

    This paper reports an experiment on the topic design fixation using 12 teams of masters students working on three design problems from (Jansson and Smith 1991). The objective of the experiment is to determine the effectiveness of two interventions to help overcome fixation on example solutions......' method during a final design task. The results showed that the method did not help the teams as it caused the fixation ratio to increase and the number of ideas per team to decrease. In addition to the above mentioned interventions, the experiment also revealed a negative correlation between the number...

  16. Overcoming Design Fixation Through Education and Creativity Methods

    DEFF Research Database (Denmark)

    Howard, Thomas J.; Maier, Anja; Onarheim, Balder

    2013-01-01

    This paper reports an experiment on the topic design fixation using 12 teams of masters students working on three design problems from (Jansson and Smith 1991). The objective of the experiment is to determine the effectiveness of two interventions to help overcome fixation on example solutions......' method during a final design task. The results showed that the method did not help the teams as it caused the fixation ratio to increase and the number of ideas per team to decrease. In addition to the above mentioned interventions, the experiment also revealed a negative correlation between the number...

  17. Research and development to overcome fouling of membranes. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Narang, S.C.; Sharma, S.K.; Hum, G.; Ventura, S.C.; Roberts, D.L.; Gottschlich, D.; Ahner, N.

    1998-11-01

    To overcome fouling of membranes, SRI International is developing a unique piezoelectric backing for ultrafiltration membranes. This backing is capable of producing local turbulence next to the membrane to minimize concentration polarization and the rate of buildup of solutes and particulate matter on the membrane surface. We have studied piezoelectrically assisted ultrafiltration in more detail, with the objective to apply this process to industrial ultrafiltrations. We conducted several ultrafiltration experiments on flat sheet membranes with model dextran solutions and with electrocoat paint to study flux enhancement as a function of parameters such as feed flow rate, feed pressure, as well as the piezodriver-membrane system.

  18. Decision Aiding to Overcome Biases in Object Identification

    Directory of Open Access Journals (Sweden)

    Mary Fendley

    2012-01-01

    Full Text Available Human decision makers typically use heuristics under time-pressured situations. These heuristics can potentially degrade task performance through the impact of their associated biases. Using object identification in image analysis as the context, this paper identifies cognitive biases that play a role in decision making. We propose a decision support system to help overcome these biases in this context. Results show that the decision support system improved human decision making in object identification, including metrics such as time taken to identify targets in an image set, accuracy of target identification, accuracy of target classification, and quantity of false positive identification.

  19. OVERCOMING POVERTY TRAP: THE CASE OF WATER & SANITATION IN INDONESIA

    Directory of Open Access Journals (Sweden)

    Hilda Leilani Masniarita Pohan

    2016-02-01

    Full Text Available Overcoming Poverty Trap : The Case of  Water & Sanitation in Indonesia. Poverty trap is a cycle in which poor individuals exhibit low health quality due to malnutrition and limited access to health related facilities. Poor health causes low productivity which eventually cycles back to low income. Indonesia significantly reduced poverty from 15.6% in 1990 to 3.3% in 2010. However, this achievement is not conveyed equally across regions. Using data form RAND Corporation, estimations showed that access to sanitation and clean water play a crucial role in improving one’s health quality.   Keywords: poverty trap, productivity, income, health facility.

  20. FINAL TECHNICAL REPORT: 20% Wind by 2030: Overcoming the Challenges

    Energy Technology Data Exchange (ETDEWEB)

    Tom Kaiserski; Dan Lloyd

    2012-02-28

    The funds allocated through the Wind Powering America (WPA) grant were utilized by the State of Montana to support broad outreach activities communicating the benefits and opportunities of increased wind energy and transmission development. The challenges to increased wind development were also clearly communicated with the understanding that a clearer comprehension of the challenges would be beneficial in overcoming the obstacles to further development. The ultimate purpose of these activities was to foster the increased development of Montana's rich wind resources through increased public acceptance and wider dissemination of technical resources.

  1. Overcoming Barriers to the Transfer and Diffusion of Climate Technologies

    DEFF Research Database (Denmark)

    Nygaard, Ivan; Hansen, Ulrich Elmer

    This guidebook provides practical and operational guidance on how to assess and overcome barriersfacing the transfer and diffusion of technologies for climate change mitigation and adaptation.The guidebook is designed to support the analysis of specific technologies, rather than pursuing asectoral...... (e.g. transport) or technology group (e.g. renewable energy) approach.Given that there is no single solution to enhancing technology transfer and diffusion policies needbe tailored to country-specific context and interests. Therefore, the guidebook presents a flexibleapproach, identifying various...

  2. EXPERIENCES OF OVERCOMING THE MASTER PRIMARY TO USE THE GEOGEBRA

    Directory of Open Access Journals (Sweden)

    María Luz Fuentes-Pérez

    2016-07-01

    Full Text Available This article presents the results of the experience of two researchers in overcoming 15 primary teachers, was used for this purpose a postgraduate course, in order to be trained so that they can use the dynamic geometry software Geogebra in the process of learning that develop in their classrooms. It is an investigation that used the systematization of experiences as a methodology and as research methods participant observation to get to know the moods and difficulties of trainees during class activities, group interview to gather data on participants in the course and with directors of primary education to meet the expectations and results related to the improvement and implementation of PNI for the views after some of the educational activities considered relevant. The results show as advances are obtained in overcoming teachers to use Geogebra and mention some lessons that emerge from the systematization about conception must have a course which is intended to prepare teachers who are not digital natives use the software mentioned.

  3. Overcoming barriers to development of cooperative medical decision support models.

    Science.gov (United States)

    Hudson, Donna L; Cohen, Maurice E

    2012-01-01

    Attempts to automate the medical decision making process have been underway for the at least fifty years, beginning with data-based approaches that relied chiefly on statistically-based methods. Approaches expanded to include knowledge-based systems, both linear and non-linear neural networks, agent-based systems, and hybrid methods. While some of these models produced excellent results none have been used extensively in medical practice. In order to move these methods forward into practical use, a number of obstacles must be overcome, including validation of existing systems on large data sets, development of methods for including new knowledge as it becomes available, construction of a broad range of decision models, and development of non-intrusive methods that allow the physician to use these decision aids in conjunction with, not instead of, his or her own medical knowledge. None of these four requirements will come easily. A cooperative effort among researchers, including practicing MDs, is vital, particularly as more information on diseases and their contributing factors continues to expand resulting in more parameters than the human decision maker can process effectively. In this article some of the basic structures that are necessary to facilitate the use of an automated decision support system are discussed, along with potential methods for overcoming existing barriers.

  4. A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers

    Science.gov (United States)

    LaBelle, James L.; Katz, Samuel G.; Bird, Gregory H.; Gavathiotis, Evripidis; Stewart, Michelle L.; Lawrence, Chelsea; Fisher, Jill K.; Godes, Marina; Pitter, Kenneth; Kung, Andrew L.; Walensky, Loren D.

    2012-01-01

    Cancer cells subvert the natural balance between cellular life and death, achieving immortality through pathologic enforcement of survival pathways and blockade of cell death mechanisms. Pro-apoptotic BCL-2 family proteins are frequently disarmed in relapsed and refractory cancer through genetic deletion or interaction-based neutralization by overexpressed antiapoptotic proteins, resulting in resistance to chemotherapy and radiation treatments. New pharmacologic strategies are urgently needed to overcome these formidable apoptotic blockades. We harnessed the natural killing activity of BCL-2–interacting mediator of cell death (BIM), which contains one of the most potent BH3 death domains of the BCL-2 protein family, to restore BH3-dependent cell death in resistant hematologic cancers. A hydrocarbon-stapled peptide modeled after the BIM BH3 helix broadly targeted BCL-2 family proteins with high affinity, blocked inhibitory antiapoptotic interactions, directly triggered proapoptotic activity, and induced dose-responsive and BH3 sequence–specific cell death of hematologic cancer cells. The therapeutic potential of stapled BIM BH3 was highlighted by the selective activation of cell death in the aberrant lymphoid infiltrates of mice reconstituted with BIM-deficient bone marrow and in a human AML xenograft model. Thus, we found that broad and multimodal targeting of the BCL-2 family pathway can overcome pathologic barriers to cell death. PMID:22622039

  5. Trackable Mitochondria-Targeting Nanomicellar Loaded with Doxorubicin for Overcoming Drug Resistance.

    Science.gov (United States)

    Zhang, Ye; Zhang, Congjun; Chen, Jing; Liu, Li; Hu, Mengyue; Li, Jun; Bi, Hong

    2017-08-02

    Multidrug resistance (MDR) has been recognized as a major obstacle to successful chemotherapy for cancer in the clinic. In recent years, more and more nanoscaled drug delivery systems (DDS) are constructed to modulate drug efflux protein (P-gp) and deliver chemotherapeutic drugs for overcoming MDR. Among them, d-α-tocopheryl polyethylene glycol succinate (TPGS) has been widely used as a drug carrier due to its capability of inhibiting overexpression of P-gp and good amphiphilicity favorable for improving permeation and long-circulation property of DDS. In the present work, a novel kind of mitochondria-targeting nanomicelles-based DDS is developed to integrate chemotherapeutics delivery with fluorescence imaging functionalities on a comprehensive nanoplatform. The mitochondria-targeting nanomicelles are prepared by self-assembly of triphenylphosphine (TPP)-modified TPGS and fluorescent carbon quantum dots (CQDs) in an n-hexane/H 2 O mixed solution, named CQDs-TPGS-TPP. Notably, although the drug loading content of doxorubicin (DOX) in the as-prepared nanomicelles is as low as 3.4%, the calculated resistant index (RI) is greatly decreased from 66.23 of free DOX to 7.16 of DOX-loaded nanomicelles while treating both parental MCF-7 cells and drug-resistant MCF-7/ADR cells. Compared with free DOX, the penetration efficiency of DOX-loaded nanomicelles in three-dimensional multicellular spheroids (MCs) of MCF-7/ADR is obviously increased. Moreover, the released DOX from the nanomicelles can cause much more damage to cells of drug-resistant MCs. These results demonstrate that our constructed mitochondria-targeting nanomicelles-based DDS have potential application in overcoming MDR of cancer cells as well as their MCs that mimic in vivo tumor tissues. The MDR-reversal mechanism of the DOX-loaded CQDs-TPGS-TPP nanomicelles is also discussed.

  6. Overcoming Resistance of Cancer Cells to PARP-1 Inhibitors with Three Different Drug Combinations.

    Directory of Open Access Journals (Sweden)

    Michal Yalon

    Full Text Available Inhibitors of poly[ADP-ribose] polymerase 1 (PARPis show promise for treatment of cancers which lack capacity for homologous recombination repair (HRR. However, new therapeutic strategies are required in order to overcome innate and acquired resistance to these drugs and thus expand the array of cancers that could benefit from them. We show that human cancer cell lines which respond poorly to ABT-888 (a PARPi, become sensitive to it when co-treated with vorinostat (a histone deacetylase inhibitor (HDACi. Vorinostat also sensitized PARPis insensitive cancer cell lines to 6-thioguanine (6-TG-a drug that targets PARPis sensitive cells. The sensitizing effect of vorinostat was associated with increased phosphorylation of eukaryotic initiation factor (eIF 2α which in and of itself increases the sensitivity of cancer cells to ABT-888. Importantly, these drug combinations did not affect survival of normal fibroblasts and breast cells, and significantly increased the inhibition of xenograft tumor growth relative to each drug alone, without affecting the mice weight or their liver and kidney function. Our results show that combination of vorinostat and ABT-888 could potentially prove useful for treatment of cancer with innate resistance to PARPis due to active HRR machinery, while the combination of vorinostat and 6-TG could potentially overcome innate or acquired resistance to PARPis due to secondary or reversal BRCA mutations, to decreased PARP-1 level or to increased expression of multiple drug resistant proteins. Importantly, drugs which increase phosphorylation of eIF2α may mimic the sensitizing effect of vorinostat on cellular response to PARPis or to 6-TG, without activating all of its downstream effectors.

  7. Overcoming dormancy and enhancing germination of Sphaeralcea munroana seeds

    Science.gov (United States)

    Olga A. Kildisheva; R. Kasten Dumroese; Anthony S. Davis

    2011-01-01

    The results of a series of experiments involving a variety of dormancy-breaking treatments indicate that Munro's globemallow [Sphaeralcea munroana (Douglas) Spach] seeds are physically dormant, possess a cap-like structure in the occlusion of the water gap, which inhibits imbibition, and can be artificially dislodged through boiling water scarification. The...

  8. Bacterial mechanisms to overcome inhibitory effects of dietary tannins

    NARCIS (Netherlands)

    Smith, A.H.; Zoetendal, E.G.; Mackie, R.I.

    2005-01-01

    High concentrations of tannins in fodder plants inhibit gastrointestinal bacteria and reduce ruminant performance. Increasing the proportion of tannin-resistant bacteria in the rumen protects ruminants from antinutritional effects. The reason for the protective effect is unclear, but could be

  9. Overcoming Barriers to Successfully Commercializing Carbon Dioxide Utilization

    Energy Technology Data Exchange (ETDEWEB)

    Kant, Marvin, E-mail: marvin.kant@tu-berlin.de [Department of Entrepreneurship and Innovation Management, Technische Universität Berlin, Berlin (Germany)

    2017-09-13

    The successful transition to a low-carbon economy hinges on innovative solutions and collaborative action on a global scale. Sustainable entrepreneurship is thereby recognized as a key driver in the creation and transformation of ecologically and socially sustainable economic systems. The purpose of this article is to contribute to this topic by understanding commercialization barriers for strong sustainability-oriented new technology ventures and to derive recommendations to overcome them. A qualitative multilevel approach is applied to identify barriers and drivers within the internal dynamic capabilities of the organization and within the organization’s external stakeholders. A model of barriers has been developed based on semi-structured interviews with new carbon dioxide utilization ventures and associated industry players in Canada, the USA, and the European Economic Area. Resulting recommendations to facilitate the (re-)design of a dedicated support system are proposed on four levels: (a) actors, (b) resources, (c) institutional settings, and (d) the coordination of the support system.

  10. Overcoming Barriers to Successfully Commercializing Carbon Dioxide Utilization

    International Nuclear Information System (INIS)

    Kant, Marvin

    2017-01-01

    The successful transition to a low-carbon economy hinges on innovative solutions and collaborative action on a global scale. Sustainable entrepreneurship is thereby recognized as a key driver in the creation and transformation of ecologically and socially sustainable economic systems. The purpose of this article is to contribute to this topic by understanding commercialization barriers for strong sustainability-oriented new technology ventures and to derive recommendations to overcome them. A qualitative multilevel approach is applied to identify barriers and drivers within the internal dynamic capabilities of the organization and within the organization’s external stakeholders. A model of barriers has been developed based on semi-structured interviews with new carbon dioxide utilization ventures and associated industry players in Canada, the USA, and the European Economic Area. Resulting recommendations to facilitate the (re-)design of a dedicated support system are proposed on four levels: (a) actors, (b) resources, (c) institutional settings, and (d) the coordination of the support system.

  11. Overcoming Path Dependency and “Lock-In”

    DEFF Research Database (Denmark)

    Soyer, Ayberk; Onar, Sezi Çevik; Sanchez, Ron

    2017-01-01

    Competence-Based Management (CBM) theory and research suggest that a firm’s competence building and leveraging processes are key factors influencing its competitive success. To achieve sustained competitive success, a firm’s competence building processes must continuously renew and extend...... the competences a firm has and can leverage. However, the ability of a firm to sustain strategically adequate levels of competence building – while also maintaining strategically successful competence leveraging – may be limited by various self-reinforcing managerial and organizational mechanisms that can arise...... competences at a strategically adequate level and eventually in competitive failure. In order to avoid such consequences, the management literature suggests that organizations must cultivate dynamic capabilities to overcome tendencies toward lock-in and to sustain ongoing competence building. This study...

  12. [Pain and Christianity. A symbol for overcoming pain?].

    Science.gov (United States)

    Markschies, C

    2007-08-01

    Pain and Christianity appear to belong together: Christ's pain stands at the centre of God's healing; his pain leads to the salvation of mankind. We can learn from Jesus' example how to bear suffering and pain. In early Christian times, the belief that Jesus Christ suffered pain on the cross was usually not accepted. In line with the "apathy axiom", freedom from emotion was something to strive for at that time. Only after the acceptance of Christianity as the state religion of the Roman Empire in 380 AD did the pain of Christ again stand in the centre of the Christian doctrine of salvation. The memory of the fact that Jesus himself had to undergo the worst pain can still help people to overcome their pain and comfort them.

  13. Oncolytic Viruses for Cancer Therapy: Overcoming the Obstacles

    Directory of Open Access Journals (Sweden)

    Yaohe Wang

    2010-01-01

    Full Text Available Targeted therapy of cancer using oncolytic viruses has generated much interest over the past few years in the light of the limited efficacy and side effects of standard cancer therapeutics for advanced disease. In 2006, the world witnessed the first government-approved oncolytic virus for the treatment of head and neck cancer. It has been known for many years that viruses have the ability to replicate in and lyse cancer cells. Although encouraging results have been demonstrated in vitro and in animal models, most oncolytic viruses have failed to impress in the clinical setting. The explanation is multifactorial, determined by the complex interactions between the tumor and its microenvironment, the virus, and the host immune response. This review focuses on discussion of the obstacles that oncolytic virotherapy faces and recent advances made to overcome them, with particular reference to adenoviruses.

  14. Marine bacteria: potential sources for compounds to overcome antibiotic resistance.

    Science.gov (United States)

    Eom, Sung-Hwan; Kim, Young-Mog; Kim, Se-Kwon

    2013-06-01

    Methicillin-resistant Staphylococcus aureus (MRSA) is the most problematic Gram-positive bacterium in the context of public health due to its resistance against almost all available antibiotics except vancomycin and teicoplanin. Moreover, glycopeptide-resistant S. aureus have been emerging with the increasing use of glycopeptides. Recently, resistant strains against linezolid and daptomycin, which are alternative drugs to treat MRSA infection, have also been reported. Thus, the development of new drugs or alternative therapies is clearly a matter of urgency. In response to the antibiotic resistance, many researchers have studied for alternative antibiotics and therapies. In this review, anti-MRSA substances isolated from marine bacteria, with their potential antibacterial effect against MRSA as potential anti-MRSA agents, are discussed and several strategies for overcoming the antibiotic resistance are also introduced. Our objective was to highlight marine bacteria that have potential to lead in developing novel antibiotics or clinically useful alternative therapeutic treatments.

  15. Overcoming Learning Time And Space Constraints Through Technological Tool

    Directory of Open Access Journals (Sweden)

    Nafiseh Zarei

    2015-08-01

    Full Text Available Today the use of technological tools has become an evolution in language learning and language acquisition. Many instructors and lecturers believe that integrating Web-based learning tools into language courses allows pupils to become active learners during learning process. This study investigate how the Learning Management Blog (LMB overcomes the learning time and space constraints that contribute to students’ language learning and language acquisition processes. The participants were 30 ESL students at National University of Malaysia. A qualitative approach comprising an open-ended questionnaire and a semi-structured interview was used to collect data. The results of the study revealed that the students’ language learning and acquisition processes were enhanced. The students did not face any learning time and space limitations while being engaged in the learning process via the LMB. They learned and acquired knowledge using the language learning materials and forum at anytime and anywhere. Keywords: learning time, learning space, learning management blog

  16. Fasciola hepatica infection in humans: overcoming problems for the diagnosis.

    Science.gov (United States)

    Carnevale, Silvana; Malandrini, Jorge Bruno; Pantano, María Laura; Sawicki, Mirna; Soria, Claudia Cecilia; Kuo, Lein Hung; Kamenetzky, Laura; Astudillo, Osvaldo Germán; Velásquez, Jorge Néstor

    2016-12-01

    Fascioliasis is a zoonosis actually considered as a foodborne trematode disease priority by the World Health Organization. Our study presents three cases of F. hepatica infection diagnosed by direct, indirect and/or imaging diagnostic techniques, showing the need of the combined use of them. In order to overcome some difficulties of the presently available methods we show for the first time the application of molecular tools to improve human fascioliasis diagnosis by employing a PCR protocol based on a repetitive element as target sequence. In conclusion, diagnosis of human fascioliasis has to be carried out by the combination of diagnostic techniques that allow the detection of infection in different disease phases, different epidemiological situations and known/new transmission patterns in the actual scenario.

  17. Overcoming Motor-Rate Limitations in Online Synchronized Robot Dancing

    Directory of Open Access Journals (Sweden)

    CatarinaB. Santiago

    2012-08-01

    Full Text Available We propose an online sensorimotor architecture for controlling a low-cost humanoid robot to perform dance movements synchronized with musical stimuli. The proposed architecture attempts to overcome the robot's motor constraints by adjusting the velocity of its actuators and inter-changing the attended beat metrical-level on-the-fly. Moreover, we propose quantitative metrics for measuring the level of beat-synchrony of the generated robot dancing motion and complement them with a qualitative survey about several aspects of the demonstrated robot dance performances. Tests with different dance movements and musical pieces demonstrated satisfactory beat-synchrony results despite the physical limitations of the robot. The comparison against robot dance sequences generated without inter-changing the attended metrical-level validated our sensorimotor approach for controlling beat-synchronous robot dancing motions using different dance movements and facing distinct musical tempo conditions.

  18. Psychological Support for Overcoming the Consequences of Aggressive Behavior

    Directory of Open Access Journals (Sweden)

    Ivanov S.

    2018-01-01

    Full Text Available This article describes the meaning of the terms „aggression“, „aggressive“ and „aggressive behavior“. It specifies the nature and basic principles of psychological counseling. It aims to present techniques and best practices for overcoming the consequences of aggressive behavior. It describes a number intervention methods such as separation of the role functions from the personal reactions; progressive muscle relaxation, pragmatism to the manifestations of undesirable behavior, breathing techniques, visualization of positive images, method of biological feedback, meditation, neuro-linguistic programming, realistic approach to events, situations and persons involved in them, clear definition of their capabilities and competencies. These ways of influence are illustrated by describing two specific cases. They are suitable for both individual and group counseling. An examination of the symptoms and consequences of the aggressive behavior provides essential information on the experiences of the counselor’s clients as well as their relationship to the past, present and future.

  19. Cell Reprogramming, IPS Limitations, and Overcoming Strategies in Dental Bioengineering

    Directory of Open Access Journals (Sweden)

    Gaskon Ibarretxe

    2012-01-01

    Full Text Available The procurement of induced pluripotent stem cells, or IPS cells, from adult differentiated animal cells has the potential to revolutionize future medicine, where reprogrammed IPS cells may be used to repair disease-affected tissues on demand. The potential of IPS cell technology is tremendous, but it will be essential to improve the methodologies for IPS cell generation and to precisely evaluate each clone and subclone of IPS cells for their safety and efficacy. Additionally, the current state of knowledge on IPS cells advises that research on their regenerative properties is carried out in appropriate tissue and organ systems that permit a safe assessment of the long-term behavior of these reprogrammed cells. In the present paper, we discuss the mechanisms of cell reprogramming, current technical limitations of IPS cells for their use in human tissue engineering, and possibilities to overcome them in the particular case of dental regeneration.

  20. Overcoming design fixation through education and creativity methods

    DEFF Research Database (Denmark)

    Howard, Thomas J.; Maier, Anja; Onarheim, Balder

    2013-01-01

    This paper reports an experiment on the topic design fixation using 12 teams of masters students working on three design problems from (Jansson and Smith 1991). The objective of the experiment is to determine the effectiveness of two interventions to help overcome fixation on example solutions....... The first intervention consisted of educating each team on the phenomena and effects of design fixation. The results showed that this intervention reduced the number of fixation elements in comparison to the control group (p=0.025). The second intervention involved using Dix et als' (2006) 'Bad Ideas......' method during a final design task. The results showed that the method did not help the teams as it caused the fixation ratio to increase and the number of ideas per team to decrease. In addition to the above mentioned interventions, the experiment also revealed a negative correlation between the number...

  1. Genecialist manifesto: overcoming the “class struggle” in medicine

    Directory of Open Access Journals (Sweden)

    Iwata K

    2013-04-01

    Full Text Available Kentaro Iwata Division of Infectious Diseases, Kobe University Hospital, Kobe, Hyogo, Japan Abstract: Generalists and specialists are often considered two completely distinct species, which culminates in the establishment of a concept of dichotomy. However, these dichotomy can at times fuel tension and even erupt into open conflict. In order to resolve this issue, the author herein proposes the concept of a “genecialist.” The genecialist refers to a hybrid comprising elements inherent to both generalists and specialists. This potentially overcomes the multitude of issues associated with both generalists and specialists in the practical aspects of medicine. The coalescence of these two contrarieties may hold the key to improving the future of health care. Mediating and integrating both categories into one consolidated entity carries the potential to stem the tide of class warfare between generalists and specialists. Keywords: genecialist, aufheben, generalist, specialist, asymmetry

  2. Study of a family that overcomes poverty issues: family resilience?

    Directory of Open Access Journals (Sweden)

    María Ángela Mattar Yunes

    2015-09-01

    Full Text Available Generally, researches with families focus the difficulties and the negative aspects of family life by bringing up their maladjustments and failures. The interest in family resilience contributes to change this logic by demonstrating the healthy aspects of the family world. Nevertheless, the term resilience presents ideological controversies which are more severe when the discussion is about families and poverty. In order to diminish these contradictions this study adopted a systemic concept of resilience which refers to “those processes that make possible to overcome adversities”. A case study was realized with a low income family who lived in a “very poor” neighborhood in the deep south of Brazil. The methodological strategies to the formal investigation of the family were: life history of the family using the principles of reflexive interview, genograms and data analyses through the approach of the grounded theory. The results showed that the family lived a number of risk experiences such as adoption, privation of basic needs, migration and diseases. Among the indicators of their abilities of “overcoming adversities”, emerged the belief system as the core of the discourses. The family showed that they value the interpersonal relationships through intra and extra familiar interactions based in the patterns of help, learning, affection and solidarity. During the crisis the family gives meaning to the difficulties in order to maintaining the situation controlled through cohesion, open communication, mutual respect and getting support of the extended family/ social network. The pos-adversity period is perceived as benefic and transforming as the family feels stronger and with feelings of solidarity, which is a mark of this family. Their attitude in relation to the neighborhood is active in the sense of promoting the welfare of other families who live in the same social address. Would those above identified processes be adequate to

  3. 38 CFR 17.152 - Devices to assist in overcoming the handicap of deafness.

    Science.gov (United States)

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Devices to assist in overcoming the handicap of deafness. 17.152 Section 17.152 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... in overcoming the handicap of deafness. Devices for assisting in overcoming the handicap of deafness...

  4. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

    Science.gov (United States)

    Tan, Li; Wang, Jun; Tanizaki, Junko; Huang, Zhifeng; Aref, Amir R.; Rusan, Maria; Zhu, Su-Jie; Zhang, Yiyun; Ercan, Dalia; Liao, Rachel G.; Capelletti, Marzia; Zhou, Wenjun; Hur, Wooyoung; Kim, NamDoo; Sim, Taebo; Gaudet, Suzanne; Barbie, David A.; Yeh, Jing-Ruey Joanna; Yun, Cai-Hong; Hammerman, Peter S.; Mohammadi, Moosa; Jänne, Pasi A.; Gray, Nathanael S.

    2014-01-01

    The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a “DFG-out” covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket. PMID:25349422

  5. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.

    Science.gov (United States)

    Tan, Li; Wang, Jun; Tanizaki, Junko; Huang, Zhifeng; Aref, Amir R; Rusan, Maria; Zhu, Su-Jie; Zhang, Yiyun; Ercan, Dalia; Liao, Rachel G; Capelletti, Marzia; Zhou, Wenjun; Hur, Wooyoung; Kim, NamDoo; Sim, Taebo; Gaudet, Suzanne; Barbie, David A; Yeh, Jing-Ruey Joanna; Yun, Cai-Hong; Hammerman, Peter S; Mohammadi, Moosa; Jänne, Pasi A; Gray, Nathanael S

    2014-11-11

    The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.

  6. Phytosphingosine can overcome resistance to ionizing radiation in ionizing radiation-resistant cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Park, Moon Taek; Choi, Jung A; Kim, Min Jeong; Bae, Sang Woo; Kang, Chang Mo; Cho, Chul Koo; Lee, Yun Sil; Lee, Su Jae [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kang, Seong Man [Graduate School of Biotechnology, Korea University, Seoul (Korea, Republic of); Chung, Hee Yong [College of Medicine, Hanyang University, Seoul (Korea, Republic of)

    2004-07-01

    Although the majority of cancer cells are killed by inonizing radiation, certain types show resistance to it. We previously reported that phytosphingosine also induces apoptotic cell death in caspase dependent pathway in human cancer cells. In the present study, we examined whether phytosphingosine could overcome radiation resistance in the variant Jurkat clones. We first selected radiation-resistant Jurkat clones and examined cross-responsiveness of the clones between radiation and phytosphingosine. Treatment with phytosphingosine significantly did not affect apoptosis in all the clones, indicating that there seemed to be cross-resistance between radiation and phytosphingosine. Nevertheless, combined treatment of phytosphingosine with radiation synergistically enhanced killing of radiation-resistant cells, compared to radiation or phytosphingosine alone. The pan-caspase inhibitor z-VAD-fmk did not completely inhibit the synergistic cell killing induced by combined treatment of ionizing radiation and phytosphingosine. These results demonstrated that apoptosis induced by combined treatment of radiation and phytosphingosine in radiation-resistant cells was associated with caspase independent pathway. We also found that apoptotic cell death induced by combined treatment of ionizing radiation and phytosphingosine correlated to the increases of ROS. The enhancement of ROS generation induced the loss of mitochondria transmembrane potential. In conclusion, ROS generation in combined treatment of phytosphingosine with radiation significantly induced the translocation of AIF to nucleus from mitochondria, suggesting a potential clinical application of combination treatment of radiation and phytosphingosine to radiation-resistant cancer cells.

  7. Nose-to-Brain Delivery of Antiviral Drugs: A Way to Overcome Their Active Efflux?

    Directory of Open Access Journals (Sweden)

    Alessandro Dalpiaz

    2018-03-01

    Full Text Available Although several viruses can easily infect the central nervous system (CNS, antiviral drugs often show dramatic difficulties in penetrating the brain from the bloodstream since they are substrates of active efflux transporters (AETs. These transporters, located in the physiological barriers between blood and the CNS and in macrophage membranes, are able to recognize their substrates and actively efflux them into the bloodstream. The active transporters currently known to efflux antiviral drugs are P-glycoprotein (ABCB1 or P-gp or MDR1, multidrug resistance-associated proteins (ABCC1 or MRP1, ABCC4 or MRP4, ABCC5 or MRP5, and breast cancer resistance protein (ABCG2 or BCRP. Inhibitors of AETs may be considered, but their co-administration causes serious unwanted effects. Nasal administration of antiviral drugs is therefore proposed in order to overcome the aforementioned problems, but innovative devices, formulations (thermoreversible gels, polymeric micro- and nano-particles, solid lipid microparticles, nanoemulsions, absorption enhancers (chitosan, papaverine, and mucoadhesive agents (chitosan, polyvinilpyrrolidone are required in order to selectively target the antiviral drugs and, possibly, the AET inhibitors in the CNS. Moreover, several prodrugs of antiretroviral agents can inhibit or elude the AET systems, appearing as interesting substrates for innovative nasal formulations able to target anti-Human Immunodeficiency Virus (HIV agents into macrophages of the CNS, which are one of the most important HIV Sanctuaries of the body.

  8. Phytosphingosine can overcome resistance to ionizing radiation in ionizing radiation-resistant cancer cells

    International Nuclear Information System (INIS)

    Park, Moon Taek; Choi, Jung A; Kim, Min Jeong; Bae, Sang Woo; Kang, Chang Mo; Cho, Chul Koo; Lee, Yun Sil; Lee, Su Jae; Park, Moon Taek; Choi, Jung A; Kim, Min Jeong; Kang, Seong Man; Chung, Hee Yong

    2004-01-01

    Although the majority of cancer cells are killed by inonizing radiation, certain types show resistance to it. We previously reported that phytosphingosine also induces apoptotic cell death in caspase dependent pathway in human cancer cells. In the present study, we examined whether phytosphingosine could overcome radiation resistance in the variant Jurkat clones. We first selected radiation-resistant Jurkat clones and examined cross-responsiveness of the clones between radiation and phytosphingosine. Treatment with phytosphingosine significantly did not affect apoptosis in all the clones, indicating that there seemed to be cross-resistance between radiation and phytosphingosine. Nevertheless, combined treatment of phytosphingosine with radiation synergistically enhanced killing of radiation-resistant cells, compared to radiation or phytosphingosine alone. The pan-caspase inhibitor z-VAD-fmk did not completely inhibit the synergistic cell killing induced by combined treatment of ionizing radiation and phytosphingosine. These results demonstrated that apoptosis induced by combined treatment of radiation and phytosphingosine in radiation-resistant cells was associated with caspase independent pathway. We also found that apoptotic cell death induced by combined treatment of ionizing radiation and phytosphingosine correlated to the increases of ROS. The enhancement of ROS generation induced the loss of mitochondria transmembrane potential. In conclusion, ROS generation in combined treatment of phytosphingosine with radiation significantly induced the translocation of AIF to nucleus from mitochondria, suggesting a potential clinical application of combination treatment of radiation and phytosphingosine to radiation-resistant cancer cells

  9. Targeting Apoptosis to Overcome Cisplatin Resistance: A Translational Study in Head and Neck Cancer

    International Nuclear Information System (INIS)

    Bauer, Joshua A.; Kumar, Bhavna; Cordell, Kitrina G.; Prince, Mark E.; Tran, Huong H.; Wolf, Gregory T.; Chepeha, Douglas B.; Teknos, Theodoros N.; Wang, Steven; Eisbruch, Avraham; Tsien, Christina I.; Urba, Susan G.; Worden, Francis P.; Lee, Julia M.S.; Griffith, Kent A.; Taylor, Jeremy; D'Silva, Nisha; Wang, Shaomeng J.; Wolter, Keith G.

    2007-01-01

    Purpose: Cisplatin resistance remains a barrier to organ-sparing and survival of patients with advanced head and neck squamous cell carcinoma (HNSCC). Targeted therapies to overcome cisplatin-resistant HNSCC are being developed. Methods and Materials: Cisplatin-sensitive parental HNSCC cell lines and cisplatin-resistant progeny were studied. Pretreatment HNSCC biopsies were used to construct tissue microarrays which were stained for p53 and Bcl-xL. Results: HNSCC cell lines selected for cisplatin resistance had wild-type p53 and high levels of Bcl-xL. Expression of wild-type p53 in cell lines with low Bcl-xL enhanced cisplatin sensitivity. Expression of both Bcl-xL and wild-type p53 caused tumor cells to become cisplatin resistant. Patients whose tumors expressed low levels of p53 and Bcl-xL enjoyed the best organ preservation and disease-free survival whereas patients whose tumors expressed low levels of p53 and high levels of Bcl-xL had the worst outcome. Novel agents that inhibit Bcl-xL or activate p53 function may target cisplatin-resistant HNSCC. Conclusion: Cisplatin resistance in HNSCC is mediated, at least in part, by high Bcl-xL and functional p53

  10. Multifunctional hyaluronic acid modified graphene oxide loaded with mitoxantrone for overcoming drug resistance in cancer

    Science.gov (United States)

    Hou, Lin; Feng, Qianhua; Wang, Yating; Yang, Xiaomin; Ren, Junxiao; Shi, Yuyang; Shan, Xiaoning; Yuan, Yujie; Wang, Yongchao; Zhang, Zhenzhong

    2016-01-01

    Multifunctional nanosheets (HA-GO/Pluronic) with targeted chemo-photothermal properties were successfully developed for controlled delivery of mitoxantrone (MIT) to overcome multidrug resistance (MDR). In vitro release profiles displayed that both an acidic environment and a NIR laser could trigger and accelerate the release of a drug, which ensured nanosheets were stable in blood circulation and released MIT within tumor cells under laser irradiation. HA-GO/Pluronic nanosheets were taken up into MCF-7/ADR cells via receptor-mediated endocytosis, which further facilitated escapement of P-gp efflux. Compared with MIT solution, MIT/HA-GO/Pluronic showed greater cytotoxicity and increase in cellular MIT accumulation in MCF-7/ADR cells. Cell apoptosis and cell cycle arrest studies also revealed that MIT/HA-GO/Pluronic was more potent than MIT/GO/Pluronic and MIT solution. The anticancer efficacy in vivo was evaluated in MCF-7 and MCF-7/ADR-bearing mice, and inhibition of tumors by MIT/HA-GO/Pluronic with NIR laser irradiation was the most effective among all MIT formulations. In summary, the MIT/HA-GO/Pluronic system had striking functions such as P-gp reversible inhibitor and anticancer efficacy, and could present a promising platform for drug-resistant cancer treatment.

  11. OVERCOMING THE ANTINOMIES OF HUMAN EXISTENCE: ONTOLOGY OF TRICKSTER

    Directory of Open Access Journals (Sweden)

    T. V. Danylova

    2014-12-01

    Full Text Available Purpose. This paper aims to study the ontological status of a trickster character in “Panchatantra” and its receptions. Methodology. The author has used analytical methodology of C. Levi-Strauss, C. Jung’s theory of archetypes, and hermeneutical methodology. Theoretical basis and results. Perception of the world in the form of a narrative is inherent in the very specifics of the human thinking. Among the most famous literary narratives that structured cultural experience of different nations are the framed story “Panchatantra” and its receptions “Kalilah and Dimnah” and “Stefanit and Ihnilat”. The framework of the analyzed text is the story about two jackals Karataka and Damanaka, Lion, and Bull. “Panchatantra” is deeply rooted in the animal epos, which is based on the totemic myth. Myths were created by primitive thinking that sought to systematize the world, to give it order through binary oppositions. Their hard core is “Life – Death” opposition. A myth deals with oppositions and seeks to neutralize them. Thus, a myth serves as the logical tool to overcome the fundamental contradictions. This is carried out by introducing a mediator. Two poles, two extreme points are unambiguous; ambiguity “occurs” at an intermediate stage only. Shift from one point to another is impossible directly – for this we need a mediator. In the given narrative the binary opposition “Life – Death” is replaced by its metaphor – Bull and Lion, herbivore (metaphor for life and carnivore (metaphor for death. These oppositions are mediated by Jackal (Karataka&Damanaka that feeds on carrion and has a dual nature. A mediator, which overcomes or at least mitigates the binary opposition, is seen as a compromise between herbivores and carnivores that embody the antinomy of life and death. This mediator is a trickster – bipolar character (good and evil at the same time. A trickster freely acts in unordered world of Chaos without Life

  12. Overcoming the obstacles: Life stories of scientists with learning disabilities

    Science.gov (United States)

    Force, Crista Marie

    Scientific discovery is at the heart of solving many of the problems facing contemporary society. Scientists are retiring at rates that exceed the numbers of new scientists. Unfortunately, scientific careers still appear to be outside the reach of most individuals with learning disabilities. The purpose of this research was to better understand the methods by which successful learning disabled scientists have overcome the barriers and challenges associated with their learning disabilities in their preparation and performance as scientists. This narrative inquiry involved the researcher writing the life stories of four scientists. These life stories were generated from extensive interviews in which each of the scientists recounted their life histories. The researcher used narrative analysis to "make sense" of these learning disabled scientists' life stories. The narrative analysis required the researcher to identify and describe emergent themes characterizing each scientist's life. A cross-case analysis was then performed to uncover commonalities and differences in the lives of these four individuals. Results of the cross-case analysis revealed that all four scientists had a passion for science that emerged at an early age, which, with strong drive and determination, drove these individuals to succeed in spite of the many obstacles arising from their learning disabilities. The analysis also revealed that these scientists chose careers based on their strengths; they actively sought mentors to guide them in their preparation as scientists; and they developed coping techniques to overcome difficulties and succeed. The cross-case analysis also revealed differences in the degree to which each scientist accepted his or her learning disability. While some demonstrated inferior feelings about their successes as scientists, still other individuals revealed feelings of having superior abilities in areas such as visualization and working with people. These individuals revealed

  13. Global Health and Emergency Care: Overcoming Clinical Research Barriers.

    Science.gov (United States)

    Levine, Adam C; Barry, Meagan A; Agrawal, Pooja; Duber, Herbert C; Chang, Mary P; Mackey, Joy M; Hansoti, Bhakti

    2017-04-01

    There are many barriers impeding the conduct of high-quality emergency care research, particularly in low- and middle-income countries. Several of these barriers were originally outlined in 2013 as part of the Academic Emergency Medicine Global Health and Emergency Care Consensus Conference. This paper seeks to establish a broader consensus on the barriers to emergency care research globally and proposes a comprehensive array of new recommendations to overcome these barriers. An electronic survey was conducted of a purposive sample of global emergency medicine research experts from around the world to describe the major challenges and solutions to conducting emergency care research in low-resource settings and rank them by importance. The Global Emergency Medicine Think Tank Clinical Research Working Group at the Society for Academic Emergency Medicine 2016 Annual Meeting utilized a modified Delphi technique for consensus-based decision making to categorize and expand upon these barriers and develop a comprehensive array of proposed solutions. The working group identified four broad categories of barriers to conducting emergency care research globally, including 1) the limited availability of research personnel, particularly those with prior research training; 2) logistic barriers and lack of standardization of data collection; 3) ethical barriers to conducting research in resource-limited settings, particularly when no local institutional review board is available; and 4) the relative dearth of funding for global emergency care research. Proposed solutions included building a diverse and interdisciplinary research team structured to promote mentorship of junior researchers, utilizing local research assistants or technologic tools such as telemedicine for language translation, making use of new tools such as mobile health (mHealth) to standardize and streamline data collection, identifying alternatives to local institutional review board approval and the use of

  14. GD1a Overcomes Inhibition of Myelination by Fibronectin via Activation of Protein Kinase A : Implications for Multiple Sclerosis

    NARCIS (Netherlands)

    Qin, Jing; Sikkema, Arend H.; van der Bij, Kristine; de Jonge, Jenny C.; Klappe, Karin; Nies, Vera; Jonker, Johan W.; Kok, Jan Willem; Hoekstra, Dick; Baron, Wia

    2017-01-01

    Remyelination failure by oligodendrocytes contributes to the functional impairment that characterizes the demyelinating disease multiple sclerosis (MS). Since incomplete remyelination will irreversibly damage axonal connections, treatments effectively promoting remyelination are pivotal in halting

  15. Barriers to women engaging in collective action to overcome sexism.

    Science.gov (United States)

    Radke, Helena R M; Hornsey, Matthew J; Barlow, Fiona Kate

    2016-12-01

    Over centuries women have fought hard to obtain increasing gender equality, but despite these successes absolute equality remains an elusive goal. Theoretically, women's numerical strength makes them well-placed to take effective collective action, and millions of women engage in feminist collective action every day. In this article, however, we argue that women also face barriers to engaging in feminist collective action; barriers that are associated with the social construction and experience of what it means to be a woman. Our review synthesizes sexism research under a contemporary collective action framework to clarify our current understanding of the literature and to offer novel theoretical explanations for why women might be discouraged from engaging in feminist collective action. Using the antecedents of collective action identified by van Zomeren, Postmes, and Spears' (2008) meta-analysis, we critically review the sexism literature to argue that women face challenges when it comes to (a) identifying with other women and feminists, (b) perceiving sexism and expressing group-based anger, and (c) recognizing the efficacy of collective action. We then outline a research agenda with a view to investigating ways of overcoming these barriers. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  16. Towards overcoming the Monte Carlo sign problem with tensor networks

    Energy Technology Data Exchange (ETDEWEB)

    Banuls, Mari Carmen; Cirac, J. Ignacio; Kuehn, Stefan [Max-Planck-Institut fuer Quantenoptik (MPQ), Garching (Germany); Cichy, Krzysztof [Frankfurt Univ. (Germany). Inst. fuer Theoretische Physik; Adam Mickiewicz Univ., Poznan (Poland). Faculty of Physics; Jansen, Karl [Deutsches Elektronen-Synchrotron (DESY), Zeuthen (Germany). John von Neumann-Inst. fuer Computing NIC; Saito, Hana [AISIN AW Co., Ltd., Aichi (Japan)

    2016-11-15

    The study of lattice gauge theories with Monte Carlo simulations is hindered by the infamous sign problem that appears under certain circumstances, in particular at non-zero chemical potential. So far, there is no universal method to overcome this problem. However, recent years brought a new class of non-perturbative Hamiltonian techniques named tensor networks, where the sign problem is absent. In previous work, we have demonstrated that this approach, in particular matrix product states in 1+1 dimensions, can be used to perform precise calculations in a lattice gauge theory, the massless and massive Schwinger model. We have computed the mass spectrum of this theory, its thermal properties and real-time dynamics. In this work, we review these results and we extend our calculations to the case of two flavours and non-zero chemical potential. We are able to reliably reproduce known analytical results for this model, thus demonstrating that tensor networks can tackle the sign problem of a lattice gauge theory at finite density.

  17. Biodiesel Production From Algae to Overcome the Energy Crisis

    Directory of Open Access Journals (Sweden)

    Suliman Khan

    2017-10-01

    Full Text Available The use of energy sources has reached at the level that whole world is relying on it. Being the major source of energy, fuels are considered the most important. The fear of diminishing the available sources thirst towards biofuel production has increased during last decades. Considering the food problems, algae gain the most attention to be used as biofuel producers. The use of crop and food-producing plants will never be a best fit into the priorities for biofuel production as they will disturb the food needs. Different types of algae having the different production abilities. Normally algae have 20%–80% oil contents that could be converted into different types of fuels such as kerosene oil and biodiesel. The diesel production from algae is economical and easy. Different species such as tribonema, ulothrix and euglena have good potential for biodiesel production. Gene technology can be used to enhance the production of oil and biodiesel contents and stability of algae. By increasing the genetic expressions, we can find the ways to achieve the required biofuel amounts easily and continuously to overcome the fuels deficiency. The present review article focusses on the role of algae as a possible substitute for fossil fuel as an ideal biofuel reactant.

  18. Overcoming social segregation in health care in Latin America.

    Science.gov (United States)

    Cotlear, Daniel; Gómez-Dantés, Octavio; Knaul, Felicia; Atun, Rifat; Barreto, Ivana C H C; Cetrángolo, Oscar; Cueto, Marcos; Francke, Pedro; Frenz, Patricia; Guerrero, Ramiro; Lozano, Rafael; Marten, Robert; Sáenz, Rocío

    2015-03-28

    Latin America continues to segregate different social groups into separate health-system segments, including two separate public sector blocks: a well resourced social security for salaried workers and their families and a Ministry of Health serving poor and vulnerable people with low standards of quality and needing a frequently impoverishing payment at point of service. This segregation shows Latin America's longstanding economic and social inequality, cemented by an economic framework that predicted that economic growth would lead to rapid formalisation of the economy. Today, the institutional setup that organises the social segregation in health care is perceived, despite improved life expectancy and other advances, as a barrier to fulfilling the right to health, embodied in the legislation of many Latin American countries. This Series paper outlines four phases in the history of Latin American countries that explain the roots of segmentation in health care and describe three paths taken by countries seeking to overcome it: unification of the funds used to finance both social security and Ministry of Health services (one public payer); free choice of provider or insurer; and expansion of services to poor people and the non-salaried population by making explicit the health-care benefits to which all citizens are entitled. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Overcoming dormancy in seeds of cotton-silk tree

    Directory of Open Access Journals (Sweden)

    Irinaldo Lima do Nascimento

    2012-06-01

    Full Text Available Cotton-silk tree Ceiba glaziovii (kuntze k. Schu belongs to family Bombacaceas and is locally known as barriguda. It is widely used in landscaping and reforestation, neverdeless seed dormancy affects reproduction in this species. The objective of this study was to evaluate the effectiveness of different methods to overcome dormancy in the germination process. Treatments included mechanical scarification with 85-grit sandpaper, chemical scarification with concentrated sulfuric acid for 5, 10, 15 and 20 minutes, physical scarification with hot water at 60°, 70°, 80°and 90° C for one minute, imbibition in distilled water for 24, 48 and 72 hours, oven heating at 65° C for 1, 2, 3 and 4 hours, and a control treatment. Each treatment included four replicates of 25 seeds, using a completely randomized experimental design, and means were compared by the Scott-Knott test at the 5% probability level. Assessed parameters included emergence percentage, emergence rate index, dry matter and length of plants. The most recommended treatments were mechanical scarification, immersion in sulfuric acid for 5, 10 and 15 minutes and immersion in distilled water for 48 hours.

  20. Emerging role of mammalian autophagy in ketogenesis to overcome starvation.

    Science.gov (United States)

    Takagi, Ayano; Kume, Shinji; Maegawa, Hiroshi; Uzu, Takashi

    2016-01-01

    Autophagy is essential for the survival of lower organisms under conditions of nutrient depletion. However, whether autophagy plays a physiological role in mammals experiencing starvation is unknown. Ketogenesis is critical for overcoming starvation in mammals. We recently revealed that hepatic and renal autophagy are involved in starvation-induced ketogenesis, by utilizing tissue-specific autophagy-deficient mouse models. The liver is the principal organ to regulate ketogenesis, and a deficiency of liver-specific autophagy partially but significantly attenuates starvation-induced ketogenesis. While deficiency of renal-specific autophagy does not affect starvation-induced ketogenesis, mice with deficiency of both liver and kidney autophagy have even lower blood ketone levels and physical activity under starvation conditions than those lacking autophagy in the liver alone. These results suggest that the kidney can compensate for impaired hepatic ketogenesis. Since ketone bodies are catabolized from fatty acids, the uptake of fatty acids, the formation of intracellular lipid droplets, and fatty acid oxidation are critical for ketogenesis. We found that starvation-induced lipid droplet formation is impaired in autophagy-deficient organs. Thus, hepatic and renal autophagy are required for starvation-induced ketogenesis. This process is essential for maintaining systemic energy homeostasis and physical activity during starvation. Our findings provide a novel insight into mammalian autophagy and the physiology of starvation.

  1. Overcoming the Obstacle of Poor Knowledge in Proving Geometry Tasks

    Directory of Open Access Journals (Sweden)

    Zlatan Magajna

    2013-12-01

    Full Text Available Proving in school geometry is not just about validating the truth of a claim. In the school setting, the main function of the proof is to convince someone that a claim is true by providing an explanation. Students consider proving to be difficult; in fact, they find the very concept of proof demanding. Proving a claim in planar geometry involves several processes, the most salient being visual observation and deductive argumentation. These two processes are interwoven, but often poor observation hinders deductive argumentation. In the present article, we consider the possibility of overcoming the obstacle of a student’s poor observation by making use of computer-aided observation with appropriate software. We present the results of two small-scale research projects, both of which indicate that students are able to work out considerably more deductions if computer-aided observation is used. Not all students use computer-aided observation effectively in proving tasks: some find an exhaustive computer-provided list of properties confusing and are not able to choose the properties that are relevant to the task.

  2. Overcoming PV grid issues in the urban areas

    Energy Technology Data Exchange (ETDEWEB)

    Ehara, T.

    2009-10-15

    This report for the International Energy Agency (IEA) made by Task 10 of the Photovoltaic Power Systems (PVPS) programme takes a look at grid issues in urban photovoltaic electricity and how to overcome them. The mission of the Photovoltaic Power Systems Programme is to enhance the international collaboration efforts which accelerate the development and deployment of photovoltaic solar energy as a significant and sustainable renewable energy option. The objective of Task 10 is stated as being to enhance the opportunities for wide-scale, solution-oriented application of photovoltaics in the urban environment. The paper discusses the goal of mainstreaming PV systems in the urban environment. In this report, PV grid interconnection issues and countermeasures based on the latest studies are identified and summarised. Appropriate and understandable information is provided for all possible stakeholders. Possible impacts and benefits of PV grid interconnection are identified, technical measures designed to eliminate negative impacts and enhance possible benefits are presented. The status of research and demonstration projects is introduced and the latest outcomes are summarised. Recommendations and conclusions based on the review process are summarised and presented.

  3. Overcoming challenges in the classification of deep geothermal potential

    Science.gov (United States)

    Breede, K.; Dzebisashvili, K.; Falcone, G.

    2015-04-01

    The geothermal community lacks a universal definition of deep geothermal systems. A minimum depth of 400 m is often assumed, with a further sub-classification into middle-deep geothermal systems for reservoirs found between 400 and 1000 m. Yet, the simplistic use of a depth cut-off is insufficient to uniquely determine the type of resource and its associated potential. Different definitions and criteria have been proposed in the past to frame deep geothermal systems. However, although they have valid assumptions, these frameworks lack systematic integration of correlated factors. To further complicate matters, new definitions such as hot dry rock (HDR), enhanced or engineered geothermal systems (EGSs) or deep heat mining have been introduced over the years. A clear and transparent approach is needed to estimate the potential of deep geothermal systems and be capable of distinguishing between resources of a different nature. In order to overcome the ambiguity associated with some past definitions such as EGS, this paper proposes the return to a more rigorous petrothermal versus hydrothermal classification. This would be superimposed with numerical criteria for the following: depth and temperature; predominance of conduction, convection or advection; formation type; rock properties; heat source type; requirement for formation stimulation and corresponding efficiency; requirement to provide the carrier fluid; well productivity (or injectivity); production (or circulation) flow rate; and heat recharge mode. Using the results from data mining of past and present deep geothermal projects worldwide, a classification of the same, according to the aforementioned criteria is proposed.

  4. Nondestructive analysis of Portuguese "dinheiros" using XRF: overcoming patina constraints

    Science.gov (United States)

    Pessanha, Sofia; Costa, Mário; Oliveira, Maria Inês; Jorge, Maria Estrela M.; Carvalho, Maria Luísa

    2015-06-01

    "Dinheiros" are the first Portuguese coins, minted with a billon alloy (majority-based copper alloyed with silver). In this work, a set of "dinheiros" from D. Fernando of Portugal was analyzed and the composition of the alloy was compared with other "dinheiros" from previous reigns. Although the coins were in good state of conservation and no active corrosion was macroscopically observable, they still presented a corrosion layer of unknown thickness that would impair the XRF quantitative determinations. In order to overcome this hindrance, the silver K/L intensity ratios were determined and compared for the analyzed samples in order to choose "clean" spots for quantitative analysis. The results show a clear decrease in the Ag content: from 7-9 % in the previous reigns to 0.2-0.3 % in the coins attributed to D. Fernando. The silver content determined is very comparable to the silver content determined in other copper or bronze artifacts analyzed, leading us to believe that this low amount of silver was not intentionally introduced to create a billon alloy but relates to impurities present in the original mineral specimen.

  5. Overcoming barriers to health service access: influencing the demand side.

    Science.gov (United States)

    Ensor, Tim; Cooper, Stephanie

    2004-03-01

    Evidence suggests that demand-side barriers may be as important as supply factors in deterring patients from obtaining treatment. Yet relatively little attention is given, either by policy makers or researchers, to ways of minimizing their effect. These barriers are likely to be more important for the poor and other vulnerable groups, where the costs of access, lack of information and cultural barriers impede them from benefiting from public spending. Demand barriers present in low- and middle-income countries and evidence on the effectiveness of interventions to overcome these obstacles are reviewed. Demand barriers are also shown to be important in richer countries, particularly among vulnerable groups. This suggests that while barriers are plentiful, there is a dearth of evidence on ways to reduce them. Where evidence does exist, the data and methodology for evaluating effectiveness and cost-effectiveness is insufficient. An increased focus on obtaining robust evidence on effective interventions could yield high returns. The likely nature of the interventions means that pragmatic policy routes that go beyond the traditional boundaries of the public health sector are required for implementing the findings.

  6. Development by Design in Western Australia: Overcoming Offset Obstacles

    Directory of Open Access Journals (Sweden)

    James Fitzsimons

    2014-02-01

    Full Text Available Biodiversity offsets can be an important tool for maintaining or enhancing environmental values in situations where development is sought despite negative environmental impacts. There are now approximately 45 compensatory mitigation programs for biodiversity impacts worldwide, with another 27 programs in development. While offsets have great potential as a conservation tool, their establishment requires overcoming a number of conceptual and methodological hurdles. In Australia, new policy changes at the national and state (i.e., Western Australia level require that offsets follow a set of general principles: (1 Environmental offsets may not be appropriate for all projects and will only be considered after avoidance and mitigation options have been pursued; (2 Environmental offsets will be based on sound environmental information and knowledge; (3 Establishing goals for offsets requires an estimate of expected direct and indirect impacts; (4 Environmental offsets will be focused on longer term strategic outcomes; (5 Environmental offsets will be cost-effective, as well as relevant and proportionate to the significance of the environmental value being impacted. Here we focus on the challenges of determining and implementing offsets using a real world example from a voluntary offset process undertaken for Barrick Gold’s Kanowna Belle mine site in Western Australia to highlight those challenges and potential solutions.

  7. [Overcoming neurological diseases-breakthrough for new era].

    Science.gov (United States)

    Mizusawa, Hidehiro

    2013-01-01

    Neurological diseases have long been thought to be difficult or intractable to be cured. Recent progress in researches on etiologies and pathogeneses of many neurological diseases, however, has made it become possible to treat some diseases such as bulbo-spinal muscular atrophy and Alzheimer's disease not only symptomatically but also in the sense of disease modification. We may be at the entrance of a new era where many neurological diseases would become treatable and overcome. My individual experiences studying 3 diseases, namely, distal myopathy with rimmed vacuoles, amyotrophic lateral sclerosis and spinocerebellar ataxia were presented and through them the following massages were conveyed to young neurologists of the Japanese Society of Neurology (JSN); To tackle the case even there is no similar case in the literature because you are the only one who could help the patient and some clues must be found, To cooperate with other colleagues and patients because you are not alone, To be reasonable, logical or scientific, To always be innovative or seek better situations, and To be global or international sharing real time information with other peoples in the world. JSN will make great leaps to the goals under the mission to contribute happiness of peoples in Japan and other countries through neurology including neurological practice, education and research.

  8. Methods for overcoming dormancy in Stryphnodendron pulcherrimum seeds

    Directory of Open Access Journals (Sweden)

    Adriano Gonçalves Pereira

    2016-09-01

    Full Text Available Seed dormancy is a phenomenon observed in several tropical species. This condition causes low and non-uniform germination. The present study was designed to identify an efficient method of breaking seed dormancy in Stryphnodendron pulcherrimum. Seeds of four mother plants were subjected to the following treatments: immersion in sulfuric acid for 2, 4, 6, 8, 10 and 12 min and scarification on 150-grit sandpaper. Seeds were sown on substrate containing sand and sawdust (1:1. It was evaluate the days to onset seedlings emergence, seedlings emergence (SE, emergence speed index (ESI, germination (G, hard seeds (HS, dead seeds (DS, dormant seeds (DMS, abnormal seedlings (AS and dry mass of aerial part (DMAP and roots (DMR. The experimental design was completely randomized with four replications of 25 seeds for each treatment. Data were subjected to analysis of variance and means compared by Tukey’s test (p < 0.05. Significant differences among treatments were observed for ESI, SE, G, HS, DMAP and DMR. Highest HS was observed in control treatment (85%. Highest G was observed in seeds scarified with sulfuric acid for 10 min (82% and 12 min (74%. These treatments also showed highest ESI, DMAP and DMR, indicating that these scarification treatments were the most efficient in overcoming dormancy.

  9. Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations

    Directory of Open Access Journals (Sweden)

    Nourah Mohammad Obaid

    2017-03-01

    Full Text Available The development of resistance to previously effective treatments has been a challenge for health care providers and a fear for patients undergoing cancer therapy. This is an unfortunately frequent occurrence for patients undergoing targeted therapy for tumours harboring the activating V600E mutation of the BRAF gene. Since the initial identification of the BRAF mutation in 2002, a series of small molecular inhibitors that target the BRAFV600E have been developed, but intrinsic and acquired resistance to these drugs has presented an ongoing challenge. More recently, improvements in therapy have been achieved by combining the use of BRAF inhibitors with other drugs, such as inhibitors of the downstream effector mitogen activated protein kinase (MAPK/extracellular-signal regulated kinase (ERK kinase (MEK. Despite improved success in response rates and in delaying resistance using combination therapy, ultimately, the acquisition of resistance remains a concern. Recent research articles have shed light on some of the underlying mechanisms of this resistance and have proposed numerous strategies that might be employed to overcome or avoid resistance to targeted therapies. This review will explore some of the resistance mechanisms, compare what is known in melanoma cancer to colorectal cancer, and discuss strategies under development to manage the development of resistance.

  10. Overcoming barriers to integrating economic analysis into risk assessment.

    Science.gov (United States)

    Hoffmann, Sandra

    2011-09-01

    Regulatory risk analysis is designed to provide decisionmakers with a clearer understanding of how policies are likely to affect risk. The systems that produce risk are biological, physical, and social and economic. As a result, risk analysis is an inherently interdisciplinary task. Yet in practice, risk analysis has been interdisciplinary in only limited ways. Risk analysis could provide more accurate assessments of risk if there were better integration of economics and other social sciences into risk assessment itself. This essay examines how discussions about risk analysis policy have influenced the roles of various disciplines in risk analysis. It explores ways in which integrated bio/physical-economic modeling could contribute to more accurate assessments of risk. It reviews examples of the kind of integrated economics-bio/physical modeling that could be used to enhance risk assessment. The essay ends with a discussion of institutional barriers to greater integration of economic modeling into risk assessment and provides suggestions on how these might be overcome. © 2011 Society for Risk Analysis.

  11. Nurse scientists overcoming challenges to lead transdisciplinary research teams.

    Science.gov (United States)

    Kneipp, Shawn M; Gilleskie, Donna; Sheely, Amanda; Schwartz, Todd; Gilmore, Robert M; Atkinson, Daryl

    2014-01-01

    Increasingly, scientific funding agencies are requiring that researchers move toward an integrated, transdisciplinary team science paradigm. Although the barriers to and rewards of conducting this type of research have been discussed in the literature, examples of how nurse investigators have led these teams to reconcile the differences in theoretical, methodological, and/or analytic perspectives that inevitably exist are lacking. In this article, we describe these developmental trajectory challenges through a case study of one transdisciplinary team, focusing on team member characteristics and the leadership tasks associated with successful transdisciplinary science teams in the literature. Specifically, we describe how overcoming these challenges has been essential to examining the complex and potentially cumulative effects that key intersections between legal, social welfare, and labor market systems may have on the health of disadvantaged women. Finally, we discuss this difficult but rewarding work within the context of lessons learned and transdisciplinary team research in relation to the future of nursing science. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Overcoming the Social Stigma on Mood Disorders with Dancing.

    Science.gov (United States)

    Tavormina, Romina; Tavormina, Maurilio Giuseppe Maria

    2017-09-01

    In our society, the social stigma against people who suffer from mood disorders is a very powerful factor that negatively affects the healing of patient. He is often isolated from the others for the fear of being judged "fool, crazy or dangerous" or discriminated and emarginated for his mental health problem. For this reason, a cornerstone of mood disorder rehabilitation is the bringing out of the patient from his isolation, the reintegration of the user in the social context with the increase and the improvement in the quality of interpersonal relationships in the family and in the external context. The method used in our project is the dance-therapy one. In particular dancing the "Bachata" becomes a rehabilitation tool to express emotions through the body and to open to the world, on the territory, overcoming the fear of being judged by others, and of the prejudice and the social stigma about mental illness. The strength and cohesion of the rehabilitation group has given to the patients the opportunity to believe in their own abilities, to accept themselves with their difficulties and to improve the relationship with their body in relation to each other.

  13. Methods to overcome dormancy in tree tomato (Solanum betaceum seeds

    Directory of Open Access Journals (Sweden)

    Carlos Kosera Neto

    2015-12-01

    Full Text Available The tree tomato (Solanum betaceum is a poorly known species that has fruits with great economic potential, as it can be consumed in natura or industrialized. However, for reaching this potential, it is necessary the development of technologies for seedlings production. The propagation of this species is mainly done by seeds, but the seed germination process is usually slow, especially under stress conditions. This study aimed at verifying whether tree tomato seeds have dormancy and which is the best method to obtain fast and uniform germination. A completely randomized design was adopted in a 5 x 2 factorial arrangement (methods to overcome dormancy x light, with four replications of 50 or 60 seeds, depending on the production cycle. The methods tested were cold stratification, hydropriming, priming with GA3 solution and control, with or without light. Seed germination and germination rate index, as well as the beginning and average time of germination, were also evaluated. The use of GA3 at a concentration of 100 mg L-1 or 300 mg L-1 is recommended to the germination of tree tomato seeds.

  14. Dormancy overcome and seedling quality of pecan in nursery

    Directory of Open Access Journals (Sweden)

    Tales Poletto

    Full Text Available ABSTRACT: This study evaluated the efficiency of methods to overcome seed dormancy in different storage periods in the production of pecan seedlings. Seeds were submitted to the following treatments: T1, T4 and T7 - control treatments (seeds with no treatment, stored at room temperature for 30, 60 and 90 days, respectively, T2, T5 and T8 - stratification (seeds were distributed in boxes with wet sand maintained at a temperature of 4°C for 30, 60 and 90 days, respectively, T3, T6 and T9 - scarification + stratification (seeds scarified with sandpaper n.80 and stratified by 30, 60 and 90 days, respectively, in completely random experimental design. Plant height, stem diameter, number of leaves, full emergence and emergence speed index (ESI were evaluated after 14 weeks of sowing. The best development of pecan 'plants, their emergence, and ESI were observed in the stratification treatment for 90 day as well as in the scarification + stratification treatment for 90 day. Storing seeds in uncontrolled environment reduced their viability.

  15. The Bellagio Declaration: overcoming hunger in the 1990's.

    Science.gov (United States)

    Alloo, F; Arizpe, L; Belford, T S; Clark, J; Csanadi, J; Davies, P J; Emmerij, L; George, S; Hyden, G; Jonsson, U

    1989-01-01

    In November 1989, 23 leading hunger experts met in Bellagio, Italy, issues a document called the "Bellagio Declaration: Overcoming Hunger in the 1990s." The report lists 4 achievable goals: eliminate famine deaths; end hunger in half of the world's poorest households; reduce by half malnutrition of mothers and small children; and eradicate iodine and vitamin A deficiencies. Famine deaths can be eliminated by setting up early-warning systems and longer-term relief objectives. The only remaining obstacle is how to prevent warring nations from blocking food deliveries and destroying food. Hunger can be eliminated in half the world's poor households by giving the poor access to resources and credit, rehabilitating degraded ecosystems, using sustainable farming, and using existing markets to distribute food equitably. Malnutrition can be halved by sustained breastfeeding, and supplementation of food and micronutrients. Iodine and vitamin A deficiencies can be eliminated by giving iodized oil injections, vitamin A capsules and iodized salt. Ways of dealing with obstacles such as population, deforestation, soil and water shortages, pollution, global warming and capital deficits in the South are discussed. There is hope that these goals can be attained because of the outbreak of peace and democracy, freeing up substantial portions of the 1 trillion US dollars spent on defense; abatement of feat of worldwide economic collapse; and evolution of a worldwide logistic system to provide emergency food aid.

  16. Overcoming multicollinearity in multiple regression using correlation coefficient

    Science.gov (United States)

    Zainodin, H. J.; Yap, S. J.

    2013-09-01

    Multicollinearity happens when there are high correlations among independent variables. In this case, it would be difficult to distinguish between the contributions of these independent variables to that of the dependent variable as they may compete to explain much of the similar variance. Besides, the problem of multicollinearity also violates the assumption of multiple regression: that there is no collinearity among the possible independent variables. Thus, an alternative approach is introduced in overcoming the multicollinearity problem in achieving a well represented model eventually. This approach is accomplished by removing the multicollinearity source variables on the basis of the correlation coefficient values based on full correlation matrix. Using the full correlation matrix can facilitate the implementation of Excel function in removing the multicollinearity source variables. It is found that this procedure is easier and time-saving especially when dealing with greater number of independent variables in a model and a large number of all possible models. Hence, in this paper detailed insight of the procedure is shown, compared and implemented.

  17. Overcoming docetaxel resistance in prostate cancer: a perspective review

    Science.gov (United States)

    2012-01-01

    The treatment of metastatic castrate-resistant prostate cancer has been historically challenging, with few therapeutic successes. Docetaxel was the first cytotoxic therapy associated with a survival benefit in castrate-resistant prostate cancer. Toxicity is typical of other cytotoxic agents, with myelosuppression being the dose-limiting toxicity and neurotoxicity also a notable side effect for some patients. Unfortunately, a significant proportion of men with castrate-resistant prostate cancer will not respond to docetaxel-based therapy and all patients will ultimately develop resistance. Because it is an effective therapy, docetaxel is likely to remain an important part of the treatment arsenal against metastatic prostate cancer for the foreseeable future, despite its toxicities and limitations. Overcoming docetaxel resistance has been a challenge since docetaxel was first established as front-line therapy for metastatic castrate-resistant prostate cancer. Recent studies have shown that several new drugs, including cabazitaxel and abiraterone, are effective after docetaxel failure, dramatically changing the therapeutic landscape for these patients. In addition, a greater understanding of the mechanisms underlying docetaxel resistance has led to several new treatment approaches which hold promise for the future. This review will discuss recent therapeutic advances in metastatic castrate-resistant prostate cancer as well as ongoing clinical trials. PMID:23118808

  18. Overcoming challenges of catastrophe modelling in data poor regions

    Science.gov (United States)

    Grassby, L.; Millinship, I.; Breinl, K.

    2012-04-01

    There is an increasing demand for loss accumulation tools in expanding international insurance markets such as India, China and Thailand. This reflects the combination of an increase in exposures in these territories as industry intensifies and urban development expands, as well as several notable natural catastrophes affecting these areas over the past few years (e.g. extreme floods in Mumbai in 2006 and in Thailand in 2011). Large, global insurers and reinsurers are embracing the opportunity to underwrite these exposures but only where adequate tools are available to provide understanding of the hazards, exposures and potential losses. Unlike more developed countries, data availability in these regions is typically limited and of poor resolution, but model development is still required in order to analyse the risk. Some of the modelling challenges associated with data limitations include: (1) dealing with a lack of hydrological data which results in greater uncertainty of the flow rate and event frequency; (2) lower DTM resolution than that available across much of Europe, which underlies the hazard component of the catastrophe model; (3) limited accessibility to data that characterises the Built Environment including information on different building types and their susceptibility to damage; and (4) a lack of claims data from previous events or engineering research into the vulnerability of different building types. This is used to generate of country and structure specific vulnerability curves that explain the relationship between hazard intensity and damages. By presenting an industry specific flood model for data-poor India in collaboration with Allianz Re, we illustrate how we have overcome many of these challenges to allow loss accumulations to be made. The resulting model was successfully validated against the floods in Mumbai and Surat in 2006 and is being developed further with the availability of new data.

  19. Overcoming equifinality: Leveraging long time series for stream metabolism estimation

    Science.gov (United States)

    Appling, Alison; Hall, Robert O.; Yackulic, Charles B.; Arroita, Maite

    2018-01-01

    The foundational ecosystem processes of gross primary production (GPP) and ecosystem respiration (ER) cannot be measured directly but can be modeled in aquatic ecosystems from subdaily patterns of oxygen (O2) concentrations. Because rivers and streams constantly exchange O2 with the atmosphere, models must either use empirical estimates of the gas exchange rate coefficient (K600) or solve for all three parameters (GPP, ER, and K600) simultaneously. Empirical measurements of K600 require substantial field work and can still be inaccurate. Three-parameter models have suffered from equifinality, where good fits to O2 data are achieved by many different parameter values, some unrealistic. We developed a new three-parameter, multiday model that ensures similar values for K600 among days with similar physical conditions (e.g., discharge). Our new model overcomes the equifinality problem by (1) flexibly relating K600 to discharge while permitting moderate daily deviations and (2) avoiding the oft-violated assumption that residuals in O2 predictions are uncorrelated. We implemented this hierarchical state-space model and several competitor models in an open-source R package, streamMetabolizer. We then tested the models against both simulated and field data. Our new model reduces error by as much as 70% in daily estimates of K600, GPP, and ER. Further, accuracy benefits of multiday data sets require as few as 3 days of data. This approach facilitates more accurate metabolism estimates for more streams and days, enabling researchers to better quantify carbon fluxes, compare streams by their metabolic regimes, and investigate controls on aquatic activity.

  20. OVERCOMING THE DISCONNECTION BETWEEN SOCIO-PEDAGOGICAL PRACTICE AND LAW

    Directory of Open Access Journals (Sweden)

    Marina P. Guriyanova

    2015-01-01

    Full Text Available The aim of the study is to discuss an urgent problem of legislative consolidation of wide spectrum for socio-pedagogical services; to demonstrate to reveal the importance of the problem decision and significance of professional work of social teachers for construction of the social state and a safe society.Methods. The research methods involve theoretical analysis of philosophical and pedagogical literature, dissertations, analysis of legislative and normative acts, system-oriented analysis of practical work of social teachers of various specializations.Results. Specifics of social teacher’s work are disclosed. Lacks of the existing standard positions regulating this activity are specified. Necessity of legislative base strengthening for a wide spectrum of socially-pedagogical services as the major measure of social policy of the state directed on support of the childhood and institute of a family is proved.Scientific novelty. The research states the problem that underlines the existing disconnection between socio-pedagogical practice and law; in formulation of a key idea of the strategic reformation in the field of the state social policy which is seen in creation of some system of guaranteed socio-pedagogical services for children and families, for other population categories that will harmonize the state social policy, as well as promote children and youth social education, overcoming family and children ill-being.Practical significance. The research findings can be used while designing legislative and regulatory acts of federal and regional levels concerning children and families protection rights, education, upbringing; developing Professional standard of social teachers by the Union of Social Teachers and Social Workers of regional divisions, and other institutions of social orientations.

  1. Cooperation of patient as key factor to overcome oral habits

    Directory of Open Access Journals (Sweden)

    Magdalena Lesmana

    2009-06-01

    Full Text Available Introduction: Orthodontic treatments have developed rapidly on the last decade even though; the sophisticated treatment has been limited by patient’s behavior. Orthodontist should acknowledge that the success of treatment not only depends on the knowledge and skill of the operator, but on the patient’s behavior as well, which is very critical to overcome the oral habit, including anterior tongue thrust swallow (ATTS. Patient’s cooperation is the key factor to set prognosis of oral habit correction and have to be proven through analysis of questioners. Methods: Patient cooperation scale (PCS was made for this research involving 68 orthodontic patients for correction of ATTS from Faculty of Dentistry Indonesia University and Ladokgi as respondents. PCS assessment was based on data sets of: Patient awareness of ATTS (PAw, Patient Acceptance to receive treatment (PAc, and Patient Comfortable for using appliances (PC. The evaluation was obtained by calculation the total score of 10 items from each component, which gave 0–30 range of scale and would be 0–90 range of cooperation scale as the final result. Result: PCS assessment can be based on data sets of PAw, PAc, and PC. It is valid and reliable. The score for the cooperative patients range between 0–25. The higher the score from this questionnaire shows less cooperation from respondent. On the other hand, the lower the score showed better cooperation. Conclusion: PCS can be used for the prognosis of the successful oral habits correction and has a significant relation with the length of successful treatment.

  2. The return to keynesianism in overcoming cyclical fluctuations?

    Directory of Open Access Journals (Sweden)

    Praščević Aleksandra

    2008-01-01

    Full Text Available The problems faced by the American economy in the second half of 2007, which intensified in 2008, have once again asked economic science, and even more so economic policy, questions relating to business cycles - the reasons for cyclical fluctuations, the character of business cycles and, naturally, economic policy measures that can be implemented to alleviate and overcome an economic recession. Since the 1970s, business cycle theories have been intensively developed - ranging from monetary theories, developed within monetarism and the first phase of New Classical Macroeconomics, to the real business cycle theory of New Classical Macroeconomics. Consequently, the triggers for the beginning of a cycle can be monetary (monetary theories or real in the form of technological shocks (real business cycles. In essence economic policy conducted since the 1970s, has rejected the Keynesian explanations of the functioning of the economic system, and thus the policy of aggregate demand management. However, the measures that are now being implemented in the USA point to a return to Keynesianism. This refers, above all, to attempts to compensate for the inefficiency of monetary policy with fiscal expansion. All three psychological propensities (propensity to consume, propensity to invest and liquidity preference in Keynes's theory and applied in Keynesian economic policy, are still the significant determinants of monetary and fiscal policies. The return to Keynesianism points to the depth of the crisis faced by the USA, but also confirms the vitality of Keynesian economics and affirms the view that - although Keynes wished to present his theory as being "general" - it is actually the theory of economic depression.

  3. Scaffold protein enigma homolog 1 overcomes the repression of myogenesis activation by inhibitor of DNA binding 2

    International Nuclear Information System (INIS)

    Nakatani, Miyuki; Ito, Jumpei; Koyama, Riko; Iijima, Masumi; Yoshimoto, Nobuo; Niimi, Tomoaki; Kuroda, Shun'ichi; Maturana, Andrés D.

    2016-01-01

    Enigma Homolog 1 (ENH1) is a scaffold protein for signaling proteins and transcription factors. Previously, we reported that ENH1 overexpression promotes the differentiation of C2C12 myoblasts. However, the molecular mechanism underlying the role of ENH1 in the C2C12 cells differentiation remains elusive. ENH1 was shown to inhibit the proliferation of neuroblastoma cells by sequestering Inhibitor of DNA binding protein 2 (Id2) in the cytosol. Id2 is a repressor of basic Helix-Loop-Helix transcription factors activity and prevents myogenesis. Here, we found that ENH1 overcome the Id2 repression of C2C12 cells myogenic differentiation and that ENH1 overexpression promotes mice satellite cells activation, the first step toward myogenic differentiation. In addition, we show that ENH1 interacted with Id2 in C2C12 cells and mice satellite cells. Collectively, our results suggest that ENH1 plays an important role in the activation of myogenesis through the repression of Id2 activity. -- Highlights: •Enigma Homolog 1 (ENH1) is a scaffold protein. •ENH1 binds to inhibitor of DNA binding 2 (Id2) in myoblasts. •ENH1 overexpression overcomes the Id2's repression of myogenesis. •The Id2-ENH1 complex play an important role in the activation of myogenesis.

  4. Scaffold protein enigma homolog 1 overcomes the repression of myogenesis activation by inhibitor of DNA binding 2

    Energy Technology Data Exchange (ETDEWEB)

    Nakatani, Miyuki [Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Nagoya, 464-8106 (Japan); Ito, Jumpei [Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Nagoya, 464-8106 (Japan); Japan Society for the Promotion of Science, Tokyo, 102-0083 (Japan); Koyama, Riko [Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Nagoya, 464-8106 (Japan); Iijima, Masumi; Yoshimoto, Nobuo [The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka, 567-0047 (Japan); Niimi, Tomoaki [Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Nagoya, 464-8106 (Japan); Kuroda, Shun' ichi [Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Nagoya, 464-8106 (Japan); The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka, 567-0047 (Japan); Maturana, Andrés D., E-mail: maturana@agr.nagoya-u.ac.jp [Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Nagoya, 464-8106 (Japan)

    2016-05-27

    Enigma Homolog 1 (ENH1) is a scaffold protein for signaling proteins and transcription factors. Previously, we reported that ENH1 overexpression promotes the differentiation of C2C12 myoblasts. However, the molecular mechanism underlying the role of ENH1 in the C2C12 cells differentiation remains elusive. ENH1 was shown to inhibit the proliferation of neuroblastoma cells by sequestering Inhibitor of DNA binding protein 2 (Id2) in the cytosol. Id2 is a repressor of basic Helix-Loop-Helix transcription factors activity and prevents myogenesis. Here, we found that ENH1 overcome the Id2 repression of C2C12 cells myogenic differentiation and that ENH1 overexpression promotes mice satellite cells activation, the first step toward myogenic differentiation. In addition, we show that ENH1 interacted with Id2 in C2C12 cells and mice satellite cells. Collectively, our results suggest that ENH1 plays an important role in the activation of myogenesis through the repression of Id2 activity. -- Highlights: •Enigma Homolog 1 (ENH1) is a scaffold protein. •ENH1 binds to inhibitor of DNA binding 2 (Id2) in myoblasts. •ENH1 overexpression overcomes the Id2's repression of myogenesis. •The Id2-ENH1 complex play an important role in the activation of myogenesis.

  5. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis

    Science.gov (United States)

    Nguyen, Mai; Marcellus, Richard C.; Roulston, Anne; Watson, Mark; Serfass, Lucile; Murthy Madiraju, S. R.; Goulet, Daniel; Viallet, Jean; Bélec, Laurent; Billot, Xavier; Acoca, Stephane; Purisima, Enrico; Wiegmans, Adrian; Cluse, Leonie; Johnstone, Ricky W.; Beauparlant, Pierre; Shore, Gordon C.

    2007-01-01

    Elevated expression of members of the BCL-2 pro-survival family of proteins can confer resistance to apoptosis in cancer cells. Small molecule obatoclax (GX15-070), which is predicted to occupy a hydrophobic pocket within the BH3 binding groove of BCL-2, antagonizes these members and induces apoptosis, dependent on BAX and BAK. Reconstitution in yeast confirmed that obatoclax acts on the pathway and overcomes BCL-2-, BCL-XL-, BCL-w-, and MCL-1-mediated resistance to BAX or BAK. The compound potently interfered with the direct interaction between MCL-1 and BAK in intact mitochondrial outer membrane and inhibited the association between MCL-1 and BAK in intact cells. MCL-1 has been shown to confer resistance to the BCL-2/BCL-XL/BCL-w-selective antagonist ABT-737 and to the proteasome inhibitor bortezomib. In both cases, this resistance was overcome by obatoclax. These findings support a rational clinical development opportunity for the compound in cancer indications or treatments where MCL-1 contributes to resistance to cell killing. PMID:18040043

  6. Combined targeting of STAT3 and STAT5: a novel approach to overcome drug resistance in chronic myeloid leukemia

    Science.gov (United States)

    Gleixner, Karoline V.; Schneeweiss, Mathias; Eisenwort, Gregor; Berger, Daniela; Herrmann, Harald; Blatt, Katharina; Greiner, Georg; Byrgazov, Konstantin; Hoermann, Gregor; Konopleva, Marina; Waliul, Islam; Cumaraswamy, Abbarna A.; Gunning, Patrick T.; Maeda, Hiroshi; Moriggl, Richard; Deininger, Michael; Lion, Thomas; Andreeff, Michael; Valent, Peter

    2017-01-01

    In chronic myeloid leukemia, resistance against BCR-ABL1 tyrosine kinase inhibitors can develop because of BCR-ABL1 mutations, activation of additional pro-oncogenic pathways, and stem cell resistance. Drug combinations covering a broad range of targets may overcome resistance. CDDO-Me (bardoxolone methyl) is a drug that inhibits the survival of leukemic cells by targeting different pro-survival molecules, including STAT3. We found that CDDO-Me inhibits proliferation and survival of tyrosine kinase inhibitor-resistant BCR-ABL1+ cell lines and primary leukemic cells, including cells harboring BCR-ABL1T315I or T315I+ compound mutations. Furthermore, CDDO-Me was found to block growth and survival of CD34+/CD38− leukemic stem cells (LSC). Moreover, CDDO-Me was found to produce synergistic growth-inhibitory effects when combined with BCR-ABL1 tyrosine kinase inhibitors. These drug-combinations were found to block multiple signaling cascades and molecules, including STAT3 and STAT5. Furthermore, combined targeting of STAT3 and STAT5 by shRNA and STAT5-targeting drugs also resulted in synergistic growth-inhibition, pointing to a new efficient concept of combinatorial STAT3 and STAT5 inhibition. However, CDDO-Me was also found to increase the expression of heme-oxygenase-1, a heat-shock-protein that triggers drug resistance and cell survival. We therefore combined CDDO-Me with the heme-oxygenase-1 inhibitor SMA-ZnPP, which also resulted in synergistic growth-inhibitory effects. Moreover, SMA-ZnPP was found to sensitize BCR-ABL1+ cells against the combination ‘CDDO-Me+ tyrosine kinase inhibitor’. Together, combined targeting of STAT3, STAT5, and heme-oxygenase-1 overcomes resistance in BCR-ABL1+ cells, including stem cells and highly resistant sub-clones expressing BCR-ABL1T315I or T315I-compound mutations. Whether such drug-combinations are effective in tyrosine kinase inhibitor-resistant patients with chronic myeloid leukemia remains to be elucidated. PMID:28596283

  7. Science, Technology and Natural Resources Policy: Overcoming Congressional Gridlock

    Science.gov (United States)

    McCurdy, K. M.

    2015-12-01

    The current status of Science, Technology and Natural Resources (STNR) policy in the United States provides an ideal context to examine the influence of committee seniority within the public policy process. Exemplars of the Policy Entrepreneur have been individuals in leadership positions, whether executive or legislative. The role of junior committee members in shaping policy innovation is less well understood, and is frequently masked either in cross-sectional research designs or in case studies. The House Natural Resources committee seniority patterns are compared to the House of Representatives Chamber data from 1975 to 2015. This expanse of congressional time captures both the policy innovation of the Class of 1974 who helped transform the public lands by pursuing a preservation agenda, along with the contemporaneous gridlock caused by disagreements about reducing the size of the federal government, a policy agenda championed and sustained by the Class of 1994. Several types of political actors have served as policy entrepreneurs, President Kennedy and Secretary of Interior Udall shepherding the Wilderness Act of 1964 from the Executive branch, or in the 111th Congress Committee chairmen Senator Christopher Dodd and Representative Barney Frank, having announced their retirements, spent their final Congress shaping the consensus that produced the Wall Street Reform and Consumer Protection Act of 2010. A less studied policy phenomenon relies on "packing the committee" to outvote the leadership. This tactic can be used by the party leadership to overcome recalcitrant senior committee members, as was the case for Democrats in the House Interior and Insular Affairs Committee shift to preservation in the 1970s, or the tactic can be employed from the grassroots, as may be happening in the case of the House Natural Resources Committee in the 114th Congress. A policy making process analog to rivers is more appropriate than a mechanistic model. As there are multiple

  8. 20% Wind by 2030: Overcoming the Challenges in West Virginia

    Energy Technology Data Exchange (ETDEWEB)

    Patrick Mann; Christine Risch

    2012-02-15

    Final Report for '20% Wind by 2030: Overcoming the Challenges in West Virginia'. The objective of this project was to examine the obstacles and constraints to the development of wind energy in West Virginia as well as the obstacles and constraints to the achievement of the national goal of 20% wind by 2030. For the portion contracted with WVU, there were four tasks in this examination of obstacles and constraints. Task 1 involved the establishment of a Wind Resource Council. Task 2 involved conducting limited research activities. These activities involved an ongoing review of wind energy documents including documents regarding the potential for wind farms being located on reclaimed surface mining sites as well as other brownfield sites. The Principal Investigator also examined the results of the Marshall University SODAR assessment of the potential for placing wind farms on reclaimed surface mining sites. Task 3 involved the conducting of outreach activities. These activities involved working with the members of the Wind Resource Council, the staff of the Regional Wind Energy Institute, and the staff of Penn Future. This task also involved the examination of the importance of transmission for wind energy development. The Principal Investigator kept informed as to transmission developments in the Eastern United States. The Principal Investigator coordinated outreach activities with the activities at the Center for Business and Economic Research at Marshall University. Task 4 involved providing technical assistance. This task involved the provision of information to various parties interested in wind energy development. The Principal Investigator was available to answer requests from interested parties regarding in formation regarding both utility scale as well as small wind development in West Virginia. Most of the information requested regarded either the permitting process for wind facilities of various sizes in the state or information regarding the

  9. The Genesis and Mechanisms to Overcome Systemic Economic Crises

    Directory of Open Access Journals (Sweden)

    Gennadii Anatol’evich Shcherbakov

    2016-05-01

    Full Text Available The paper aims to look into the origin and nature of global economic crises, the least studied phenomena of the global economic life – the phenomena, the nature of which still has not received a generally accepted explanation in economic science. Market economy has its own laws, the spontaneous nature of which is revealed in times of crises. However, the analysis of global “crisis experience” draws attention to an important feature in the implementation of various forms of crises that remains at all the stages of economic development. Some economic shocks, despite their urgency and scale, gradually give way to recovery and then – to complete recovery. Other end up with weak revival and depression, gradually turning into a new recession. Such crises, depressions, and periods of sluggish economic recovery form the “waves of crisis development” that hold the economy in a depressed condition for a long time. The impact and the consequences of these “waves” of economic shocks that are sequential or overlapping in time go beyond the medium-term economic dynamics. They occur within a long-term (Kondratiev cycle and coincide with its descending phase, when, according to empirically confirmed ideas of the great Russian economist Nikolai Kondratiev, the economy is undergoing a difficult stage of the crisis-depression development that shapes the parameters of future economic growth. The present paper unites the economic events of this stage in the concept of “systemic economic crisis”. This concept is introduced for the purpose of structuring in the single economic process the diverse phenomena occurring at the downward phase of the long-term cycle. Each of them may be due to special causes and have a separate history, but initially, all these events are subordinated to the decision of general systemic problems, and for this reason can be considered as part of the single systemic crisis, the overcoming of which provides the rise of the

  10. Jumping Hurdles: Peptides Able To Overcome Biological Barriers.

    Science.gov (United States)

    Sánchez-Navarro, Macarena; Teixidó, Meritxell; Giralt, Ernest

    2017-08-15

    diketoperazines (DKPs), (N-MePhe) n , or (PhPro) n . On the other hand, we have investigated BBB-shuttles that utilize active transport mechanisms such as SGV, THRre, or MiniAp-4. For the development of both groups, we have explored several approaches, such as the use of peptide libraries, both chemical and phage display, or hit-to-lead optimization processes. In this Account, we describe, in chronologic order, our contribution to the development of peptides able to overcome various biological barriers and our efforts to understand the mechanisms that they display. In addition, the potential use of both CPPs and BBB-shuttles to improve the transport of promising therapeutic compounds is described.

  11. Chromosome doubling to overcome the chrysanthemum cross barrier based on insight from transcriptomic and proteomic analyses.

    Science.gov (United States)

    Zhang, Fengjiao; Hua, Lichun; Fei, Jiangsong; Wang, Fan; Liao, Yuan; Fang, Weimin; Chen, Fadi; Teng, Nianjun

    2016-08-09

    Cross breeding is the most commonly used method in chrysanthemum (Chrysanthemum morifolium) breeding; however, cross barriers always exist in these combinations. Many studies have shown that paternal chromosome doubling can often overcome hybridization barriers during cross breeding, although the underlying mechanism has seldom been investigated. In this study, we performed two crosses: C. morifolium (pollen receptor) × diploid C. nankingense (pollen donor) and C. morifolium × tetraploid C. nankingense. Seeds were obtained only from the latter cross. RNA-Seq and isobaric tags for relative and absolute quantitation (iTRAQ) were used to investigate differentially expressed genes and proteins during key embryo development stages in the latter cross. A previously performed cross, C. morifolium × diploid C. nankingense, was compared to our results and revealed that transcription factors (i.e., the agamous-like MADS-box protein AGL80 and the leucine-rich repeat receptor protein kinase EXS), hormone-responsive genes (auxin-binding protein 1), genes and proteins related to metabolism (ATP-citrate synthase, citrate synthase and malate dehydrogenase) and other genes reported to contribute to embryo development (i.e., LEA, elongation factor and tubulin) had higher expression levels in the C. morifolium × tetraploid C. nankingense cross. In contrast, genes related to senescence and cell death were down-regulated in the C. morifolium × tetraploid C. nankingense cross. The data resources helped elucidate the gene and protein expression profiles and identify functional genes during different development stages. When the chromosomes from the male parent are doubled, the genes contributing to normal embryo developmentare more abundant. However, genes with negative functions were suppressed, suggesting that chromosome doubling may epigenetically inhibit the expression of these genes and allow the embryo to develop normally.

  12. Overcoming Barriers of Age to Enhance Efficacy of Cancer Immunotherapy: The Clout of the Extracellular Matrix

    Directory of Open Access Journals (Sweden)

    Mark Owyong

    2018-03-01

    Full Text Available There is a growing list of cancer immunotherapeutics approved for use in a population with an increasing number of aged individuals. Cancer immunotherapy (CIT mediates tumor destruction by activating anti-tumor immune responses that have been silenced through the oncogenic process. However, in an aging individual, immune deregulation is positively correlated with age. In this context, it is vital to examine the age-related changes in the tumor microenvironment (TME and specifically, those directly affecting critical players to ensure CIT efficacy. Effector T cells, regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and tumor-associated neutrophils play important roles in promoting or inhibiting the inflammatory response, while cancer-associated fibroblasts are key mediators of the extracellular matrix (ECM. Immune checkpoint inhibitors function optimally in inflamed tumors heavily invaded by CD4 and CD8 T cells. However, immunosenescence curtails the effector T cell response within the TME and causes ECM deregulation, creating a biophysical barrier impeding both effective drug delivery and pro-inflammatory responses. The ability of the chimeric antigen receptor T (CAR-T cell to artificially induce an adaptive immune response can be modified to degrade essential components of the ECM and alleviate the age-related changes to the TME. This review will focus on the age-related alterations in ECM and immune-stroma interactions within the TME. We will discuss strategies to overcome the barriers of immunosenescence and matrix deregulation to ameliorate the efficacy of CIT in aged subjects.

  13. Complement-Opsonized HIV-1 Overcomes Restriction in Dendritic Cells.

    Directory of Open Access Journals (Sweden)

    Wilfried Posch

    2015-06-01

    Full Text Available DCs express intrinsic cellular defense mechanisms to specifically inhibit HIV-1 replication. Thus, DCs are productively infected only at very low levels with HIV-1, and this non-permissiveness of DCs is suggested to go along with viral evasion. We now illustrate that complement-opsonized HIV-1 (HIV-C efficiently bypasses SAMHD1 restriction and productively infects DCs including BDCA-1 DCs. Efficient DC infection by HIV-C was also observed using single-cycle HIV-C, and correlated with a remarkable elevated SAMHD1 T592 phosphorylation but not SAMHD1 degradation. If SAMHD1 phosphorylation was blocked using a CDK2-inhibitor HIV-C-induced DC infection was also significantly abrogated. Additionally, we found a higher maturation and co-stimulatory potential, aberrant type I interferon expression and signaling as well as a stronger induction of cellular immune responses in HIV-C-treated DCs. Collectively, our data highlight a novel protective mechanism mediated by complement opsonization of HIV to effectively promote DC immune functions, which might be in the future exploited to tackle HIV infection.

  14. Overcoming regulatory barriers: DOE environmental technology development program

    International Nuclear Information System (INIS)

    Kurtyka, B.M.; Clodfelter-Schumack, K.; Evans, T.T.

    1995-01-01

    The potential to improve environmental conditions via compliance or restoration is directly related to the ability to produce and apply innovative technological solutions. However, numerous organizations, including the US General Accounting Office (GAO), the EPA National Advisory Council for Environmental Policy and Technology (NACEPT), the DOE Environmental Management Advisory Board (EMAB), and the National Science and Technology Council (NSTC) have determined that significant regulatory barriers exist that inhibit the development and application of these technologies. They have noted the need for improved efforts in identifying and rectifying these barriers for the purpose of improving the technology development process, providing innovative alternatives, and enhancing the likelihood of technology acceptance by all. These barriers include, among others, regulator and user bias against ''unknown/unproven'' technologies; multi-level/multi-media permit disincentives; potential liability of developers and users for failed implementation; wrongly defined or inadequate data quality objectives: and lack of customer understanding and input. The ultimate goal of technology development is the utilization of technologies. This paper will present information on a number of regulatory barriers hindering DOE's environmental technology development program and describe DOE efforts to address these barriers

  15. Overcoming Barriers in the Implementation of Environmental Remediation Projects

    International Nuclear Information System (INIS)

    2013-01-01

    characterization techniques and strategies; assessment of remediation technologies; techniques and strategies for post-remediation compliance monitoring; special issues such as the remediation of sites with dispersed radioactive contamination or mixed contamination by hazardous and radioactive substances, as well as monitored natural attenuation; and long term management issues at sites with residual contamination. It was noted that, although the understanding of the need to address radiological liabilities had gained considerable momentum since the end of the Cold War, in many Member States actual remediation programmes have made little progress beyond the assessment and perhaps the planning phase. This publication analyses the various drivers for remediation projects, possible obstacles and potential solutions to overcome those obstacles. It is noted that care must be taken when establishing measures that are intended to foster increased protection, for example a very prescriptive regulatory framework, as such measures may turn out to be counterproductive. The main obstacle in most cases is a lack of funding. A number of creative ways to structure projects and to identify sources of funds are discussed in this book.

  16. Using Play and Art Therapy to Help Culturally Diverse Students Overcome Barriers to School Success.

    Science.gov (United States)

    Cochran, Jeff L.

    1996-01-01

    Counseling approaches for elementary school students using play and art therapy techniques can help overcome cultural barriers. Discusses benefits of play and art therapy for helping culturally different students overcome barriers to school success, and reviews two programs that use art and play therapy as primary tools. (JPS)

  17. Adolescents' Self-Efficacy to Overcome Barriers to Physical Activity Scale

    Science.gov (United States)

    Dwyer, John J. M.; Chulak, Tala; Maitland, Scott; Allison, Kenneth R.; Lysy, Daria C.; Faulkner, Guy E. J.; Sheeshka, Judy

    2012-01-01

    This paper describes a revised measure of self-efficacy to overcome barriers to moderate and vigorous physical activity in a sample of 484 high school students in Toronto, Ontario. The students had a mean age of 15.3 years. Principal axis factoring with oblique rotation yielded five factors: self-efficacy to overcome internal, harassment, physical…

  18. Sustainability and energy self-sufficiency; overcoming the barriers

    Directory of Open Access Journals (Sweden)

    Rania Abdel Galil

    2015-12-01

    on the energy sustainability front (WEC, 2013. That is not to say that social barriers do not exist. They are manifested in the hindrance of knowledge transfer between social actors including misinformation, inadequate public consultation, and lack of inertia, access to relevant professional services, expertise and skills. Also, community concern over aesthetics, environmental issues and a perception of unequal distribution of benefits. However, in the MENA there is barely any awareness on the issue of energy security, equity and sustainability among individuals and the society, with lack of education and information on production and consumption, and no incentives for change. The rate of adoption, although not homogenous across the region, has been slow to date. Policy makers will not be persuaded to change, as a bottom-up approach is unlikely and the market will not develop accordingly, for lack of demand. Also, top-bottom approaches will be ineffective as the adoption of new systems are often met with resistance and the uptake will require change of entrenched practices and incentives for adoption.Challenges to the wider adoption of renewable energy lie in two areas; provision and choice. The later can be overcome by awareness campaigns, incentive-based initiatives, and involving and empowering individuals and local communities in the development of renewable energy solutions. There is an urgent need to support initiatives in the MENA region to collaborate on environmental and energy related issues, build capacities to enable civil society engagement in the context of developing and implementing national energy plans and increase awareness on the needed shift towards a sustainable energy future. Meaningful global price for carbon is but one example to provide incentives for everyone to play their role in meeting the world’s increasing energy needs whilst combating climate change and maintaining good air and water quality.  To conclude, a quote by the United

  19. The Existential Turn: Reappraising Being and Time’s Overcoming of Metaphysics

    OpenAIRE

    Rufus Duits

    2010-01-01

    The task of this paper is to propose an answer to these relatedquestions. It amounts to an attempt to work through conceptually step by step Heidegger’s so called “overcoming of metaphysics”. It is true of course that the locution, “the overcoming of metaphysics”, does not appear in Being and Time. The discourse of the overcoming of metaphysics is held by Heidegger’s commentators to belong to a period post-dating the early work, after the so called Kehre. I shall stubbornly evade this knotty ...

  20. Renewable energy strategies to overcome power shortage in Kurdistan Region of Iraq

    Directory of Open Access Journals (Sweden)

    Al-Din Salar Salah Muhy

    2017-01-01

    Full Text Available The aim of this paper is to investigate the possibility of applying renewable energy strategies in Kurdistan Region of Iraq to overcome the shortage of electricity supply. Finding alternative renewable sources could overcome the problem. The renewable energy will reduce CO2 emission in the cities which considers the main source of pollution. That will participate in reducing the effect of global warming. The study tries to investigate the direct solar renewable energy through two of the main renewable energy categories to produce electricity based on a survey of literature review. Photovoltaic and wind power technologies are possible to be conducted in the region to overcome power shortage.

  1. Prioritising the implementation of practices to overcome operational barriers in reverse logistics

    Directory of Open Access Journals (Sweden)

    Amanda Badenhorst

    2016-09-01

    Conclusion: The framework developed in this article will enable organisations to identify the operational barriers they experience in reverse logistics and the practices they can implement on a priority basis to overcome these barriers.

  2. Overcoming Resistance to Change: An Analysis to the Department of Defense's Anthrax Vaccine Immunization Program

    National Research Council Canada - National Science Library

    Johnson, Irene

    2004-01-01

    The goal of this research was to investigate the impact of change on organizations, in the absence of a preparedness program and to develop strategies for overcoming resistance to change, in the midst...

  3. Effect of creativity on overcoming the person`s existential crisis

    Directory of Open Access Journals (Sweden)

    V. S. Grekova

    2014-05-01

    The problem of the modern study of the impact of creativity to overcome existential crisis and subsequent mapping of human existential experiences in her creative life position is relevant to the subject of scientific research.

  4. Sulfite pretreatment to overcome recalcitrance of lignocellulose (SPORL) for robust enzymatic saccharification of hardwoods

    Science.gov (United States)

    G. S. Wang; X. J. Pan; Junyong Zhu; Roland Gleisner; D. Rockwood

    2009-01-01

    This study demonstrates sulfite pretreatment to overcome recalcitrance of lignocellulose (SPORL) for robust bioconversion of hardwoods. With only about 4% sodium bisulfite charge on aspen and 30-min pretreatment at temperature 180[...

  5. Overcoming barriers to ITS : lessons from other technologies : final task E report

    Science.gov (United States)

    1995-12-01

    The Task E report involves an analysis of franchises and license agreements for the provision of public : services, which is the fourth in a series in the study. Overcoming Barriers to ITS - Lessons from Other : Technologies. This report follows alte...

  6. Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells.

    Science.gov (United States)

    Cheng, Ran; Liu, Ya-Jing; Cui, Jun-Wei; Yang, Man; Liu, Xiao-Ling; Li, Peng; Wang, Zhan; Zhu, Li-Zhang; Lu, Si-Yi; Zou, Li; Wu, Xiao-Qin; Li, Yu-Xia; Zhou, You; Fang, Zheng-Yu; Wei, Wei

    2017-05-02

    Tamoxifen is still the most commonly used endocrine therapy drug for estrogen receptor (ER)-positive breast cancer patients and has an excellent outcome, but tamoxifen resistance remains a great impediment to successful treatment. Recent studies have prompted an anti-tumor effect of aspirin. Here, we demonstrated that aspirin not only inhibits the growth of ER-positive breast cancer cell line MCF-7, especially when combined with tamoxifen, but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. Aspirin combined with tamoxifen can down regulate cyclinD1 and block cell cycle in G0/G1 phase. Besides, tamoxifen alone represses c-myc, progesterone receptor (PR) and cyclinD1 in MCF-7 cell line but not in MCF-7/TAM, while aspirin combined with tamoxifen can inhibit the expression of these proteins in the resistant cell line. When knocking down c-myc in MCF-7/TAM, cells become more sensitive to tamoxifen, cell cycle is blocked as well, indicating that aspirin can regulate c-myc and cyclinD1 proteins to overcome tamoxifen resistance. Our study discovered a novel role of aspirin based on its anti-tumor effect, and put forward some kinds of possible mechanisms of tamoxifen resistance in ER-positive breast cancer cells, providing a new strategy for the treatment of ER-positive breast carcinoma.

  7. OVERCOMING THE FEAR OF OPEN WATER AT THE INITIAL STAGE OF LEARNING TO SWIM

    OpenAIRE

    Obrazhey, Olga

    2017-01-01

    The article deals with the fear of children of primary school age to open water, which appears at the initial stage of teaching swimming and is a serious obstacle to mastering the skills of swimming. Analysis of the scientific researches indicate a lack of reasonable methods of overcoming fears associated with the water during swimming training and scientific methodological developments in the prevention and overcoming fears associated with water, which leads to certain problems and violation...

  8. Overcoming Resistance to Inhibitors of the Akt Protein Kinase by Modulation of the Pim Kinase Pathway

    Science.gov (United States)

    2017-01-01

    prostate cancer patients have abnormalities in the AKT signaling pathway. These abnormalities are driven by mutations in the PTEN and AKT proteins as...AWARD NUMBER: W81XWH-12-1-0560 TITLE: Overcoming Resistance to Inhibitors of the Akt Protein Kinase by Modulation of the Pim Kinase Pathway...2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Overcoming Resistance to Inhibitors of the Akt Protein Kinase by Modulation of the Pim Kinase

  9. TV Inhibiting Creative Ideas

    Science.gov (United States)

    Intellect, 1977

    1977-01-01

    Television may be inhibiting our ability to create new ideas, according to Eric Somers, assistant professor of journalism at Drake University. Discusses television's role as facilitator of information and how it should improve to increase organization and the creative process. (Editor/RK)

  10. Enzyme inhibition by iminosugars

    DEFF Research Database (Denmark)

    López, Óscar; Qing, Feng-Ling; Pedersen, Christian Marcus

    2013-01-01

    Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes...

  11. Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs.

    Science.gov (United States)

    Bunjobpol, W; Dulloo, I; Igarashi, K; Concin, N; Matsuo, K; Sabapathy, K

    2014-08-01

    Enhanced resistance to chemotherapy has been correlated with high levels of Delta-Np73 (DNp73), an anti-apoptotic protein of the p53 tumor-suppressor family which inhibits the pro-apoptotic members such as p53 and TAp73. Although genotoxic drugs have been shown to induce DNp73 degradation, lack of mechanistic understanding of this process precludes strategies to enhance the targeting of DNp73 and improve treatment outcomes. Antizyme (Az) is a mediator of ubiquitin-independent protein degradation regulated by the polyamine biosynthesis pathway. We show here that acetylpolyamine oxidase (PAOX), a catabolic enzyme of this pathway, upregulates DNp73 levels by suppressing its degradation via the Az pathway. Conversely, downregulation of PAOX activity by siRNA-mediated knockdown or chemical inhibition leads to DNp73 degradation in an Az-dependent manner. PAOX expression is suppressed by several genotoxic drugs, via selected members of the activator protein-1 (AP-1) transcription factors, namely c-Jun, JunB and FosB, which are required for stress-mediated DNp73 degradation. Finally, chemical- and siRNA-mediated inhibition of PAOX significantly reversed the resistant phenotype of DNp73-overexpressing cancer cells to genotoxic drugs. Together, these data define a critical mechanism for the regulation of DNp73 abundance, and reveal that inhibition of PAOX could widen the therapeutic index of cytotoxic drugs and overcome DNp73-mediated chemoresistance in tumors.

  12. Prevention of dipyrone (metamizole) induced inhibition of aspirin antiplatelet effects.

    Science.gov (United States)

    Polzin, Amin; Richter, Stefan; Schrör, Karsten; Rassaf, Tienush; Merx, Marc W; Kelm, Malte; Hohlfeld, Thomas; Zeus, Tobias

    2015-07-01

    We have recently shown that dipyrone (metamizole), a non-opioid analgesic, can nullify aspirin (acetylsalicylic acid; ASA) antiplatelet effects in patients with coronary artery disease (CAD). In this study, we analysed the aspirin and dipyrone drug-drug interaction in order to identify strategies to prevent the dipyrone induced inhibition of asprin antiplatelet effects. Platelet function was measured by arachidonic acid-induced light-transmission aggregometry, thromboxane (TX) B2- formation by immunoassay. Dipyrone metabolite plasma levels were determined by high-performance-liquid-chromatography (HPLC). In seven healthy individuals, in vitro ASA (30 µM/ 100 µM/ 300 µM/ 1,000 µM) and dipyrone (10 µM) coincubation revealed, that the aspirin and dipyrone interaction can be overcome by increasing doses of aspirin. In 36 aspirin and dipyrone comedicated CAD patients, addition of ASA (30 µM/ 100 µM) in vitro inhibited, but did not completely overcome the dipyrone induced reduction of aspirin antiplatelet effects. Notably, the inhibition of thromboxane formation in aspirin and dipyrone comedicated CAD patients coincided with dipyrone plasma levels. In a cross-over designed study in four healthy individuals, we were able to prove that inhibition of aspirin (100 mg/ day) effects by dipyrone (750 mg/ day) was reversible. Furthermore, aspirin (100 mg/ day) medication prior to dipyrone (750 mg/ day) intake prevented the inhibition of antiplatelet effects by dipyrone in 12 healthy individuals. In conclusion, aspirin medication prior to dipyrone intake preserves antiplatelet effects, circumventing the pharmacodynamic drug-drug interaction at the level of cyclooxygenase-1.

  13. Systematic evaluation of multifunctional paclitaxel-loaded polymeric mixed micelles as a potential anticancer remedy to overcome multidrug resistance.

    Science.gov (United States)

    Zhang, Jiulong; Zhao, Xiufeng; Chen, Qing; Yin, Xiaoyi; Xin, Xiu; Li, Kexin; Qiao, Mingxi; Hu, Haiyang; Chen, Dawei; Zhao, Xiuli

    2017-03-01

    Multidrug resistance (MDR) of tumor cells is becoming the main reason for the failure of chemotherapy and P-glycoprotein (P-gp) mediated drug efflux has demonstrated to be the key factor for MDR. To address this issue, a novel pH-responsive mixed micelles drug delivery system composed of dextran-g-poly(lactide-co-glycolide)-g-histidine (HDP) and folate acid-D-α-tocopheryl polyethylene glycol 2000 (FA-TPGS2K) copolymers has been designed for the delivery of antitumor agent, paclitaxel (PTX) via FA-receptor mediated cell endocytosis, into PTX-resistant breast cancer MCF-7 cells (MCF-7/PTX). PTX-loaded FA-TPGS2K/HDP mixed micelles were characterized to have a small size distribution, high loading content and excellent pH-responsive drug release profiles. Compared with HDP micelles, FA-TPGS2K/HDP mixed micelles showed a higher cytotoxicity against MCF-7 and MCF-7/PTX cells due to the synergistic effect of FA-receptor mediated cell endocytosis, pH-responsive drug release and TPGS mediated P-gp inhibition. P-gp expression level, ATP content and mitochondrial membrane potential change have been measured, the results indicated blank FA-TPGS2K/HDP mixed micelles could inhibit the P-gp activity by reducing the mitochondrial membrane potential and depleting ATP content but not down-regulating the P-gp expression. In vivo antitumor activities demonstrated FA-TPGS2K/HDP mixed micelles could reach higher antitumor activity compared with HDP micelles for MCF-7/PTX tumor cells. Histological assay also indicated that FA-TPGS2K/HDP mixed micelles showed strongly apoptosis inducing effect, anti-proliferation effect and anti-angiogenesis effect. All these evidences demonstrated this pH-sensitive FA-TPGS2K/HDP micelle-based drug delivery system is a promising approach for overcoming MDR. In this work, a novel FA-TPGS2K copolymer has been synthesized and used it to construct mixed micelles with HDP copolymer to overcome MDR effect. Furthermore, a series in vitro and in vivo evaluations

  14. Inhibiting the inevitable

    DEFF Research Database (Denmark)

    Shashoua, Yvonne

    2006-01-01

    conservation is to ‘buy time’ for the object. Inhibitive conservation of plastics involves the removal or reduction of factors causing or accelerating degradation including light, oxygen, acids, relative humidity and acidic breakdown products. Specific approaches to conservation have been developed......Once plastics objects are registered in museum collections, the institution becomes responsible for their long term preservation, until the end of their useful lifetime. Plastics appear to deteriorate faster than other materials in museum collections and have a useful lifetime between 5 and 25...... years. Preventive or inhibitive conservation involves controlling the environments in which objects are placed during storage and display, with the aim of slowing the major deterioration reactions. Once in progress, degradation of plastics cannot be stopped or reversed, so the aim of preventive...

  15. Plastics for corrosion inhibition

    CERN Document Server

    Goldade, Victor A; Makarevich, Anna V; Kestelman, Vladimir N

    2005-01-01

    The development of polymer composites containing inhibitors of metal corrosion is an important endeavour in modern materials science and technology. Corrosion inhibitors can be located in a polymer matrix in the solid, liquid or gaseous phase. This book details the thermodynamic principles for selecting these components, their compatibility and their effectiveness. The various mechanisms of metal protection – barrier, inhibiting and electromechanical – are considered, as are the conflicting requirements placed on the structure of the combined material. Two main classes of inhibited materials (structural and films/coatings) are described in detail. Examples are given of structural plastics used in friction units subjected to mechano-chemical wear and of polymer films/coatings for protecting metal objects against corrosion.

  16. Overcoming challenges

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  4. Overcoming Absence

    DEFF Research Database (Denmark)

    Paldam, Camilla Skovbjerg

    2017-01-01

    In this chapter, I address the rhetoric of modern love correspondence – its various purposes, modes of communication, and meta-reflections on writing and media – from the beginning of the 20th century till today. I analyze how love and the beloved are mediated in the articulated desire and longin......-time video chat like Skype....

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  6. Barriers to Social Innovation and Ways of Overcoming them in Latvia

    Directory of Open Access Journals (Sweden)

    Karine Oganisjana

    2017-10-01

    Full Text Available The paper presents the findings of research conducted to determine the main barriers to social innovation in Latvia and explore the ways they are overcome. The analysis of the qualitative and quantitative data collected while interviewing social innovation projects revealed eight barriers to social innovation. Lack of financing, passivity in the society and administrative and bureaucratic barriers are most frequently faced here. The qualitative content analysis disclosed nine means for overcoming the barriers to social innovation. Three of them: promotional activities, external financial support and external support are most common. Each barrier to social innovation was analyzed also in regard with the means utilized for overcoming it. It showed that there is no universal way to overcome a certain barrier. There could be different combinations of means and actions undertaken. However, the most powerful mean in overcoming barriers to social innovation in Latvia turned out to be promotional activities defined as a set of activities aimed to: educate the society, encourage stakeholders to participate in the project, raise awareness about the topicality of the problem and share information about solutions with the project's target group.

  7. The Existential Turn: Reappraising Being and Time’s Overcoming of Metaphysics

    Directory of Open Access Journals (Sweden)

    Rufus Duits

    2010-06-01

    Full Text Available The task of this paper is to propose an answer to these relatedquestions. It amounts to an attempt to work through conceptually step by step Heidegger’s so called “overcoming of metaphysics”. It is true of course that the locution, “the overcoming of metaphysics”, does not appear in Being and Time. The discourse of the overcoming of metaphysics is held by Heidegger’s commentators to belong to a period post-dating the early work, after the so called Kehre. I shall stubbornly evade this knotty issue of Heidegger interpretation here. For my purposes it suffices merely if our understanding ofBeing and Time, its content, intent and consequence, can be deepened or expanded if it is read in the light of the task of overcoming metaphysics—or at least in the light of that task as it is to be conceived in the context I shall present here. What is to be understood by the phrase “the overcoming of metaphysics”?

  8. Scaffold protein enigma homolog 1 overcomes the repression of myogenesis activation by inhibitor of DNA binding 2.

    Science.gov (United States)

    Nakatani, Miyuki; Ito, Jumpei; Koyama, Riko; Iijima, Masumi; Yoshimoto, Nobuo; Niimi, Tomoaki; Kuroda, Shun'ichi; Maturana, Andrés D

    2016-05-27

    Enigma Homolog 1 (ENH1) is a scaffold protein for signaling proteins and transcription factors. Previously, we reported that ENH1 overexpression promotes the differentiation of C2C12 myoblasts. However, the molecular mechanism underlying the role of ENH1 in the C2C12 cells differentiation remains elusive. ENH1 was shown to inhibit the proliferation of neuroblastoma cells by sequestering Inhibitor of DNA binding protein 2 (Id2) in the cytosol. Id2 is a repressor of basic Helix-Loop-Helix transcription factors activity and prevents myogenesis. Here, we found that ENH1 overcome the Id2 repression of C2C12 cells myogenic differentiation and that ENH1 overexpression promotes mice satellite cells activation, the first step toward myogenic differentiation. In addition, we show that ENH1 interacted with Id2 in C2C12 cells and mice satellite cells. Collectively, our results suggest that ENH1 plays an important role in the activation of myogenesis through the repression of Id2 activity. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Thermoresponsive Supramolecular Chemotherapy by "V"-Shaped Armed β-Cyclodextrin Star Polymer to Overcome Drug Resistance.

    Science.gov (United States)

    Fan, Xiaoshan; Cheng, Hongwei; Wang, Xiaoyuan; Ye, Enyi; Loh, Xian Jun; Wu, Yun-Long; Li, Zibiao

    2018-04-01

    Pump mediated drug efflux is the key reason to result in the failure of chemotherapy. Herein, a novel star polymer β-CD-v-(PEG-β-PNIPAAm) 7 consisting of a β-CD core, grafted with thermo-responsive poly(N-isopropylacrylamide) (PNIPAAm) and biocompatible poly(ethylene glycol) (PEG) in the multiple "V"-shaped arms is designed and further fabricated into supramolecular nanocarriers for drug resistant cancer therapy. The star polymer could encapsulate chemotherapeutics between β-cyclodextrin and anti-cancer drug via inclusion complex (IC). Furthermore, the temperature induced chain association of PNIPAAm segments facilitated the IC to form supramolecular nanoparticles at 37 °C, whereas the presence of PEG impart great stability to the self-assemblies. When incubated with MDR-1 membrane pump regulated drug resistant tumor cells, much higher and faster cellular uptake of the supramolecular nanoparticles were detected, and the enhanced intracellular retention of drugs could lead to significant inhibition of cell growth. Further in vivo evaluation showed high therapeutic efficacy in suppressing drug resistant tumor growth without a significant impact on the normal functions of main organs. This work signifies thermo-responsive supramolecular chemotherapy is promising in combating pump mediated drug resistance in both in vitro and in vivo models, which may be encouraging for the advanced drug delivery platform design to overcome drug resistant cancer. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Bispecific antibody to ErbB2 overcomes trastuzumab resistance through comprehensive blockade of ErbB2 heterodimerization.

    Science.gov (United States)

    Li, Bohua; Meng, Yanchun; Zheng, Lei; Zhang, Xunmin; Tong, Qing; Tan, Wenlong; Hu, Shi; Li, Hui; Chen, Yang; Song, Jinjing; Zhang, Ge; Zhao, Lei; Zhang, Dapeng; Hou, Sheng; Qian, Weizhu; Guo, Yajun

    2013-11-01

    The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer. However, resistance to trastuzumab is common. Heterodimerization between ErbB2 and other ErbBs may redundantly trigger cell proliferation signals and confer trastuzumab resistance. Here, we developed a bispecific anti-ErbB2 antibody using trastuzumab and pertuzumab, another ErbB2-specific humanized antibody that binds to a distinct epitope from trastuzumab. This bispecific antibody, denoted as TPL, retained the full binding activities of both parental antibodies and exhibited pharmacokinetic properties similar to those of a conventional immunoglobulin G molecule. Unexpectedly, TPL showed superior ErbB2 heterodimerization-blocking activity over the combination of both parental monoclonal antibodies, possibly through steric hindrance and/or inducing ErbB2 conformational change. Further data indicated that TPL potently abrogated ErbB2 signaling in trastuzumab-resistant breast cancer cell lines. In addition, we showed that TPL was far more effective than trastuzumab plus pertuzumab in inhibiting the growth of trastuzumab-resistant breast cancer cell lines, both in vitro and in vivo. Importantly, TPL treatment eradicated established trastuzumab-resistant tumors in tumor-bearing nude mice. Our results suggest that trastuzumab-resistant breast tumors remain dependent on ErbB2 signaling and that comprehensive blockade of ErbB2 heterodimerization may be an effective therapeutic avenue. The unique potential of TPL to overcome trastuzumab resistance warrants its consideration as a promising treatment in the clinic.

  11. Rationally engineered nanoparticles target multiple myeloma cells, overcome cell-adhesion-mediated drug resistance, and show enhanced efficacy in vivo

    International Nuclear Information System (INIS)

    Kiziltepe, T; Ashley, J D; Stefanick, J F; Qi, Y M; Alves, N J; Handlogten, M W; Suckow, M A; Navari, R M; Bilgicer, B

    2012-01-01

    In the continuing search for effective cancer treatments, we report the rational engineering of a multifunctional nanoparticle that combines traditional chemotherapy with cell targeting and anti-adhesion functionalities. Very late antigen-4 (VLA-4) mediated adhesion of multiple myeloma (MM) cells to bone marrow stroma confers MM cells with cell-adhesion-mediated drug resistance (CAM-DR). In our design, we used micellar nanoparticles as dynamic self-assembling scaffolds to present VLA-4-antagonist peptides and doxorubicin (Dox) conjugates, simultaneously, to selectively target MM cells and to overcome CAM-DR. Dox was conjugated to the nanoparticles through an acid-sensitive hydrazone bond. VLA-4-antagonist peptides were conjugated via a multifaceted synthetic procedure for generating precisely controlled number of targeting functionalities. The nanoparticles were efficiently internalized by MM cells and induced cytotoxicity. Mechanistic studies revealed that nanoparticles induced DNA double-strand breaks and apoptosis in MM cells. Importantly, multifunctional nanoparticles overcame CAM-DR, and were more efficacious than Dox when MM cells were cultured on fibronectin-coated plates. Finally, in a MM xenograft model, nanoparticles preferentially homed to MM tumors with ∼10 fold more drug accumulation and demonstrated dramatic tumor growth inhibition with a reduced overall systemic toxicity. Altogether, we demonstrate the disease driven engineering of a nanoparticle-based drug delivery system, enabling the model of an integrative approach in the treatment of MM

  12. Bioassay-Guided Isolation of Compounds from Datura stramonium with TRAIL-Resistance Overcoming Activity.

    Science.gov (United States)

    Karmakar, Utpal K; Toume, Kazufumi; Ishikawa, Naoki; Arai, Midori A; Sadhu, Samir K; Ahmed, Firoj; Ishibashi, Masami

    2016-02-01

    TRAIL is a potent inducer of apoptosis in most cancer cells, but not in normal cells, and therefore has deserved intense interest as a promising agent for cancer therapy. In the search for bioactive natural products for overcoming TRAIL-resistance, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionation of the MeOH extract of Datura stramonium leaves led to the isolation of three alkaloids--scopolamine (1), trigonelline (2), and tyramine (3). Compounds 1, 2, and 3 exhibited TRAIL-resistance overcoming activity at 50, 150, and 100 µM, respectively in TRAIL-resistant AGS cells.

  13. Overcome of Carbon Catabolite Repression of Bioinsecticides Production by Sporeless Bacillus thuringiensis through Adequate Fermentation Technology

    Directory of Open Access Journals (Sweden)

    Saoussen Ben Khedher

    2014-01-01

    Full Text Available The overcoming of catabolite repression, in bioinsecticides production by sporeless Bacillus thuringiensis strain S22 was investigated into fully controlled 3 L fermenter, using glucose based medium. When applying adequate oxygen profile throughout the fermentation period (75% oxygen saturation, it was possible to partially overcome the catabolite repression, normally occurring at high initial glucose concentrations (30 and 40 g/L glucose. Moreover, toxin production yield by sporeless strain S22 was markedly improved by the adoption of the fed-batch intermittent cultures technology. With 22.5 g/L glucose used into culture medium, toxin production was improved by about 36% when applying fed-batch culture compared to one batch. Consequently, the proposed fed-batch strategy was efficient for the overcome of the carbon catabolite repression. So, it was possible to overproduce insecticidal crystal proteins into highly concentrated medium.

  14. Analyzing pictorial artifacts from psychotherapy and art therapy when overcoming stress and trauma

    DEFF Research Database (Denmark)

    Gerge, Anna; Pedersen, Inge Nygaard

    2017-01-01

    Abstract This process based article tries to zoom into the need for assessment tools from a wider perspective to come to a preliminary understanding of what to analyze in relation to overcome traumatization and dissociation. The article wants to discuss and build understanding on what we ought...... to look for in pictorial artifacts related overcome traumatization and dissociation. After an introduction to psychotraumatology and it’s adaptions to creative arts therapy and art therapy, a literature review on assessment tools in art therapy, which can be applicable for measuring overcome...... traumatization, will be addressed. The need of a multi-dimensional tool for analysis of pictorial artifacts done in therapy is asked for and the needed components are briefly sketched. Finally the value of pictorial artifacts, made by clients in psycho-social interventions, as valid “windows” of implicit change...

  15. Enabling older homeless minority women to overcome homelessness by using a life management enhancement group intervention.

    Science.gov (United States)

    Washington, Olivia G M; Moxley, David P; Taylor, Jacquelyn Y

    2009-02-01

    This paper describes the importance of a life management enhancement (LME) group intervention for older minority women in developing personal control and self-confidence in social relationships as they overcome homelessness. Women in the treatment group showed significantly greater personal control and higher levels of self-confidence following the six-week intervention than women in the control group. Increasing personal control and developing self-confidence in social relationships can help individuals achieve desired outcomes as a result of their actions, efforts, and abilities. These attributes can help women increase and sustain appropriate coping methods and overcome homelessness.

  16. Beneficial bacteria inhibit cachexia

    Science.gov (United States)

    Varian, Bernard J.; Goureshetti, Sravya; Poutahidis, Theofilos; Lakritz, Jessica R.; Levkovich, Tatiana; Kwok, Caitlin; Teliousis, Konstantinos; Ibrahim, Yassin M.; Mirabal, Sheyla; Erdman, Susan E.

    2016-01-01

    Muscle wasting, known as cachexia, is a debilitating condition associated with chronic inflammation such as during cancer. Beneficial microbes have been shown to optimize systemic inflammatory tone during good health; however, interactions between microbes and host immunity in the context of cachexia are incompletely understood. Here we use mouse models to test roles for bacteria in muscle wasting syndromes. We find that feeding of a human commensal microbe, Lactobacillus reuteri, to mice is sufficient to lower systemic indices of inflammation and inhibit cachexia. Further, the microbial muscle-building phenomenon extends to normal aging as wild type animals exhibited increased growth hormone levels and up-regulation of transcription factor Forkhead Box N1 [FoxN1] associated with thymus gland retention and longevity. Interestingly, mice with a defective FoxN1 gene (athymic nude) fail to inhibit sarcopenia after L. reuteri therapy, indicating a FoxN1-mediated mechanism. In conclusion, symbiotic bacteria may serve to stimulate FoxN1 and thymic functions that regulate inflammation, offering possible alternatives for cachexia prevention and novel insights into roles for microbiota in mammalian ontogeny and phylogeny. PMID:26933816

  17. Empowering breeding programs with new approaches to overcome constraints for selecting superior quality traits of rice

    NARCIS (Netherlands)

    Calingacion, M.N.

    2015-01-01

    Empowering breeding programs with new approaches to overcome constraints for selecting superior quality traits of rice

    Mariafe N. Calingacion

    Most rice breeding programs have focused on improving agronomic traits such as yield, while enhancing grain quality traits

  18. TOOLS FOR OVERCOMING OBSTACLES TO REVITALIZATION: SMARTE AND START-UP

    Science.gov (United States)

    In 2001, the US-German Bilateral Working Group (BWG) identified more than 40 obstacles to site revitalization which occurred in both countries. From 2001-2005, the BWG developed tools and techniques for overcoming these obstacles. Five joint workshops were held on the following r...

  19. Show small close comfort and listen - How to overcome barriers in the use of social media

    NARCIS (Netherlands)

    Verjans, Steven

    2011-01-01

    Verjans, S. (2011, 23 November). Show small close comfort and listen - How to overcome barriers in the use of social media. Presentation at the SVEA Final Conference "Next Generation Learning - How to Integrate Social Media in Vocational and Adult Training", Brussels, Belgium.

  20. The Dirac equation in quantum chemistry: Strategies to overcome the current computational problems

    NARCIS (Netherlands)

    Visscher, L.

    2002-01-01

    A perspective on the use of the relativistic Dirac equation in quantum chemistry is given. It is demonstrated that many of the computational problems that plague the current implementations of the different electronic structure methods can be overcome by utilizing the locality of the small component

  1. Effectiveness of Targeted Musical Therapy on Sleep Quality and Overcoming Insomnia in Seniors

    Directory of Open Access Journals (Sweden)

    Reza Mottaghi

    2016-07-01

    Conclusion: The present study showed that targeted music therapy can lead to the improvement in the overall sleep quality, daily functioning, and subjective sleep quality thereby resulting in a sharp decline in the number of sleep drugs in seniors with primary insomnia disorder. Therefore, it is highly recommended by the music therapy and mental health experts for overcoming the sleep problems in older adults.

  2. Using Ontological Engineering to Overcome AI-ED Problems: Contribution, Impact and Perspectives

    Science.gov (United States)

    Mizoguchi, Riichiro; Bourdeau, Jacqueline

    2016-01-01

    This article reflects on the ontology engineering methodology discussed by the paper entitled "Using Ontological Engineering to Overcome AI-ED Problems" published in this journal in 2000. We discuss the achievements obtained in the last 10 years, the impact of our work as well as recent trends and perspectives in ontology engineering for…

  3. Comments by ABCT's first female president on overcoming the glass ceiling.

    Science.gov (United States)

    Nelson-Gray, Rosemery O

    2012-12-01

    At the annual convention of the Association for Behavioral and Cognitive Therapies in New York City in November 2009, a most interesting panel discussion occurred: Overcoming the Glass Ceiling: A Conversation With the Trailblazers. This article is a written version of my oral presentation at this panel discussion in my role as ABCT's first female president. Copyright © 2012. Published by Elsevier Ltd.

  4. Agora: A proposal to overcome the limitations of the current knowledge creation process

    OpenAIRE

    ScientistFive

    2015-01-01

    Agora: A proposal to overcome the limitations of the current knowledge creation process ======================================================================================= By Scientistsfive () Abstract: The knowledge creation process is broken and can be improved by a combination of currently emerging tools. The rationale for this proposal is the notion that the current scientific process is not optimal: * Artificially staged competitions (g...

  5. Development of active guidance systems to overcome problems of disorientation and low visibility following severe explosions.

    CSIR Research Space (South Africa)

    Phillips, HR

    1995-01-01

    Full Text Available The objective of this research project was to review methods of overcoming the disorientation of underground mine workers following an explosion or severe fire. The results of this project indicate that different strategies may be required for fires...

  6. No One Is Unemployable: Creative Solutions for Overcoming Barriers to Employment.

    Science.gov (United States)

    Harney, Elisabeth E.

    The goal of the WorkNet Model Career Development & Job Placement for people with barriers is to help even the most challenged job seekers begin and advance in careers they enjoy. This paper presents one key component of the WorkNet Model, a practical process for creatively overcoming any barrier a candidate faces. The chapter includes: the…

  7. Modelling Difficulties and Their Overcoming Strategies in the Solution of a Modelling Problem

    Science.gov (United States)

    Dede, Ayse Tekin

    2016-01-01

    The purpose of the study is to reveal the elementary mathematics student teachers' difficulties encountered in the solution of a modelling problem, the strategies to overcome those difficulties and whether the strategies worked or not. Nineteen student teachers solved the modelling problem in their four or five-person groups, and the video records…

  8. Problem Solving Instruction for Overcoming Students' Difficulties in Stoichiometric Problems

    Science.gov (United States)

    Shadreck, Mandina; Enunuwe, Ochonogor Chukunoye

    2017-01-01

    The study sought to find out difficulties encountered by high school chemistry students when solving stoichiometric problems and how these could be overcome by using a problem-solving approach. The study adopted a quasi-experimental design. 485 participants drawn from 8 highs schools in a local education district in Zimbabwe participated in the…

  9. Overcoming Pedagogical, Social/Cultural, and Attitudinal Barriers to Technology Integration in K-5 Schools

    Science.gov (United States)

    Durff, Lisa

    2017-01-01

    Technology engages and increases academic achievement for K-5 students, but teachers face attitudinal, social/cultural, and pedagogical barriers when they integrate technology for student learning. Although some teachers overcome these barriers, it remains unclear how they do so. The purpose of this qualitative multiple case study was to analyze…

  10. Qualitative Examination of Strategies to Overcome Resistance to Change in Lean Manufacturing

    Science.gov (United States)

    Burmester, Elizabeth

    2017-01-01

    Approximately 80% of lean manufacturing program initiatives are abandoned in the first year of implementation. Only 2% of organizations that embark on the lean journey complete it with the results and the sustainability they expected. There is a gap in past research regarding, the leadership strategies organizations can use to overcome resistance…

  11. The use of ion beam to overcome interspecific hybrid inviability in plants

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, Masayoshi [Kyoto Prefectural Univ. (Japan); Watanabe, Hiroshi

    1997-03-01

    In order to overcome sexual incompatibility between distantly related species in Nicotiana, the crosses with {sup 4}He{sup 2+} beam-irradiated pollen were carried out, and survival hybrids were obtained. They were resistant to tobacco mosaic virus and green peach aphid. (author)

  12. Overcoming Unintelligibility in Aphasia: The Impact of Non-Verbal Interactive Strategies

    Science.gov (United States)

    Damico, Jack S.; Wilson, Brent T.; Simmons-Mackie, Nina N.; Tetnowski, John A.

    2008-01-01

    As a follow-up to previous research, this report focuses on the wide range of gestures employed by an individual with aphasia to overcome instances of unintelligibility and re-establish intelligibility. The gestures observed are woven seamlessly into the fabric of the interactions and range from deictic to metaphorical or symbolic in nature.…

  13. Operation Cartwheel, 1943-1944: Integrated Force Projection to Overcome Limited Access

    Science.gov (United States)

    2014-06-13

    They accomplished their mission while overcoming adversity in terrain, sickness, weather , and the ever present Japanese, ensuring Allied supply and......that Germany posed the greatest threat to Allied security led to implementation of the RAINBOW -5 strategy. This was the overarching strategy for the

  14. Tips to overcome technical challenges in EUS-guided tissue acquisition

    DEFF Research Database (Denmark)

    Vilmann, Peter; Seicean, Andrada; Săftoiu, Adrian

    2014-01-01

    . The endosonographic technique can be improved when several tips and tricks useful to overcome challenges of FNA are known. Technical challenges of FNA are related to the characteristics of the lesion and its surroundings, sonographic imaging, and limitations related to the needle. Several tips and tricks necessary...

  15. Overcoming Uncertainty: Agency, Stance and the Rise of Collective Action in Times of Crisis

    NARCIS (Netherlands)

    Heidemann, Kai

    2017-01-01

    How do people exert their agency in the face of large-scale societal crises? Merging strands of sociolinguistic scholarship with social movement theory, this article offers a way of looking at how grassroots actors work to overcome dramatic episodes of macro-structural instability and uncertainty

  16. Overcoming Low Self-Efficacy Beliefs in Teaching English to Young Learners

    Science.gov (United States)

    Wyatt, Mark

    2013-01-01

    Drawing on data from observations and interviews, this article presents a case study of one teacher's efforts to overcome low self-efficacy beliefs in teaching English to young learners in a Middle Eastern context. It provides insights into the growth processes involved, highlighting how the teacher drew reflectively upon her experiences to…

  17. The small and rural academic library leveraging resources and overcoming limitations

    CERN Document Server

    Davis Kendrick, Kaetrena

    2016-01-01

    Through the use of case studies, research, and practical interviews, The Small or Rural Academic Library: Leveraging Resources and Overcoming Limitations explores how academic librarians in such environments can keep pace with, create, and improve modern library practices and services, network with colleagues, and access continuing education and professional development opportunities.

  18. Using Appropriate Digital Tools to Overcome Barriers to Collaborative Learning in Classrooms

    Science.gov (United States)

    Wardlow, Liane; Harm, Eian

    2015-01-01

    Collaborative learning provides students with vital opportunities to create and build knowledge. Existing technologies can facilitate collaborative learning. However, barriers exist to enacting collaborative practices related to the coverage of material for assessments and classroom management concerns, among others. Teachers can overcome these…

  19. A Literature Review of School Practices to Overcome School Failure. OECD Education Working Papers, No. 68

    Science.gov (United States)

    Faubert, Brenton

    2012-01-01

    The purpose of this report is to review the body of literature concerned with reducing school failure by improving equity in schools and classrooms. The literature review will be used to inform the Organisation for Economic Cooperation and Development (OECD) Project "Overcoming School Failure: Policies that Work" and hopefully, future educational…

  20. Overcoming Pedagogical Solitude: The Transformative Power of Discipline-Specific Faculty Learning Communities

    Science.gov (United States)

    Tovar, Mariela; Jukier, Rosalie; Ferris, Jennie; Cardoso, Kristen

    2015-01-01

    This article describes a multiyear Faculty Learning Community (FLC) program as a strategy to overcome pedagogical solitude (Shulman, 1993) in a discipline-specific context. Participant interviews shed light on their FLC experiences and perceived impact on their teaching and students' learning. Grounded within the particularities of the…

  1. Empowering breeding programs with new approaches to overcome constraints for selecting superior quality traits of rice

    NARCIS (Netherlands)

    Calingacion, M.N.

    2015-01-01

    Empowering breeding programs with new approaches to overcome constraints for selecting superior quality traits of rice Mariafe N. Calingacion Most rice breeding programs have focused on improving agronomic traits such as yield, while enhancing grain quality traits such as flavour

  2. Building America Guidance for Identifying and Overcoming Code, Standard, and Rating Method Barriers

    Energy Technology Data Exchange (ETDEWEB)

    Cole, P. C. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Halverson, M. A. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2013-09-01

    This guidance document was prepared using the input from the meeting summarized in the draft CSI Roadmap to provide Building America research teams and partners with specific information and approaches to identifying and overcoming potential barriers to Building America innovations arising in and/or stemming from codes, standards, and rating methods.

  3. Falling into LINE: School Strategies for Overcoming Challenges Associated with Learning in Natural Environments (LINE)

    Science.gov (United States)

    Edwards-Jones, Andrew; Waite, Sue; Passy, Rowena

    2018-01-01

    As the benefits of outdoor learning have become of increasing interest to the education sector, so the importance of understanding and overcoming challenges associated with this pedagogy has gained greater significance. The Natural Connections Demonstration Project recruited primary, secondary, and special schools across south-west England with a…

  4. EXTERNAL BORROWING – A SOLUTION IN OVERCOMING THE CURRENT ECONOMIC CRISIS?

    Directory of Open Access Journals (Sweden)

    Maria Pascal (căs. Andriescu

    2010-06-01

    Full Text Available The government decisions to call, in recent years, more and more reimbursable financing gave birth to fierce reactions among politicians and economy specialists. The present article aims to analyze how the external borrowing may be a solution to overcome the difficult situation where we are.

  5. Explaining the Effects of Narrative in an Entertainment Television Program: Overcoming Resistance to Persuasion

    Science.gov (United States)

    Moyer-Guse, Emily; Nabi, Robin L.

    2010-01-01

    Research has examined the ability of entertainment-education (E-E) programs to influence behavior across a variety of health and social issues. However, less is known about the underlying mechanisms that account for these effects. In keeping with the extended elaboration likelihood model (E-ELM) and the entertainment overcoming resistance model…

  6. Overcoming Resistance to the Use of Instructional Computing in Higher Education.

    Science.gov (United States)

    Waldrop, Phillip B.; Adams, Thomas M., II

    Selected reasons for resistance to change in education are discussed, the kinds of resulting behaviors are noted, and suggestions for plausible means of overcoming this resistance are offered. Though the search for excellence and innovation in education are desirable, they are often not sustained for any appreciable period of time and the…

  7. Study on a Suspension of a Planetary Exploration Rover to Improve Driving Performance During Overcoming Obstacles

    Directory of Open Access Journals (Sweden)

    We-Sub Eom

    2012-12-01

    Full Text Available The planetary exploration rover executes various missions after moving to the target point in an unknown environment in the shortest distance. Such missions include the researches for geological and climatic conditions as well as the existence of water or living creatures. If there is any obstacle on the way, it is detected by such sensors as ultrasonic sensor, infrared light sensor, stereo vision, and laser ranger finder. After the obtained data is transferred to the main controller of the rover, decisions can be made to either overcome or avoid the obstacle on the way based on the operating algorithm of the rover. All the planetary exploration rovers which have been developed until now receive the information of the height or width of the obstacle from such sensors before analyzing it in order to find out whether it is possible to overcome the obstacle or not. If it is decided to be better to overcome the obstacle in terms of the operating safety and the electric consumption of the rover, it is generally made to overcome it. Therefore, for the purpose of carrying out the planetary exploration task, it is necessary to design the proper suspension system of the rover which enables it to safely overcome any obstacle on the way on the surface in any unknown environment. This study focuses on the design of the new double 4-bar linkage type of suspension system applied to the Korea Aerospace Research Institute rover (a tentatively name that is currently in the process of development by our institute in order to develop the planetary exploration rover which absolutely requires the capacity of overcoming any obstacle. Throughout this study, the negative moment which harms the capacity of the rover for overcoming an obstacle was induced through the dynamical modeling process for the rocker-bogie applied to the Mars exploration rover of the US and the improved version of rocker-bogie as well as the suggested double 4-bar linkage type of suspension

  8. [Penicillium-inhibiting yeasts].

    Science.gov (United States)

    Benítez Ahrendts, M R; Carrillo, L

    2004-01-01

    The objective of this work was to establish the in vitro and in vivo inhibition of post-harvest pathogenic moulds by yeasts in order to make a biocontrol product. Post-harvest pathogenic moulds Penicillium digitatum, P. italicum, P. ulaiense, Phyllosticta sp., Galactomyces geotrichum and yeasts belonging to genera Brettanomyces, Candida, Cryptococcus, Kloeckera, Pichia, Rhodotorula were isolated from citrus fruits. Some yeasts strains were also isolated from other sources. The yeasts were identified by their macro and micro-morphology and physiological tests. The in vitro and in vivo activities against P. digitatum or P. ulaiense were different. Candida cantarellii and one strain of Pichia subpelliculosa produced a significant reduction of the lesion area caused by the pathogenic moulds P. digitatum and P. ulaiense, and could be used in a biocontrol product formulation.

  9. Regorafenib overcomes chemotherapeutic multidrug resistance mediated by ABCB1 transporter in colorectal cancer: In vitro and in vivo study.

    Science.gov (United States)

    Wang, Yi-Jun; Zhang, Yun-Kai; Zhang, Guan-Nan; Al Rihani, Sweilem B; Wei, Meng-Ning; Gupta, Pranav; Zhang, Xiao-Yu; Shukla, Suneet; Ambudkar, Suresh V; Kaddoumi, Amal; Shi, Zhi; Chen, Zhe-Sheng

    2017-06-28

    Chemotherapeutic multidrug resistance (MDR) is a significant challenge to overcome in clinic practice. Several mechanisms contribute to MDR, one of which is the augmented drug efflux induced by the upregulation of ABCB1 in cancer cells. Regorafenib, a multikinase inhibitor targeting the RAS/RAF/MEK/ERK pathway, was approved by the FDA to treat metastatic colorectal cancer and gastrointestinal stromal tumors. We investigated whether and how regorafenib overcame MDR mediated by ABCB1. The results showed that regorafenib reversed the ABCB1-mediated MDR and increased the accumulation of [ 3 H]-paclitaxel in ABCB1-overexpressing cells by suppressing efflux activity of ABCB1, but not altering expression level and localization of ABCB1. Regorafenib inhibited ATPase activity of ABCB1. In mice bearing resistant colorectal tumors, regorafenib raised the intratumoral concentration of paclitaxel and suppressed the growth of resistant colorectal tumors. But regorafenib did not induce cardiotoxicity/myelosuppression of paclitaxel in mice. Strategy to reposition one FDA-approved anticancer drug regorafenib to overcome the resistance of another FDA-approved, widely used chemotherapeutic paclitaxel, may be a promising direction for the field of adjuvant chemotherapy. This study provides clinical rationale for combination of conventional chemotherapy and targeted anticancer agents. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Scientific provision of the problems of overcoming the Chernobyl catastrophe consequences. Chapter 7

    International Nuclear Information System (INIS)

    Konoplya, E.F.; Rolevich, I.V.; Gurachevskij, V.L.; Poplyko, I.Ya.; Semeshko, A.V.

    1998-01-01

    At present in the Republic of Belarus the research works on the problems of overcoming of the Chernobyl accident consequences are carried out in the following directions: radiation protection of the population; health of the population affected by the Chernobyl NPP accident; complex radiation-ecological estimation of the environment and conditions of the life activity of the population; rehabilitation of the contaminated territories; instrumental and methodical provision of the radiation control. The experience of the scientific approach to the decision of wide-scale and multiple-discipline tasks of overcoming of the Chernobyl accident consequences promotes for transformation of separate knowledge about radiation safety in holistic conception of safety and protection of the population in emergency caused by industrial accidents, catastrophes, natural disasters

  11. PATIENTS OVERCOME ANXIETY AND ARE ENCOURAGED TO BE PHYSICAL ACTIVETHROUGH EXERCISE-BASED CARDIAC REHABILITATION

    DEFF Research Database (Denmark)

    Simonÿ, Charlotte; Dreyer, Pia; Pedersen, Birthe D.

    2015-01-01

    into that the heart endures physical activity. In addition to serving as physical guidance, exercise-based cardiac rehabilitation offers valuable mental support. The patients find help to overcome an initial anxiety and move forward towards a physically active life featuring a feeling of improved health and new...... interviews were performed 1-2 months later. A phenomenological hermeneutic interpretation was conducted, comprising three methodological steps: naïve reading, structural analysis and comprehensive interpretation. Results. The preliminary findings are that although physically and especially mentally...... other to begin exercising; and growing confidence in the heart, whereby the patients overcome anxiety and dare to be physically active. Conclusions. Exercise-based cardiac rehabilitation provides a comfort-giving setting that offers peer support and a positive physical perception leading to confidence...

  12. Overcoming resistance to culture change: nursing home administrators' use of education, training, and communication.

    Science.gov (United States)

    Tyler, Denise A; Lepore, Michael; Shield, Renee R; Looze, Jessica; Miller, Susan C

    2014-01-01

    Nursing home culture change is becoming more prevalent, and research has demonstrated its benefits for nursing home residents and staff-but little is known about the role of nursing home administrators in culture change implementation. The purpose of this study was to determine what barriers nursing home administrators face in implementing culture change practices, and to identify the strategies used to overcome them. The authors conducted in-depth individual interviews with 64 administrators identified through a nationally representative survey. Results showed that a key barrier to culture change implementation reported by administrators was staff, resident, and family member resistance to change. Most nursing home administrators stressed the importance of using communication, education and training to overcome this resistance. Themes emerging around the concepts of communication and education indicate that these efforts should be ongoing, communication should be reciprocal, and that all stakeholders should be included.

  13. Open access for the non-English-speaking world: overcoming the language barrier

    Directory of Open Access Journals (Sweden)

    Fung Isaac CH

    2008-01-01

    Full Text Available Abstract This editorial highlights the problem of language barrier in scientific communication in spite of the recent success of Open Access Movement. Four options for English-language journals to overcome the language barrier are suggested: 1 abstracts in alternative languages provided by authors, 2 Wiki open translation, 3 international board of translator-editors, and 4 alternative language version of the journal. The Emerging Themes in Epidemiology announces that with immediate effect, it will accept translations of abstracts or full texts by authors as Additional files. Editorial note: In an effort towards overcoming the language barrier in scientific publication, ETE will accept translations of abstracts or the full text of published articles. Each translation should be submitted separately as an Additional File in PDF format. ETE will only peer review English-language versions. Therefore, translations will not be scrutinized in the review-process and the responsibility for accurate translation rests with the authors.

  14. Devices for overcoming biological barriers: the use of physical forces to disrupt the barriers.

    Science.gov (United States)

    Mitragotri, Samir

    2013-01-01

    Overcoming biological barriers including skin, mucosal membranes, blood brain barrier as well as cell and nuclear membrane constitutes a key hurdle in the field of drug delivery. While these barriers serve the natural protective function in the body, they limit delivery of drugs into the body. A variety of methods have been developed to overcome these barriers including formulations, targeting peptides and device-based technologies. This review focuses on the use of physical methods including acoustic devices, electric devices, high-pressure devices, microneedles and optical devices for disrupting various barriers in the body including skin and other membranes. A summary of the working principles of these devices and their ability to enhance drug delivery is presented. Copyright © 2012. Published by Elsevier B.V.

  15. OVERCOMING OF UNILATERAL INCOMPATIBILITY OF SWEET PEPPER CV. BELOSNEZHKA AND KARLIK BY COLD STRESS OF POLLEN

    Directory of Open Access Journals (Sweden)

    E. G. Kozar

    2014-01-01

    Full Text Available The article describes a technique for overcoming the unilateral cross- incompatibility of of sweet pepper cultivars Belosnezhka and Karlik (Capsicum annuumL. by pre- coating the stigma of the parental plants by own frozen pollen (fertile, but lost fertilizing capacity in order to initiate the necessary changes in the tissues of the pistil that ensures germination of pollen tubes of foreign pollen , successful fertilization and hybrid seeds formation.

  16. Characterizing and Overcoming Spectral Artifacts in Imaging Fourier-Transform Spectroscopy of Turbulent Exhaust Plumes

    Science.gov (United States)

    2009-10-01

    Hyperspectral Imagery (Imagerie hyperspectrale thermique ). Meeting Proceedings of Sensors and Electronics Panel (SET) Specialists Meeting held at the Belgian...Schäfer et al. use a more sophisticated radiative transfer model which takes into account temperature gradients and the effects of emission and self...Quantitative Spectroscopy and Radiative Transfer , 92, 447–455 (2005). Characterizing and Overcoming Spectral Artifacts in Imaging Fourier-Transform

  17. Measuring women's perceived ability to overcome barriers to healthcare seeking in Burkina Faso

    Directory of Open Access Journals (Sweden)

    Nikiema Béatrice

    2012-02-01

    Full Text Available Abstract Background In sub-Saharan Africa, women must overcome numerous barriers when they need modern healthcare. Respect of gender norms within the household and the community may still influence women's ability to obtain care. A lack of gender-sensitive instruments for measuring women's ability to overcome barriers compromises attempts to adequately quantify the burden and risk of exclusion they face when seeking modern healthcare. The aim of this study was to create and validate a synthetic measure of women's access to healthcare from a publicly available and possibly internationally comparable population-based survey. Method Seven questionnaire items from the Burkina Faso 2003 DHS were combined to create the index. Cronbach's alpha coefficient was used to test the reliability of the index. Exploratory factor analyses (EFA and confirmatory factor analyses (CFA were applied to evaluate the factorial structure and construct validity of the index while taking into account the hierarchical structure of the data. Results The index has a Cronbach's alpha of 0.75, suggesting adequate reliability. In EFA, three correlated factors fitted the data best. In CFA, the construct of perceived ability to overcome barriers to healthcare seeking emerged as a second-order latent variable with three domains: socioeconomic barriers, geographical barriers and psychosocial barriers. Model fit indices support the index's global validity for women of reproductive age in Burkina Faso. Evidence for construct validity comes from the finding that women's index scores increase with household living standard. Conclusion The DHS items can be combined into a reliable and valid, gender-sensitive index quantifying reproductive-age women's perceived ability to overcome barriers to healthcare seeking in Burkina Faso. The index complies conceptually with the sector-cross-cutting capability approach and enables measuring directly the perceived access to healthcare. Therefore it

  18. DNA Repair and Photoprotection: Mechanisms of Overcoming Environmental Ultraviolet Radiation Exposure in Halophilic Archaea

    OpenAIRE

    Daniel L. Jones; Bonnie K. Baxter

    2017-01-01

    Halophilic archaea push the limits of life at several extremes. In particular, they are noted for their biochemical strategies in dealing with osmotic stress, low water activity and cycles of desiccation in their hypersaline environments. Another feature common to their habitats is intense ultraviolet (UV) radiation, which is a challenge that microorganisms must overcome. The consequences of high UV exposure include DNA lesions arising directly from bond rearrangement of adjacent bipyrimidine...

  19. SELLING CANANG SARI (As an Alternative of Effort in Informal Sector to overcome household economics problem

    Directory of Open Access Journals (Sweden)

    Desak Putu Eka Nilakusmawati

    2012-11-01

    Full Text Available Decrease in family income represent an impact of economic pressures, as an effect of economic crisis. Other side, the existing problems that extension of the job opportunity in the urban area with existence of development in the various sector do not absorb entire labour force which is progressively growing larger its amount.Economic problem force woman of lower economic class to involved take part in earning for increase family income by working beyond domestic sectors. Involvement of woman in labor market trigered by family’s economic problems, besides existence of the job opportunity factor. Alternative effort being carried out is by selling canang.Increasing of urban community activities in Denpasar City makes them have no time to make banten or canang. To find an easier way to overcome this situation, many people tend to buy canang/banten which is ready to use, also more practical and spent less time than the time spent when they make by themselves . This phenomenon gives a chance to canang sellers to get income additional. In the difficult condition of the economics problem, many woman have to take part to overcome economic problems which they face. One of the alternative is involved into labour market, and involve in trade is one of the choice. Because of the existence of opportunity as explained above, many women overcome their economic problems and try to give contribution to their family income by selling the canang.Phenomenon more and more canang sellers which are spread alongside the road side in Denpasar City shown that the informal sector have a great role to maintaining and also improving household economics. The effort as the canang seller can represent an alternative of effort in informal sector to overcome economics problem in the household level. Roles of woman as a subject of this informal sector, have a big contribution in maintaining household economics.

  20. Proposals to overcome limitations in the EU chemical risk assessment scheme

    DEFF Research Database (Denmark)

    Trapp, Stefan; Schwartz, S.

    2000-01-01

    , it is shown that in certain cases uptake is underestimated by the model due to processes not considered. This may lead to a wrong security in risk assessment. To overcome these limitations, a set of alternative models with di€erent application ranges should be developed. When no applicable method is available......, it might be better not to use a model at all instead of an inadequate model, and look for other sources of information. Ó 2000 Elsevier Science Ltd. All rights reserved....

  1. Effect of creativity on overcoming the person`s existential crisis

    OpenAIRE

    V. S. Grekova

    2014-01-01

    In this article author analyzes the existential crisis as a factor in the formation of personality and position in life how to overcome it, including creativity as one of the main methods and ways of experiencing. For definition of the term existential crisis as reviewed existing literature in modern philosophical interpretation. The author gives methodological research concept of existential crisis and the crisis in general, are considered milestones person experiences the «boundary situatio...

  2. Overcoming Resistance to Culture Change: Nursing Home Administrators’ Use of Education, Training and Communication

    OpenAIRE

    Tyler, Denise A.; Lepore, Michael; Shield, Renee R.; Looze, Jessica; Miller, Susan C.

    2013-01-01

    Nursing home culture change is becoming more prevalent and research has demonstrated its benefits for nursing home residents and staff, but little is known about the role of nursing home administrators in culture change implementation. The purpose of this study was to determine what barriers nursing home administrators faced in implementing culture change practices and to identify the strategies used to overcome these. We conducted in-depth individual interviews with 64 administrators identif...

  3. HR-Mediated Defense Response is Overcome at High Temperatures in Capsicum Species

    Directory of Open Access Journals (Sweden)

    Bong Nam Chung

    2018-02-01

    Full Text Available Resistance to Tomato spotted wilt virus isolated from paprika (TSWV-Pap was overcome at high temperatures (30 ± 2°C in both accessions of Capsicum annuum S3669 (Hana Seed Company and C. chinense PI15225 (AVRDC Vegetable Genetic Resources. S3669 and PI15225, which carrying the Tsw gene, were mechanically inoculated with TSWV-Pap, and then maintained in growth chambers at temperatures ranging from 15 ± 2°C to 30 ± 2°C (in 5°C increments. Seven days post inoculation (dpi, a hypersensitivity reaction (HR was induced in inoculated leaves of PI152225 and S3669 plants maintained at 25°C ± 2°C. Meanwhile, necrotic spots were formed in upper leaves of 33% of PI15225 plants maintained at 30 ± 2°C, while systemic mottle symptoms developed in 50% of S3669 plants inoculated. By 15 dpi, 25% of S3669 plants had recovered from systemic mottling induced at 30 ± 2°C. These results demonstrated that resistance to TSWV-Pap can be overcome at higher temperatures in both C. chinense and C. annuum. This is the first study reporting the determination of temperatures at which TSWV resistance is overcome in a C. annuum genetic resource expressing the Tsw gene. Our results indicated that TSWV resistance shown from pepper plants possess the Tsw gene could be overcome at high temperature. Thus, breeders should conduct evaluation of TSWV resistance in pepper cultivars at higher temperature than 30°C (constant temperature.

  4. Overcoming of the 1/2 reflectivity limit in Laue neutron diffraction

    International Nuclear Information System (INIS)

    Boeuf, A.; Rustichelli, F.; Melone, S.; Puliti, P.

    1978-01-01

    Experimental evidence for the overcoming of the 50% peak reflectivity limit in neutron diffraction in the Laue geometry is presented. Peak reflectivity up to 75%, in spite of the neutron absorption, has been obtained with a bent germanium crystal. This effect has been explained by a simple model based in the dynamical theory of neutron diffraction and appears as a consequence of the elimination, due to a proper curvature, of the Pendelloesung effect. (author)

  5. Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism

    OpenAIRE

    Ai, Zhihong; Lu, Yang; Qiu, Songbo; Fan, Zhen

    2016-01-01

    Cisplatin is currently one of the most effective chemotherapeutic drugs used for treating ovarian cancer; however, resistance to cisplatin is common. In this study, we explored an experimental strategy for overcoming cisplatin resistance of human ovarian cancer from the new perspective of cancer cell metabolism. By using two pairs of genetically matched cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines, we tested the hypothesis that downregulating hypoxia-inducible factor-...

  6. A framework for prioritising practices to overcome cost-related problems in reverse logistics

    OpenAIRE

    Amanda Badenhorst

    2013-01-01

    Reverse logistics has gained increasing attention in recent years. One of the biggest problems for organisations and supply chains is reducing cost in reverse logistics. This study attempted to gain a better understanding of reverse logistics and the costs associated with it. A literature study was conducted to identify the cost problems in reverse logistics and possible practices to overcome them. Following that, a survey was conducted to determine whether the practices identified in literat...

  7. The Attempt to Overcome Time Dynamic Theory in the Concept Of Eternal Return

    Directory of Open Access Journals (Sweden)

    Elizbar Elizbarashvili

    2014-05-01

    Full Text Available The article discusses the various variants of time rotation eternal concept, and how it was directed to overcome time dynamical theory. The article describes time cycle theory in the period of the Vedas, antiques philosophy and Nietzsche’s philosophy. The article highlights three major features of the time dynamic theory but none of them is finally overcame in time cycling concept. It is concluded that the time dynamic theory is theoretically not established.

  8. Modeling and management of water in the Klamath River Basin: overcoming politics and conflicts

    Science.gov (United States)

    Flug, Marshall; Scott, John F.; Abt, Steven R.; Young-Pezeshk, Jayne; Watson, Chester C.

    1998-01-01

    The network flow model MODSIM, which was designed as a water quantity mass balance model for evaluating and selecting water management alternatives, has been applied to the Klamath River basin. A background of conflicting issues in the basin is presented. The complexity of water quantity model development, while satisfying the many stakeholders and involved special interest groups is discussed, as well as the efforts taken to have the technical model accepted and used, and overcome stakeholder criticism, skepticism, and mistrust of the government.

  9. Spiritual values of heads of general education institutions as a factor of professional crises’ overcoming

    Directory of Open Access Journals (Sweden)

    Алла Степанівна Москальова

    2015-12-01

    Full Text Available The article is devoted to the important problem of psychology – the research of the spiritual values of heads of general education institutions. The content and indicators of development of spiritual values of managers are determined. The results of empirical research levels of spiritual values of managers are presented. It has been proved correlation between the levels of development of spiritual values of heads of general education institutions and their ability to overcome professional crises

  10. SOCIAL INFRASTRUCTURE OF ACTUARIAL PENSION PAYMENTS AS A WAY OF OVERCOMING A BUDGET DEFICIT

    Directory of Open Access Journals (Sweden)

    Oleg A. Donichev

    2013-01-01

    Full Text Available The article is devoted to the problem of overcoming the lack of funding the revenue side of the Pension Fund of the Russian Federation. The ways of further development of the funded component of future pension payments are proposed in the article. The need to form in regions the adequate social infrastructure which could enable to develop the funded pension systems is specified in the article.

  11. Components of Hospital Perioperative Infrastructure Can Overcome the Weekend Effect in Urgent General Surgery Procedures.

    Science.gov (United States)

    Kothari, Anai N; Zapf, Matthew A C; Blackwell, Robert H; Markossian, Talar; Chang, Victor; Mi, Zhiyong; Gupta, Gopal N; Kuo, Paul C

    2015-10-01

    We hypothesized that perioperative hospital resources could overcome the "weekend effect" (WE) in patients undergoing emergent/urgent surgeries. The WE is the observation that surgeon-independent patient outcomes are worse on the weekend compared with weekdays. The WE is often explained by differences in staffing and resources resulting in variation in care between the week and weekend. Emergent/urgent surgeries were identified using the Healthcare Cost and Utilization Project State Inpatient Database (Florida) from 2007 to 2011 and linked to the American Hospital Association (AHA) Annual Survey Database to determine hospital level characteristics. Extended median length of stay (LOS) on the weekend compared with the weekdays (after controlling for hospital, year, and procedure type) was selected as a surrogate for WE. Included were 126,666 patients at 166 hospitals. A total of 17 hospitals overcame the WE during the study period. Logistic regression, controlling for patient characteristics, identified full adoption of electronic medical records (OR 4.74), home health program (OR 2.37), pain management program [odds ratio (OR) 1.48)], increased registered nurse-to-bed ratio (OR 1.44), and inpatient physical rehabilitation (OR 1.03) as resources that were predictors for overcoming the WE. The prevalence of these factors in hospitals exhibiting the WE for all 5 years of the study period were compared with those hospitals that overcame the WE (P general surgery procedures. Improved hospital perioperative infrastructure represents an important target for overcoming disparities in surgical care.

  12. Strategies to overcome type 1 diabetes-related social stigma in the Iranian society.

    Science.gov (United States)

    Irani, Mehri Doosti; Abdoli, Samereh; Bijan, Iraj; Parvizy, Soroor; Fatemi, Naimeh Seyed; Amini, Massoud

    2014-09-01

    This study explored the strategies to overcome diabetes-related social stigma in Iran. This paper is part of an action research study which was designed in Iran in 2012 to plan and implement a program for overcoming diabetes-related stigma. Participants were people with type 1 diabetes, their family members, people without diabetes, and care providers in a diabetes center. Data collection was done through unstructured in-depth interviews, focus groups, e-mail, Short Message Service (SMS), and telephone interview. Data were analyzed using inductive content analysis approach. Participants believed that it is impossible to overcome the stigma without community-based strategies. Community-based strategies include education, advocacy, contact, and protest. The anti-stigma strategies obtained in the study are based on the cultural context in Iran. They are extracted from statements of a wide range of people (with and without diabetes). However, during planning for stigma reduction, it is necessary to note that the effectiveness of social strategies varies in different studies and in different stigmatizing conditions and many factors are involved. These strategies should be implemented simultaneously at different levels to produce structural and social changes. It should be accepted that research on reducing health-related stigma has shown that it is very difficult to change beliefs and behavior. Evidence suggests that individuals and their families should be involved in all aspects of the program, and plans should be made according to the local conditions.

  13. Adaptation of avian influenza A virus polymerase in mammals to overcome the host species barrier.

    Science.gov (United States)

    Mänz, Benjamin; Schwemmle, Martin; Brunotte, Linda

    2013-07-01

    Avian influenza A viruses, such as the highly pathogenic avian H5N1 viruses, sporadically enter the human population but often do not transmit between individuals. In rare cases, however, they establish a new lineage in humans. In addition to well-characterized barriers to cell entry, one major hurdle which avian viruses must overcome is their poor polymerase activity in human cells. There is compelling evidence that these viruses overcome this obstacle by acquiring adaptive mutations in the polymerase subunits PB1, PB2, and PA and the nucleoprotein (NP) as well as in the novel polymerase cofactor nuclear export protein (NEP). Recent findings suggest that synthesis of the viral genome may represent the major defect of avian polymerases in human cells. While the precise mechanisms remain to be unveiled, it appears that a broad spectrum of polymerase adaptive mutations can act collectively to overcome this defect. Thus, identification and monitoring of emerging adaptive mutations that further increase polymerase activity in human cells are critical to estimate the pandemic potential of avian viruses.

  14. Coherent anti-Stokes Raman scattering microscopy: overcoming technical barriers for clinical translation.

    Science.gov (United States)

    Tu, Haohua; Boppart, Stephen A

    2014-01-01

    Clinical translation of coherent anti-Stokes Raman scattering microscopy is of great interest because of the advantages of noninvasive label-free imaging, high sensitivity, and chemical specificity. For this to happen, we have identified and review the technical barriers that must be overcome. Prior investigations have developed advanced techniques (features), each of which can be used to effectively overcome one particular technical barrier. However, the implementation of one or a small number of these advanced features in previous attempts for clinical translation has often introduced more tradeoffs than benefits. In this review, we outline a strategy that would integrate multiple advanced features to overcome all the technical barriers simultaneously, effectively reduce tradeoffs, and synergistically optimize CARS microscopy for clinical translation. The operation of the envisioned system incorporates coherent Raman micro-spectroscopy for identifying vibrational biomolecular markers of disease and single-frequency (or hyperspectral) Raman imaging of these specific biomarkers for real-time in vivo diagnostics and monitoring. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Patient-Reported Outcomes and Survivorship in Radiation Oncology: Overcoming the Cons

    Science.gov (United States)

    Siddiqui, Farzan; Liu, Arthur K.; Watkins-Bruner, Deborah; Movsas, Benjamin

    2014-01-01

    Purpose Although patient-reported outcomes (PROs) have become a key component of clinical oncology trials, many challenges exist regarding their optimal application. The goal of this article is to methodically review these barriers and suggest strategies to overcome them. This review will primarily focus on radiation oncology examples, will address issues regarding the “why, how, and what” of PROs, and will provide strategies for difficult problems such as methods for reducing missing data. This review will also address cancer survivorship because it closely relates to PROs. Methods Key articles focusing on PROs, quality of life, and survivorship issues in oncology trials are highlighted, with an emphasis on radiation oncology clinical trials. Publications and Web sites of various governmental and regulatory agencies are also reviewed. Results The study of PROs in clinical oncology trials has become well established. There are guidelines provided by organizations such as the US Food and Drug Administration that clearly indicate the importance of and methodology for studying PROs. Clinical trials in oncology have repeatedly demonstrated the value of studying PROs and suggested ways to overcome some of the key challenges. The Radiation Therapy Oncology Group (RTOG) has led some of these efforts, and their contributions are highlighted. The current state of cancer survivorship guidelines is also discussed. Conclusion The study of PROs presents significant benefits in understanding and treating toxicities and enhancing quality of life; however, challenges remain. Strategies are presented to overcome these hurdles, which will ultimately improve cancer survivorship. PMID:25113760

  16. A preliminary survey into ways of overcoming self-incompatibility in theobroma cacao L

    International Nuclear Information System (INIS)

    Adu-Ampomah, Y.; Klu, G.Y.P.; Lamptey, T.V.O.; Novak, F.

    1990-01-01

    Varying concentrations of NAA and GA 3 (100-500 mg/l) were applied to the base of self-incompatible cocoa flowers with the view to delaying floral abscission and thus lengthening the time needed for the fusion of self-incompatible male and female gametes. NAA above 300 mg/l slightly delayed floral abscission but this did not help overcome the self-incompatibility whilst none of the GA 3 concentrations used either delayed floral abscission or promoted self-compatibility. Similar concentrations of both hormones when applied to the stigma before selfing also did not help to overcome the self-incompatibility. Self-incompatibility was partially overcome by treating compatible pollen with 60Gy of gamma rays and mixing it with self-incompatible pollen. Compatible pollen treated at 60Gy and used alone to pollinate self-incompatible flowers resulted in 100 percent flat, non-viable cocoa beans whilst gamma treated pollen mixed with self-incompatible pollen produced about 30 percent fully formed and viable cocoa beans. This appears to suggest that the irradiated compatible pollen is acting as mentor pollen and promoting selfing. (author)

  17. A (R)evaluation of Nietzsche's Anti-Democratic Pedagogy: The Overman, Perspectivism, and Self-Overcoming

    Science.gov (United States)

    Jonas, Mark E.

    2009-01-01

    In this paper, I argue that Friedrich Nietzsche's concept of self-overcoming has been largely misinterpreted in the philosophy of education journals. The misinterpretation partially stems from a misconstruction of Nietzsche's perspectivism, and leads to a conception of self-overcoming that is inconsistent with Nietzsche's educational ideals. To…

  18. Strategies to Inhibit Myc and Their Clinical Applicability

    Science.gov (United States)

    Whitfield, Jonathan R.; Beaulieu, Marie-Eve; Soucek, Laura

    2017-01-01

    Myc is an oncogene deregulated in most—perhaps all—human cancers. Each Myc family member, c-, L-, and N-Myc, has been connected to tumor progression and maintenance. Myc is recognized as a “most wanted” target for cancer therapy, but has for many years been considered undruggable, mainly due to its nuclear localization, lack of a defined ligand binding site, and physiological function essential to the maintenance of normal tissues. The challenge of identifying a pharmacophore capable of overcoming these hurdles is reflected in the current absence of a clinically-viable Myc inhibitor. The first attempts to inhibit Myc used antisense technology some three decades ago, followed by small molecule inhibitors discovered through “classical” compound library screens. Notable breakthroughs proving the feasibility of systemic Myc inhibition were made with the Myc dominant negative mutant Omomyc, showing both the great promise in targeting this infamous oncogene for cancer treatment as well as allaying fears about the deleterious side effects that Myc inhibition might have on normal proliferating tissues. During this time many other strategies have appeared in an attempt to drug the undruggable, including direct and indirect targeting, knockdown, protein/protein and DNA interaction inhibitors, and translation and expression regulation. The inhibitors range from traditional small molecules to natural chemicals, to RNA and antisense, to peptides and miniproteins. Here, we briefly describe the many approaches taken so far, with a particular focus on their potential clinical applicability. PMID:28280720

  19. Multifaceted mechanisms of HIV inhibition and resistance to CCR5 inhibitors PSC-RANTES and Maraviroc.

    Science.gov (United States)

    Lobritz, Michael A; Ratcliff, Annette N; Marozsan, Andre J; Dudley, Dawn M; Tilton, John C; Arts, Eric J

    2013-06-01

    Small-molecule CCR5 antagonists, such as maraviroc (MVC), likely block HIV-1 through an allosteric, noncompetitive inhibition mechanism, whereas inhibition by agonists such as PSC-RANTES is less defined and may involve receptor removal by cell surface downregulation, competitive inhibition by occluding the HIV-1 envelope binding, and/or allosteric effects by altering CCR5 conformation. We explored the inhibitory mechanisms of maraviroc and PSC-RANTES by employing pairs of virus clones with differential sensitivities to these inhibitors. Intrinsic PSC-RANTES-resistant virus (YA versus RT) or those selected in PSC-RANTES treated macaques (M584 versus P3-4) only displayed resistance in multiple-cycle assays or with a CCR5 mutant that cannot be downregulated. In single-cycle assays, these HIV-1 clones displayed equal sensitivity to PSC-RANTES inhibition, suggesting effective receptor downregulation. Prolonged PSC-RANTES exposure resulted in desensitization of the receptor to internalization such that increasing virus concentration (substrate) could saturate the receptors and overcome PSC-RANTES inhibition. In contrast, resistance to MVC was observed with the MVC-resistant HIV-1 (R3 versus S2) in both multiple- and single-cycle assays and with altered virus concentrations, which is indicative of allosteric inhibition. MVC could also mediate inhibition and possibly resistance through competitive mechanisms.

  20. Restoration of contact inhibition in human glioblastoma cell lines after MIF knockdown

    Directory of Open Access Journals (Sweden)

    Meyer Bernhard

    2009-12-01

    Full Text Available Abstract Background Studies of the role of the cytokine macrophage-migration-inhibitory-factor (MIF in malignant tumors have revealed its stimulating influence on cell-cycle progression, angiogenesis and anti-apoptosis. Results Here we show that in vitro targeting MIF in cultures of human malignant glioblastoma cells by either antisense plasmid introduction or anti-MIF antibody treatment reduced the growth rates of tumor cells. Of note is the marked decrease of proliferation under confluent and over-confluent conditions, implying a role of MIF in overcoming contact inhibition. Several proteins involved in contact inhibition including p27, p21, p53 and CEBPalpha are upregulated in the MIF antisense clones indicating a restoration of contact inhibition in the tumor cells. Correspondingly, we observed a marked increase in MIF mRNA and protein content under higher cell densities in LN18 cells. Furthermore, we showed the relevance of the enzymatic active site of MIF for the proliferation of glioblastoma cells by using the MIF-tautomerase inhibitor ISO-1. Conclusion Our study adds another puzzle stone to the role of MIF in tumor growth and progression by showing the importance of MIF for overcoming contact inhibition.

  1. Restoration of contact inhibition in human glioblastoma cell lines after MIF knockdown

    International Nuclear Information System (INIS)

    Schrader, Jörg; Reese, Jens P; Bacher, Michael; Deuster, Oliver; Rinn, Birgit; Schulz, Martina; Kautz, Andreas; Dodel, Richard; Meyer, Bernhard; Al-Abed, Yousef; Balakrishnan, Karthikeyan

    2009-01-01

    Studies of the role of the cytokine macrophage-migration-inhibitory-factor (MIF) in malignant tumors have revealed its stimulating influence on cell-cycle progression, angiogenesis and anti-apoptosis. Here we show that in vitro targeting MIF in cultures of human malignant glioblastoma cells by either antisense plasmid introduction or anti-MIF antibody treatment reduced the growth rates of tumor cells. Of note is the marked decrease of proliferation under confluent and over-confluent conditions, implying a role of MIF in overcoming contact inhibition. Several proteins involved in contact inhibition including p27, p21, p53 and CEBPalpha are upregulated in the MIF antisense clones indicating a restoration of contact inhibition in the tumor cells. Correspondingly, we observed a marked increase in MIF mRNA and protein content under higher cell densities in LN18 cells. Furthermore, we showed the relevance of the enzymatic active site of MIF for the proliferation of glioblastoma cells by using the MIF-tautomerase inhibitor ISO-1. Our study adds another puzzle stone to the role of MIF in tumor growth and progression by showing the importance of MIF for overcoming contact inhibition

  2. Dual inhibition of DNMTs and EZH2 can overcome both intrinsic and acquired resistance of myeloma cells to IMiDs in a cereblon-independent manner

    DEFF Research Database (Denmark)

    Dimopoulos, Konstantinos; Søgaard Helbo, Alexandra; Fibiger Munch-Petersen, Helga

    2018-01-01

    methylation and an even greater reduction in chromatin accessibility. Transcriptome analysis confirmed that resistant cell lines are mainly characterized by a reduction in gene expression, identifying SMAD3 as a commonly downregulated gene in IMiD-resistant cell lines. Moreover, we show that these changes...... are potentially reversible, as combination of 5-azacytidine and EPZ-6438 not only restored the observed accessibility changes and the expression of SMAD3, but also resensitized the resistant cells to both lenalidomide and pomalidomide. Interestingly, the resensitization process was independent of CRBN. Our data......Thalidomide and its derivatives, lenalidomide and pomalidomide (also known as IMiDs), have significantly changed the treatment landscape of multiple myeloma, and the recent discovery of cereblon (CRBN) as their direct biological target has led to a deeper understanding of their complex mechanism...

  3. Inhibition of p70S6K1 activation by Pdcd4 overcomes the resistance to an IGF-1R/IR inhibitor in colon carcinoma cells

    OpenAIRE

    Zhang, Yan; Wang, Qing; Chen, Li; Yang, Hsin-Sheng

    2015-01-01

    Agents targeting insulin-like growth factor 1 receptor (IGF-1R) are being actively examined in clinical trials. Although there has been some initial success of single agent targeting IGF-1R, attempts in later studies failed due to resistance. This study aimed to understand the effects of programmed cell death 4 (Pdcd4) on the chemosensitivity of the IGF-1R inhibitor, OSI-906, in colorectal cancer (CRC) cells and the mechanism underlying this impact. Using OSI-906 resistant and sensitive CRC c...

  4. Selective inhibition of distracting input.

    Science.gov (United States)

    Noonan, MaryAnn P; Crittenden, Ben M; Jensen, Ole; Stokes, Mark G

    2017-10-16

    We review a series of studies exploring distractor suppression. It is often assumed that preparatory distractor suppression is controlled via top-down mechanisms of attention akin to those that prepare brain areas for target enhancement. Here, we consider two alternative mechanisms: secondary inhibition and expectation suppression within a predictive coding framework. We draw on behavioural studies, evidence from neuroimaging and some animal studies. We conclude that there is very limited evidence for selective top-down control of preparatory inhibition. By contrast, we argue that distractor suppression often relies secondary inhibition of non-target items (relatively non-selective inhibition) and on statistical regularities of the environment, learned through direct experience. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  5. [Concepts of inhibition in psychiatry].

    Science.gov (United States)

    Auroux, Y; Bourrat, M M; Brun, J P

    1978-01-01

    Following a historical approach, the authors first describe the original development of the concept of inhibition in neurophysiology and then analyze the subsequent adaptations made in psychiatry around such concept including those of: -- Pavlov, Hull, Watson and the behaviorists, -- Freud and the Freudian School, -- clinicians and psychopharmacologists. The concept of inhibition has thus various meanings in psychiatry. Although some unity is achieved on the semiological level, this aspect cannot explain the extent of the process.

  6. Age-differences in cognitive flexibility when overcoming a preexisting bias through feedback.

    Science.gov (United States)

    Wilson, Cristina G; Nusbaum, Amy T; Whitney, Paul; Hinson, John M

    2017-11-21

    Older adults are often worse than younger adults at adapting to changing situational demands, and this difference is commonly attributed to an age-related decline in acquiring and updating information. Previous research on aging and cognitive flexibility has used measures that require adapting to novel associations learned during a laboratory task (e.g., choice X led to positive outcomes but now leads to negative outcomes). However, in everyday life people must frequently overcome associations based on preexisting beliefs and biases (e.g., you like to eat cake, but your doctor said to limit your sugar intake). The goal of the present study was to examine possible age-differences in overcoming a preexisting bias and determine whether age-related changes in the acquisition and updating of information influence this form of flexibility. Older (n = 20) and younger (n = 20) adults completed a novel task in which repeated choices were made between a sure option (gain or loss) and one of two risky options that were initially ambiguous. Optimal performance required overcoming a framing bias toward being risk seeking to avoid a sure loss and risk averse when offered a sure gain. Probe questions assessed knowledge of choice outcomes, while skin conductance assessed physiological reactions to choices and choice outcomes. Both older and younger adults demonstrated flexibility by reducing the impact of bias over trials, but younger adults had better performance overall. Age-differences were associated with distinct aspects of processing. Young adults had more precise knowledge of choice outcomes and developed skin conductance responses in anticipation of bad choices that were not apparent in older adults. Older adults showed significant improvement over trials in their ability to decrease bias-driven choices, but younger showed greater flexibility. Age-differences in task performance were based on differences in learning and corresponding representations of task

  7. Hedgehog Signaling Overcomes an EZH2-Dependent Epigenetic Barrier to Promote Cholangiocyte Expansion

    Science.gov (United States)

    Lu, Jie; Almada, Luciana L.; Lomberk, Gwen; Fernandez-Zapico, Martin E.; Urrutia, Raul; Huebert, Robert C.

    2016-01-01

    Background & Aims Developmental morphogens play an important role in coordinating the ductular reaction and portal fibrosis occurring in the setting of cholangiopathies. However, little is known about how membrane signaling events in ductular reactive cells (DRCs) are transduced into nuclear transcriptional changes to drive cholangiocyte maturation and matrix deposition. Therefore, the aim of this study was to investigate potential mechanistic links between cell signaling events and epigenetic regulators in DRCs. Methods Using directed differentiation of induced pluripotent stem cells (iPSC), isolated DRCs, and in vivo models, we examine the mechanisms whereby sonic hedgehog (Shh) overcomes an epigenetic barrier in biliary precursors and promotes both cholangiocyte maturation and deposition of fibronectin (FN). Results We demonstrate, for the first time, that Gli1 influences the differentiation state and fibrogenic capacity of iPSC-derived hepatic progenitors and isolated DRCs. We outline a novel pathway wherein Shh-mediated Gli1 binding in key cholangiocyte gene promoters overcomes an epigenetic barrier conferred by the polycomb protein, enhancer of zeste homolog 2 (EZH2) and initiates the transcriptional program of cholangiocyte maturation. We also define previously unknown functional Gli1 binding sites in the promoters of cytokeratin (CK)7, CK19, and FN. Our in vivo results show that EZH2 KO mice fed the choline-deficient, ethanolamine supplemented (CDE) diet have an exaggerated cholangiocyte expansion associated with more robust ductular reaction and increased peri-portal fibrosis. Conclusion We conclude that Shh/Gli1 signaling plays an integral role in cholangiocyte maturation in vitro by overcoming an EZH2-dependent epigenetic barrier and this mechanism also promotes biliary expansion in vivo. PMID:27936185

  8. Methods employed to overcome difficult embryo transfer during assisted reproduction treatment.

    Science.gov (United States)

    Akhtar, M A; Netherton, R; Majumder, K; Edi-Osagie, E; Sajjad, Y

    2015-08-01

    Multiple steps, at both scientific and clinical level, are involved in assisted reproduction technology (ART). Optimization of each of these steps contributes to maximize the success of ART. Embryo transfer is one of the vital steps in ART. An easy embryo transfer increases the success of ART. Adequate training is required to undertake embryo transfer, but anatomical difficulties in completing this procedure alter the success of treatment. Difficult embryo transfer is challenging for clinicians but has an overwhelming negative impact on patients. Difficult embryo transfer may cause cervical or endometrial trauma with uterine contractions which can lead to unsuccessful implantation and poor outcome after ART. Literature review of published material looking at all interventions that were employed to overcome difficult embryo transfers during ART. We identified 5 methods (17 studies) were employed to overcome difficult embryo transfer which are: Hysteroscopic methods in 4 studies (2 case reports, 2 case series). Malecot catheters after hysteroscopic evaluation were used in 2 studies (1 case report, 1 case series). Dilators including hygroscopic dilators were used in 2 studies (1 case report, 1 case series) and mechanical dilators were used in 3 studies (2 case series, 1 RCT-patients 367). Intrafollopian transfer was reported in 1 case report. Transmyometrial embryo transfers were reported in 5 studies (2 case reports, 2 case series, 1 RCT). There were only two randomized controlled studies (RCTs) identified in the review. All other were either case series or case reports. We found that there was no uniform classification or grading of difficulty of embryo transfer in the literature. A grading system has been suggested in this review. We recommend that there should be a consensus guideline formulated for interventions to overcome difficult embryo transfer. A large multicenter randomized controlled study is required to compare different methods for women with difficult

  9. A systemwide formula for continence care: overcoming barriers, clarifying solutions, and defining team members' roles.

    Science.gov (United States)

    Etheridge, Francis; Tannenbaum, Cara; Couturier, Yves

    2008-03-01

    To seek input from long-term care (LTC) administrators and staff on solutions for overcoming established barriers to continence care and the roles each team member must play in implementing them. Cross-sectional, qualitative study using in-depth semi-structured individual interviews. Four LTC institutions in Montreal, Quebec. Sixteen health administrators, including the general director, the medical director, the director of nursing and the head nurse of the 4 institutions were interviewed. As well, 16 front-line health care workers including 8 nurses and 8 nursing assistants participated in the interviewing process. During the interviews, participants were asked to comment on a list of established barriers to continence care and to recommend solutions, involving themselves or other members of the LTC team, for overcoming these barriers. The interviews were recorded and transcribed verbatim. Data obtained during the interviews were analyzed and specific solutions to each barrier were identified, as well as the roles each team member should play in implementing them. Analysis of our data revealed 10 solutions, involving administrators as well as staff members: (1) setting continence care as an institutional priority; (2) establishing a continence committee; (3) involving the staff from the onset; (4) tailoring the continence program to each institution and resident; (5) providing training on incontinence; (6) elevating the standard of care for incontinence; (7) creating an incontinence-efficient working environment; (8) improving communication around continence care; (9) supervision, feedback and accountability; (10) championing the effectiveness of continence care. Typically, top-down solutions were proposed, but the value of bottom-up processes was included as part of the systemwide approach. Implementing and maintaining a continence program in LTC requires a systemwide approach involving LTC administrators and staff. The results of our research provide guidance

  10. Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism.

    Science.gov (United States)

    Ai, Zhihong; Lu, Yang; Qiu, Songbo; Fan, Zhen

    2016-04-01

    Cisplatin is currently one of the most effective chemotherapeutic drugs used for treating ovarian cancer; however, resistance to cisplatin is common. In this study, we explored an experimental strategy for overcoming cisplatin resistance of human ovarian cancer from the new perspective of cancer cell metabolism. By using two pairs of genetically matched cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines, we tested the hypothesis that downregulating hypoxia-inducible factor-1 (HIF-1), which regulates metabolic enzymes involved in glycolysis, is a promising strategy for overcoming cisplatin resistance of human ovarian cancer cells. We found that cisplatin downregulated the level of the regulatable α subunit of HIF-1, HIF-1α, in cisplatin-sensitive ovarian cancer cells through enhancing HIF-1α degradation but did not downregulate HIF-1α in their cisplatin-resistant counterparts. Overexpression of a degradation-resistant HIF-1α (HIF-1α ΔODD) reduced cisplatin-induced apoptosis in cisplatin-sensitive cells, whereas genetic knockdown of HIF-1α or pharmacological promotion of HIF-1α degradation enhanced response to cisplatin in both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. We further demonstrated that knockdown of HIF-1α improved the response of cisplatin-resistant ovarian cancer cells to cisplatin by redirecting the aerobic glycolysis in the resistant cancer cells toward mitochondrial oxidative phosphorylation, leading to cell death through overproduction of reactive oxygen species. Our findings suggest that the HIF-1α-regulated cancer metabolism pathway could be a novel target for overcoming cisplatin resistance in ovarian cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Overcoming Barriers to Skills Training in Borderline Personality Disorder: A Qualitative Interview Study.

    Directory of Open Access Journals (Sweden)

    Kirsten Barnicot

    Full Text Available Despite evidence suggesting that skills training is an important mechanism of change in dialectical behaviour therapy, little research exploring facilitators and barriers to this process has been conducted. The study aimed to explore clients' experiences of barriers to dialectical behaviour therapy skills training and how they felt they overcame these barriers, and to compare experiences between treatment completers and dropouts. In-depth qualitative interviews were conducted with 40 clients with borderline personality disorder who had attended a dialectical behaviour therapy programme. A thematic analysis of participants' reported experiences found that key barriers to learning the skills were anxiety during the skills groups and difficulty understanding the material. Key barriers to using the skills were overwhelming emotions which left participants feeling unable or unwilling to use them. Key ways in which participants reported overcoming barriers to skills training were by sustaining their commitment to attending therapy and practising the skills, personalising the way they used them, and practising them so often that they became an integral part of their behavioural repertoire. Participants also highlighted a number of key ways in which they were supported with their skills training by other skills group members, the group therapists, their individual therapist, friends and family. Treatment dropouts were more likely than completers to describe anxiety during the skills groups as a barrier to learning, and were less likely to report overcoming barriers to skills training via the key processes outlined above. The findings of this qualitative study require replication, but could be used to generate hypotheses for testing in further research on barriers to skills training, how these relate to dropout, and how they can be overcome. The paper outlines several such suggestions for further research.

  12. BRAF in Melanoma: Pathogenesis, Diagnosis, Inhibition, and Resistance

    International Nuclear Information System (INIS)

    Sullivan, R. J.; Flaherty, K. T.

    2011-01-01

    Since the initial discovery that a subset of patients with cutaneous melanoma harbor BRAF mutations, substantial research has been focused on determining the pathologic consequences of BRAF mutations, optimizing diagnostic techniques to identify these mutations, and developing therapeutic interventions to inhibit the function of this target in mutation-bearing tumors. Recently, advances have been made which are revolutionizing the standard of care for patients with BRAF mutant melanoma. This paper provides an overview on the pathogenic ramifications of mutant BRAF signaling, the latest molecular testing methods to detect BRAF mutations, and the most recent clinical data of BRAF pathway inhibitors in patients with melanoma and BRAF mutations. Finally, emerging mechanisms of resistance to BRAF inhibitors and ways of overcoming this resistance are discussed.

  13. Leading effective virtual teams overcoming time and distance to achieve exceptional results

    CERN Document Server

    Settle-Murphy, Nancy M

    2013-01-01

    A proliferation of new technologies has lulled many into thinking that we actually have to think less about how we communicate. In fact, communicating and collaborating across time, distance, and cultures has never been more complex or difficult.Written as a series of bulleted tips drawn from client experiences and best practices, Leading Effective Virtual Teams: Overcoming Time and Distance to Achieve Exceptional Results presents practical tips to help leaders engage and motivate their geographically dispersed project team members. If you're a leader of any type of virtual team and want to he

  14. HOW DOES SMALL MEDIUM ENTERPRISE IN DEVELOPING COUNTRIES OVERCOME INFORMATION AND COMMUNICATION TECHNOLOGY ADOPTION PROBLEMS?

    Directory of Open Access Journals (Sweden)

    Ambar Sari Dewi

    2016-09-01

    Full Text Available The role of Small Medium Enterprise (SME has been proven to be important in economic development. Many research also believed that the rapid rise of SME’s development caused by Information and Communication Technology (ICT adaption in their business. However, its adoption in developing countries faces several problems. Using Rogers’ (1995 diffusion of innovation theory and Manueli’s et.al (2007 recommendations, this essay will argue that to overcome the problem, a strong cooperation should be taken, interpersonal communication should be use as well as type of ICTs should be chosen wisely, based on specifi needs.

  15. The Role of Therapy Education of Islamic Meaning to Overcome Today’s Global Human Crisis

    Directory of Open Access Journals (Sweden)

    Nina Aminah

    2016-02-01

    Full Text Available Modern community are exposed to current issues related to the very complex personality. Islam offers a therapeutic meaning to overcome the global human crisis through the holy Qu’ran. This study aims to provide a qualitative analysis of logotherapy alternative to global human who experience critical conditions such as the door of death (sakaratul maut, acute illnesses, HIV Aids, kidney illness, stroke, coma, depression / stress, due to the hazards, and other refractory disease. The study showed that the therapy of Islamic meaning based on the holy Qur’an is broader and more comprehensive than the meaning therapy by Viktor E. Frankl.

  16. Strategies for Overcoming Key Barriers to Development of a National Security Workforce

    Energy Technology Data Exchange (ETDEWEB)

    None

    2008-06-30

    This report documents the strategies for overcoming identified key barriers to development of an adequate national security workforce as part of the National Security Preparedness Project (NSPP) being performed under a Department of Energy (DOE) National Nuclear Security Administration (NNSA) grant. Many barriers currently exist that prevent the development of an adequate number of properly trained national security personnel. The identified strategies to address the barriers will focus on both short-term and long-term efforts, as well as strategies to capture legacy knowledge of retiring national security workforce personnel.

  17. Overcoming Hospital Resistance to Create a Successful Donation After Circulatory Death Program.

    Science.gov (United States)

    O'Meeghan, R; Pedral, L

    2016-09-01

    In the setting of an ever-increasing transplantation need, and a relatively static number of brain dead donors, donation after circulatory death (DCD) has heightened importance as a process to increase the number of organs available for transplantation. This article describes the barriers to the DCD process at a community hospital, what occurred to change the situation, and how data were used to overcome administrative and cultural barriers to create a successful DCD program. The program has become a role model in the local community. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Overcoming strategy to strengthen the History of Medicine in Santiago of Cuba

    Directory of Open Access Journals (Sweden)

    Ana María Durán-Fonseca

    2018-03-01

    Full Text Available A strategy of improvement in the Medical Sciences is proposed, integrated to the performance of every teacher that forms part of the Cuban educational system associated with health. The overcoming of the teachers of Medical Sciences in History of Medicine, takes into account the new conceptions and demands of the training of the doctor at present, for what constitutes a challenge from recognizing that the History of Medicine is not a appendix of Medicine, or History, but with its own legitimacy erected in science synthesis with structural and methodological architecture, deduced by the independent position that Medicine occupies in the set of Natural and Humanistic sciences.

  19. Understanding and overcoming the “positive profits with negative surplus-value” paradox

    Directory of Open Access Journals (Sweden)

    GUSTAVO DAOU LUCAS

    Full Text Available ABSTRACT This paper explains the “positive profits with negative surplus-value” example of Steedman (1975 and shows that while in joint production systems individual labour values can be negative, the claim that the total labour embodied in the surplus product of the economy (surplus-value can also be negative is based on assumptions that have no economic meaning (such as negative activity levels.The paper also provides a way to measure the surplus-value of joint production systems which overcomes the problems of the traditional concept and restates the proposition that a positive amount of surplus labour is a necessary condition for positive profits.

  20. How to overcome some of the challenges that African scholars are facing in conducting informetrics research

    Directory of Open Access Journals (Sweden)

    Isola Ajiferuke

    2011-01-01

    Full Text Available This article provides evidence to show that the contributions of African researchers to the informetrics literature are minimal. The three main challenges identified as limiting the contributions of African scholars to the informetrics literature are lack of appropriate skills, inadequate data collection sources, and unaffordable analytical tools. To overcome these challenges, it is suggested that regular pre-conference workshops on informetrics should be organized, an African Citation Index should be developed, and the use of free analytical tools should be encouraged.

  1. Effects arising from charged particles overcoming of the light velocity barrier

    International Nuclear Information System (INIS)

    Afanas'ev, G.N.; Eliseev, S.M.; Stepanovskij, Yu.P.

    1997-01-01

    The effects arising from accelerated and decelerated motion of the charged point particle inside the medium are studied. It is shown explicitly that in addition to the Bremsstrahlung and Cherenkov shock wave, the electromagnetic shock wave arising from the charge overcoming the light velocity in the medium should be observed. This shock wave has the same singularity as the Cherenkov one and, therefore, it is more singular than the Bremsstrahlung shock wave. The space-time regions where these shock waves exist and conditions under which they appear are determined

  2. Near Real-Time MOPITT Data - Its Architecture, Obstacles Overcome, and Strategic Decisions

    Science.gov (United States)

    Ziskin, D.; Mao, D.; Worden, H. M.; Deeter, M. N.; D'Attilo, G.; Fredrick, T.; Martinez-Alonso, S.; Francis, G.; Drews, C.

    2017-12-01

    Measurements Of Pollution In The Troposphere (MOPITT) is an instrument that has been flying aboard NASA's Terra satellite and collecting CO data since March 2000. The standard MOPITT product uses ancillary data that can delay its production by several weeks. Furthermore, final processing does not occur until after the annual calibration event, creating a lag of up to a year. In contrast, MOPITT produces a Near Real-Time (NRT) product available through the Land, Atmosphere Near real-time Capability for EOS (LANCE) interface with a latency of less than three hours. This presentation details the architecture of the system, obstacles overcome, and strategic decisions made in order become a LANCE node.

  3. Agents that increase phosphatidic acid inhibit the LH-induced testosterone production

    DEFF Research Database (Denmark)

    Lauritzen, L.; Nielsen, L.-L.A.; Vinggaard, Anne Marie

    1994-01-01

    The results of the present study point to phosphatidic acid (PtdOH) as a possible intracellular messenger, which might be involved in local modulation of testicular testosterone production in vivo. Propranolol (27-266 µM) induced an increased level of [H]PtdOH in isolated rat Leydig cells......, prelabeled with [H]myristate, and at the same time a strong dose-dependent inhibition of the acute testosterone production stimulated by luteinizing hormone (LH). The inhibition was not bypassed by the addition of dibutyryl-cAMP but was overcome, when 22(R)-hydroxycholesterol was added as a direct substrate...... for cytochrome P-450 side chain cleavage enzyme. Thus, the inhibition appears to be exerted at a point distal to cAMP-generation but before the first enzyme in the testosterone synthetic pathway. Treatment with other agents (4ß-phorbol 12-myristate 13-acetate (PMA), A23187, and sphingosine) giving rise...

  4. Mycobacterium tuberculosis inhibits macrophage responses to IFN-gamma through myeloid differentiation factor 88-dependent and -independent mechanisms.

    Science.gov (United States)

    Fortune, Sarah M; Solache, Alejandra; Jaeger, Alejandra; Hill, Preston J; Belisle, John T; Bloom, Barry R; Rubin, Eric J; Ernst, Joel D

    2004-05-15

    Mycobacterium tuberculosis overcomes macrophage bactericidal activities and persists intracellularly. One mechanism by which M. tuberculosis avoids macrophage killing might be through inhibition of IFN-gamma-mediated signaling. In this study we provide evidence that at least two distinct components of M. tuberculosis, the 19-kDa lipoprotein and cell wall peptidoglycan (contained in the mycolylarabinogalactan peptidoglycan (mAGP) complex), inhibit macrophage responses to IFN-gamma at a transcriptional level. Moreover, these components engage distinct proximal signaling pathways to inhibit responses to IFN-gamma: the 19-kDa lipoprotein inhibits IFN-gamma signaling in a Toll-like receptor (TLR)2-dependent and myeloid differentiation factor 88-dependent fashion whereas mAGP inhibits independently of TLR2, TLR4, and myeloid differentiation factor 88. In addition to inhibiting the induction of specific IFN-gamma responsive genes, the 19-kDa lipoprotein and mAGP inhibit the ability of IFN-gamma to activate murine macrophages to kill virulent M. tuberculosis without inhibiting production of NO. These results imply that inhibition of macrophage responses to IFN-gamma may contribute to the inability of an apparently effective immune response to eradicate M. tuberculosis.

  5. PARP Inhibition Restores Extrinsic Apoptotic Sensitivity in Glioblastoma

    Science.gov (United States)

    Karpel-Massler, Georg; Pareja, Fresia; Aimé, Pascaline; Shu, Chang; Chau, Lily; Westhoff, Mike-Andrew; Halatsch, Marc-Eric; Crary, John F.; Canoll, Peter; Siegelin, Markus D.

    2014-01-01

    Background Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo. Methods The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low-passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model. Results The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP) homology protein (CHOP). Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone. Conclusions PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM. PMID:25531448

  6. NIETZSCHEAN READING OF TOM MURPHY’S PLAY: “THE SANCTUARY LAMP” AND OVERCOMING NIHILISM

    Directory of Open Access Journals (Sweden)

    VICTORIA BILGE YILMAZ

    2012-11-01

    Full Text Available This article is an analysis of a play by Tom Murphy, “The Sanctuary Lamp”, against the background of Nietzschean philosophical concept of overcoming nihilism as well as an attempt at discovering the parallelisms between Murphy’s characters in their search for the essence of existence and their desire for a meaningful life and Nietzschean philosophy. In the play, self-realisation of an individual, that is, overcoming nihilism, is mainly achieved by means of one’s individual strength, which is characterised by the ability to combine destruction and creation, employ one’s will to power, create new values, affirm life as it is, forget and forgive one’s enemies, and employ art in life. The playwright conveys an individual’s loss of purpose and the inevitable chaos in the aftermath of the death of God and the methods to surmount this nihilistic condition. The study comes to the conclusion that all the above Nietzschean elements build a solid background for Murphy’s drama, where the dramatist draws a picture of systematicity of existence of an individual who struggles to attain meaning.

  7. Internationalization as a strategy to overcome industry barriers-An assessment of the marine energy industry

    International Nuclear Information System (INIS)

    Lovdal, Nicolai; Neumann, Frank

    2011-01-01

    Research on conditions to develop new innovations within emerging renewable energy industries is often done with a national focus. However, recent research on international entrepreneurship has revealed that firms operate on international levels very early in their life time. Thus, based on former research on international entrepreneurship and case examples, we build the propositions that firms in the marine energy industry use internationalization as a strategy to overcome industry barriers. Our primary source of data is a unique dataset from a global survey of all the companies in the marine energy industry who are aiming to commercialize a wave or tidal energy device. This paper is organized in two steps: first we identified the most challenging industry barriers perceived by companies. Second we use these to form propositions which we assess through empirical data. The two most challenging barriers perceived by the companies are need for capital and need for supportive political schemes. Our findings reveal that internationalization certainly is a common strategy to access capital and attractive support schemes in foreign countries. The early internationalization has implications for researchers, managers and policy makers. - Research highlights: → Industry barriers identified as access to capital and supportive political schemes. → International entrepreneurship is used to overcome industry barriers. → Start-ups in emerging energy industries 'shop' national support schemes. → Future research to provide policy advice should adapt to the international reality. → Research based on a worldwide survey of wave and tidal energy device developers.

  8. Virtuality and efficiency - overcoming past antinomy in the remote collaboration experience

    International Nuclear Information System (INIS)

    Fernandes, Joao; Bjorkli, Knut; Clavo, David Martin; Baron, Thomas

    2010-01-01

    Several recent initiatives have been put in place by the CERN IT Department to improve the user experience in remote dispersed meetings and remote collaboration at large in the LHC communities worldwide. We will present an analysis of the factors which were historically limiting the efficiency of remote dispersed meetings and describe the consequent actions which were undertaken at CERN to overcome these limitations. After giving a status update of the different equipment available at CERN to enable the virtual sessions and the various collaborative tools which are currently proposed to users, we will focus on the evolution of this market: how can the new technological trends (among others, HD videoconferencing, Telepresence, Unified Communications, etc.) impact positively the user experience and how to attain the best usage of them. Finally, by projecting ourselves in the future, we will give some hints as to how to answer the difficult question of selecting the next generation of collaborative tools: which set of tools among the various offers (systems like Vidyo H264 SVC, next generation EVO, Groupware offers, standard H323 systems, etc.) is best suited for our environment and how to unify this set for the common user. This will finally allow us to definitively overcome the past antinomy between virtuality and efficiency.

  9. Effect of storage in overcoming seed dormancy of Annona coriacea Mart. seeds

    Directory of Open Access Journals (Sweden)

    DAIANE M. DRESCH

    2014-12-01

    Full Text Available The aim of this study was to evaluate the effect of pre-treatments on overcoming dormancy of A. coriacea seeds. Seeds were processed and stored in polyethylene bags at temperatures of at -18°C (42% RH, 5°C (34% RH, 15°C (60% RH and 25°C (34% RH, during 0, 30, 60, 90, 120 and 150 days. After storage, seeds were immersed in 350 mg.L−1 gibberellic acid for 144 hours. Sowing was carried out in plastic bags containing Red Latosol + Bioplant®. Moisture content, emergence percentage, emergence speed index, length and dry mass of seedlings, were evaluated. The experimental design was completely randomized in a factorial with four replications of 50 seeds each. The seed storage at 5°C and subsequent immersion in gibberellic acid was efficient to reach high percentage, emergence speed and plant growth. A. coriacea seeds showed non-deep simple morphophysiological dormancy wherein the physiological component can be overcome after the seeds are storage at 5°C for a maximum period of 53 days and subsequent immersed in exogenous GA (350 mg.L−1 for 144 hours.

  10. Effect of storage in overcoming seed dormancy of Annona coriacea Mart. seeds.

    Science.gov (United States)

    Dresch, Daiane M; Scalon, Silvana P Q; Masetto, Tathiana E

    2014-12-01

    The aim of this study was to evaluate the effect of pre-treatments on overcoming dormancy of A. coriacea seeds. Seeds were processed and stored in polyethylene bags at temperatures of at -18°C (42% RH), 5°C (34% RH), 15°C (60% RH) and 25°C (34% RH), during 0, 30, 60, 90, 120 and 150 days. After storage, seeds were immersed in 350 mg.L-1 gibberellic acid for 144 hours. Sowing was carried out in plastic bags containing Red Latosol + Bioplant®. Moisture content, emergence percentage, emergence speed index, length and dry mass of seedlings, were evaluated. The experimental design was completely randomized in a factorial with four replications of 50 seeds each. The seed storage at 5°C and subsequent immersion in gibberellic acid was efficient to reach high percentage, emergence speed and plant growth. A. coriacea seeds showed non-deep simple morphophysiological dormancy wherein the physiological component can be overcome after the seeds are storage at 5°C for a maximum period of 53 days and subsequent immersed in exogenous GA (350 mg.L-1 for 144 hours).

  11. Overcoming Recruitment Barriers in Urban Older Adults Residing in Congregate Living Facilities

    Directory of Open Access Journals (Sweden)

    Adam Simning

    2015-01-01

    Full Text Available Background. Participation of minority older adults in mental health research has been limited by mistrust, transportation difficulties, lack of knowledge, and insufficient community partnership. We describe strategies utilized to overcome these recruitment barriers. Methods. Our target population included 553 public housing residents of older adult high-rise buildings in Rochester, NY. We had a two-stage cross-sectional study: Stage 1 was a health survey for all residents and Stage 2 was a psychiatric interview of English-speaking residents aged 60 years and older. Recruitment occurred through mailings, onsite activities, and resident referrals. Results. Stage 1 had 358 participants (64.7% response and Stage 2 had 190 (61.6% target population response, with higher participation among African Americans. We found some strategies effective for overcoming recruitment barriers. First, we partnered with a community agency and organized onsite educational activities to improve residents’ trust. Second, the study occurred entirely onsite, which facilitated participation of functionally impaired residents. Third, onsite activities allowed the residents to learn about the study and complete surveys in person. Fourth, we provided immediate incentives that resulted in many study referrals. Conclusions. Although recruitment of minority older adults presents unique challenges, a multifaceted community-tailored approach mitigated several recruitment barriers in this mental health study.

  12. Nanotransformation of Vancomycin Overcomes the Intrinsic Resistance of Gram-Negative Bacteria.

    Science.gov (United States)

    Fernandes, Margarida M; Ivanova, Kristina; Hoyo, Javier; Pérez-Rafael, Sílvia; Francesko, Antonio; Tzanov, Tzanko

    2017-05-03

    The increased emergence of antibiotic-resistant bacteria is a growing public health concern, and although new drugs are constantly being sought, the pace of development is slow compared with the evolution and spread of multidrug-resistant species. In this study, we developed a novel broad-spectrum antimicrobial agent by simply transforming vancomycin into nanoform using sonochemistry. Vancomycin is a glycopeptide antibiotic largely used for the treatment of infections caused by Gram-positive bacteria but inefficient against Gram-negative species. The nanospherization extended its effect toward Gram-negative Escherichia coli and Pseudomonas aeruginosa, making these bacteria up to 10 and 100 times more sensitive to the antibiotic, respectively. The spheres were able to disrupt the outer membranes of these bacteria, overcoming their intrinsic resistance toward glycopeptides. The penetration of nanospheres into a Langmuir monolayer of bacterial membrane phospholipids confirmed the interaction of the nanoantibiotic with the membrane of E. coli cells, affecting their physical integrity, as further visualized by scanning electron microscopy. Such mechanism of antibacterial action is unlikely to induce mutations in the evolutionary conserved bacterial membrane, therefore reducing the possibility of acquiring resistance. Our results indicated that the nanotransformation of vancomycin could overcome the inherent resistance of Gram-negative bacteria toward this antibiotic and disrupt mature biofilms at antibacterial-effective concentrations.

  13. Designing PDT-based combinations to overcome chemoresistance in heterocellular 3D tumor models (Conference Presentation)

    Science.gov (United States)

    Rizvi, Imran; Briars, Emma A.; Bulin, Anne-Laure; Anbil, Sriram; Vecchio, Daniela; Alkhateeb, Ahmed; Hanna, William R.; Celli, Jonathan P.; Hasan, Tayyaba

    2016-03-01

    A major barrier to treating advanced-stage cancers is heterogeneity in the responsiveness of metastatic disease to conventional therapies leading to resistance and treatment failure. Photodynamic therapy (PDT) has been shown to synergize with conventional agents and to overcome the evasion pathways that cause resistance. Developing PDT-based combinations that target resistant tumor populations and cooperate mechanistically with conventional agents is an increasingly promising approach to improve therapeutic efficacy while minimizing toxicity, particularly in complex disease sites. Identifying the molecular, cellular, and microenvironmental cues that lead to heterogeneity and treatment resistance is critical to developing strategies to target unresponsive regions of stubborn disease. Cell-based research platforms that integrate key microenvironmental cues are emerging as increasingly important tools to improve the translational efficiency of new agents, and to design combination regimens. Among the challenges associated with developing and scaling complex cell-based screening platforms is the need to integrate, and balance, biological relevance with appropriate, high-content imaging routines that provide meaningful quantitative readouts of therapeutic response. The benefits and challenges associated with deriving meaningful insights from complex cell-based models will be presented, with a particular emphasis on overcoming chemoresistance mediated by physical stress and communication with stromal partners (e.g. tumor endothelial cells, which are emerging as dynamic regulators of treatment resistance) using PDT-based combinations.

  14. Awareness On Microgrids And Various Protection Issues To Overcome In It

    Directory of Open Access Journals (Sweden)

    Rachna Verma

    2015-05-01

    Full Text Available ABSTRACT As we know India faces problem of Power blackout every year due to the overloading on the main electrical grid. To avoid the above problem Microgrids are the best solution. Basically Microgrids are the small version of electrical grid. They are independent power system. Microgrids can be connected with renewable energy sources such as solar and wind. The use of renewable energy introduces the need of various storing devices and supplies it whenever required. Microgrids can provide wide range of applications in buildings military camps and corporateacademic campuses etc. They can have efficient and effective provision of electricity to off-grid areas as well as keep the lights on in times of crisis for critical applications like hospital. Though Microgrids being so advantageous it has several technical challenging issues to overcome i.e. voltage and frequency control islanding and its protection in Microgrids. This paper discusses the overview of Microgrids and issue to overcome in it-its Protection.

  15. METHODS FOR OVERCOMING SEED DORMANCY AND THE INITIAL GROWTH OF Ziziphus joazeiro Mart. IN DIFFERENT SOILS

    Directory of Open Access Journals (Sweden)

    JOSENARA DAIANE DE SOUZA COSTA

    2016-01-01

    Full Text Available Considering the potential and importance of biodiversity of the Caatinga biome, studies on endemic species are relevant to conservation of its natural resources. The objectives of this work was to evaluate seed viability and physical methods for overcoming seed dormancy in juazeiro (Ziziphus joazeiro Mart. and assess the influence of different types of soil on the initial growth of juazeiro plants. The experiments were conducted in three stages. In the first stage, the viability of seeds from different lots was evaluated using the tetrazolium test. The second stage was conducted in a plant nursery, evaluating the application of physical processes (scarification with sandpaper and hammer in overcoming seed dormancy, and the initial growth of the plants. In the third step, the chlorophyll a and b contents, gas exchange and dry matter accumulation were evaluated in young juazeiro plants in three types of soil (Oxisol, Entisol and Vertisol. The results indicate that the viability of juazeiro seeds is greatly influenced by differences between the progenitor plants and by storage conditions, which enable a longevity of two years when stored at 22°C and 16% of relative humidity. The scarification methods with sandpaper and hammer are not efficient to reduce the time and uniform seed germination. The juazeiro plants have high growth potential in different edaphic environments, adapting well to soils of different textures and chemical compositions.

  16. A framework for prioritising practices to overcome cost-related problems in reverse logistics

    Directory of Open Access Journals (Sweden)

    Amanda Badenhorst

    2013-11-01

    Full Text Available Reverse logistics has gained increasing attention in recent years. One of the biggest problems for organisations and supply chains is reducing cost in reverse logistics. This study attempted to gain a better understanding of reverse logistics and the costs associated with it. A literature study was conducted to identify the cost problems in reverse logistics and possible practices to overcome them. Following that, a survey was conducted to determine whether the practices identified in literature are perceived to be important in South Africa and if they are viable to implement. This was done by means of a gap and opportunity analysis. Results indicated that most practices are important, but some may be difficult to implement. The framework developed in this study provides a guideline for organisations to consider, adapt and adopt the most important implementable practices to overcome cost problems in reverse logistics. The limitation of this study is that only ten respondents participated in the survey. The approach followed in this study can be used as a foundation for future studies in reverse logistics.

  17. Internationalization as a strategy to overcome industry barriers-An assessment of the marine energy industry

    Energy Technology Data Exchange (ETDEWEB)

    Lovdal, Nicolai, E-mail: nicolai.lovdal@iot.ntnu.n [Industrial Economics and Technology Management, Norwegian University of Science and Technology, 7491 Trondheim (Norway); Neumann, Frank, E-mail: frank@wave-energy-centre.or [Wave Energy Centre, Av. Manuel Maia, 36, r/c Dto., 1000-201 Lisboa (Portugal)

    2011-03-15

    Research on conditions to develop new innovations within emerging renewable energy industries is often done with a national focus. However, recent research on international entrepreneurship has revealed that firms operate on international levels very early in their life time. Thus, based on former research on international entrepreneurship and case examples, we build the propositions that firms in the marine energy industry use internationalization as a strategy to overcome industry barriers. Our primary source of data is a unique dataset from a global survey of all the companies in the marine energy industry who are aiming to commercialize a wave or tidal energy device. This paper is organized in two steps: first we identified the most challenging industry barriers perceived by companies. Second we use these to form propositions which we assess through empirical data. The two most challenging barriers perceived by the companies are need for capital and need for supportive political schemes. Our findings reveal that internationalization certainly is a common strategy to access capital and attractive support schemes in foreign countries. The early internationalization has implications for researchers, managers and policy makers. - Research highlights: {yields} Industry barriers identified as access to capital and supportive political schemes. {yields} International entrepreneurship is used to overcome industry barriers. {yields} Start-ups in emerging energy industries 'shop' national support schemes. {yields} Future research to provide policy advice should adapt to the international reality. {yields} Research based on a worldwide survey of wave and tidal energy device developers.

  18. Economic damage and state policy on the overcoming of the Chernobyl NPP catastrophe consequences. Chapter 2

    International Nuclear Information System (INIS)

    Konoplya, E.F.; Rolevich, I.V.

    1998-01-01

    The economic consequences of the Chernobyl NPP accident for the Republic of Belarus are given. The damage, taking into account the 30-years period needed for its overcoming, is estimated to be 235 billion US$ that is equal to 32 annual budgets of the republic of 1985. The losses connected with the deterioration of population health, damage incurred in industry and social sphere, agriculture, building complex, transport and communication, housing, with contamination of raw, mineral, land, water, forest and other resources are shown. The main directions of the state and legislative bodies activity on overcoming of the Chernobyl NPP accident consequences are directed on realization of complex of measures on maximum decreasing the radiation exposure dose; providing safety of people's health at the expense of medical preventive measures, improvement of their health, social insurance and resettlement from the zones where the safe living criteria are not observed; providing safe living conditions in regions subjected to radioactive contamination; rise of population life quality in these regions; scientific research of the problems connected with radiation influence on ecosystem, etc. The medical care and social protection systems of the affected population are describe

  19. Counter-stereotypical pictures as a strategy for overcoming spontaneous gender stereotypes

    Directory of Open Access Journals (Sweden)

    Eimear eFinnegan

    2015-08-01

    Full Text Available The present research investigated the use of counter-stereotypical pictures as a strategy for overcoming spontaneous gender stereotypes when certain social role nouns and professional terms are read. Across two experiments, participants completed a judgement task in which they were presented with word pairs comprised of a role noun with a stereotypical gender bias (e.g. beautician and a kinship term with definitional gender (e.g. brother. Their task was to quickly decide whether or not both terms could refer to one person. In each experiment they completed 2 blocks of such judgement trials separated by a training session in which they were presented with pictures of people working in gender counter-stereotypical (Experiment 1 or gender stereotypical roles (Experiment 2. To ensure participants were focused on the pictures, they were also required to answer 4 questions on each one relating to the character’s leisure activities, earnings, job satisfaction and personal life. Accuracy of judgements to stereotype incongruent pairings was found to improve significantly across blocks when participants were exposed to counter-stereotype images (9.87% as opposed to stereotypical images (0.12%, while response times decreased significantly across blocks in both studies. It is concluded that exposure to counter-stereotypical pictures is a valuable strategy for overcoming spontaneous gender stereotype biases in the short term.

  20. Economic damage and state policy on the overcoming of the Chernobyl NPP catastrophe consequences. Chapter 2

    International Nuclear Information System (INIS)

    Konoplya, E.F.; Lych, G.M.; Pateeva, Z.G.; Smolyar, I.N.; Kudin, V.V.; Koval', I.G.

    1996-01-01

    The economic consequences of the Chernobyl NPP accident for the Republic of Belarus are given. The damage, taking into account the 30-years period needed for its overcoming, is estimated to be 235 billion US$ that is equal to 32 annual budgets of the republic of 1985. The losses connected with the deterioration of population health, damage incurred in industry and social sphere, agriculture, building complex, transport and communication, housing, with contamination of raw, mineral, land, water, forest and other resources are shown. The main directions of the state and legislative bodies activity on overcoming of the Chernobyl NPP accident consequences are directed on realization of complex of measures on maximum decreasing the radiation exposure dose; providing safety of people's health at the expense of medical preventive measures, improvement of their health, social insurance and resettlement from the zones where the safe living criteria are not observed; providing safe living conditions in regions subjected to radioactive contamination; rise of population life quality in these regions; scientific research of the problems connected with radiation influence on ecosystem, etc. The medical care and social protection systems of the affected population are describe. 3 figs

  1. Factors in Overcoming Barriers to Implementing Co-management in British Columbia Salmon Fisheries

    Directory of Open Access Journals (Sweden)

    Evelyn Pinkerton

    1999-12-01

    Full Text Available Ten years of research and efforts to implement co-management in British Columbia fisheries have demonstrated that we lack neither good models nor the political will in communities to design and test local and regional institutions for successful involvement in various aspects of management. The barriers lie rather in the distrust and resistance of management agencies and the lack of broadly organized political support. The nature of the barriers and some of the elements of a successful approach to overcoming them are identified and discussed. The analysis is focused around the barriers encountered by two differently situated fishing communities or regions that have launched conservation initiatives through cooperation between local aboriginal and nonaboriginal fishing groups. In attempting to overcome the political barriers, the communities seek to develop expertise in selective fishing technology for more sustainable harvest, principled multi-stakeholder negotiation, marketing, shared databases, and preliminary ecosystem monitoring. The communities exemplify small- and medium-scale bottom-up approaches to adaptive management. The analysis shows the key and possibly unique contributions of processes at these levels, and suggests how they can be scaled up and linked to processes at other levels. Both types of analysis are largely missing in adaptive management theory, which has tended to focus on larger scale processes and to dismiss the potential of smaller scale ones to transform, expand, and link. This analysis focuses on salmon (Oncorhynchus spp. fisheries of British Columbia, Canada, but the literature suggests that the findings have far broader applicability.

  2. Pseudomonas sax genes overcome aliphatic isothiocyanate-mediated non-host resistance in Arabidopsis

    Science.gov (United States)

    Jun Fan; Casey Crooks; Gary Creissen; Lionel Hill; Shirley Fairhurst; Peter Doerner; Chris Lamb

    2011-01-01

    Most plant-microbe interactions do not result in disease; natural products restrict non-host pathogens. We found that sulforaphane (4-methylsulfinylbutyl isothiocyanate), a natural product derived from aliphatic glucosinolates, inhibits growth in Arabidopsis of non-host Pseudomonas bacteria in planta. Multiple sax genes (saxCAB/F/D/G) were identified in Pseudomonas...

  3. Overcoming constraints to the implementation of water demand management in southern Africa

    Science.gov (United States)

    Mwendera, E. J.; Hazelton, D.; Nkhuwa, D.; Robinson, P.; Tjijenda, K.; Chavula, G.

    This paper presents results of a study on water demand management status and overcoming constraints to implementation of water demand management in the southern African region, as part of Phase II of water demand management (WDM) programme implemented by the IUCN (The World Conservation Union). The study was conducted in Malawi, Namibia, South Africa, Swaziland, Zambia and Zimbabwe. The study methodology consisted of a survey of literature, and interviewing and communicating with stakeholders in order to learn from stakeholders on the critical constraints to WDM implementation and strategies to overcome them. The study has shown that, despite the potential savings that would accrue from implementation of WDM, the water sector across the southern African region continues to focus on water supply augmentation. There are inadequate financial and human resources for rehabilitation, operation and maintenance of water conveyance systems resulting in system leaks, which contribute to high levels of unaccounted-for water, a situation that masks the potential benefits of WDM. In most countries, the water sector operates on ad-hoc sub-sector water user objectives, which provided guidelines only for development and management purposes. Most of the institutional frameworks have remained diffuse, resulting into poor performance in the sector, and into crisis management in the water resources development. Though the WDM policy in most countries is already accessible through guidelines for catchment management institutions and water supply institutions; there is a lack of broad commitment to implementing them. In other countries the instruments are relatively new and have not been applied widely. Similarly, the effectiveness of instruments has not been well evaluated in most countries. In countries where policy is weak there is often a lack of clarity as to who is responsible for WDM implementation, and even less clarity on who is responsible for facilitating and monitoring

  4. Homo economicus belief inhibits trust.

    Directory of Open Access Journals (Sweden)

    Ziqiang Xin

    Full Text Available As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners' benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals' homo economicus belief and inhibit their trust. It seems that people's increasing homo economicus belief may serve as one cause of the worldwide decline of trust.

  5. Homo economicus belief inhibits trust.

    Science.gov (United States)

    Xin, Ziqiang; Liu, Guofang

    2013-01-01

    As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners' benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals' homo economicus belief and inhibit their trust. It seems that people's increasing homo economicus belief may serve as one cause of the worldwide decline of trust.

  6. Overcoming ocular drug delivery barriers through the use of physical forces.

    Science.gov (United States)

    Huang, Di; Chen, Ying-Shan; Rupenthal, Ilva D

    2017-09-12

    Overcoming the physiological barriers in the eye remains a key obstacle in the field of ocular drug delivery. While ocular barriers naturally have a protective function, they also limit drug entry into the eye. Various pharmaceutical strategies, such as novel formulations and physical force-based techniques, have been investigated to weaken these barriers and transport therapeutic agents effectively to both the anterior and the posterior segments of the eye. This review summarizes and discusses the recent research progress in the field of ocular drug delivery with a focus on the application of physical methods, including electrical fields, sonophoresis, and microneedles, which can enhance penetration efficiency by transiently disrupting the ocular barriers in a minimally or non-invasive manner. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. The Implementation Effort Islamic Law Norms in Activities for Overcoming Pornography and Pornoaction on Mass Media

    Directory of Open Access Journals (Sweden)

    Ramlani Lina Sinaulan

    2017-02-01

    Full Text Available This paper discusses the effort Islamic Law norms in activities for overcoming pornography and porno-action on mass media. By using normative legal research, the result found that the concept of Islamic law, behave based on sharia, shows the importance of shaping the personality traits of Islam (syakhsiyya Islāmiyya and based on the devotion and faith. Because of the relation to the formulation of the rule of law against pornography behavior, it can not be designed, prepared and formulated based on social values. Based on the facts of society, as a result of the moral decadence that led to a permissive attitude towards their cultural infiltration, the social values in assessing the behavior may become more permissive toward behavior. However, the use of religious norms which have universal properties will not change, and even capable of elastic with the times.

  8. PATIENTS OVERCOME ANXIETY AND ARE ENCOURAGED TO BE PHYSICAL ACTIVE THROUGH EXERCISE-BASED CARDIAC REHABILITATION

    DEFF Research Database (Denmark)

    Simonÿ, Charlotte; Dreyer, Pia; Pedersen, Birthe D.

    into that the heart endures physical activity. In addition to serving as physical guidance, exercise-based cardiac rehabilitation offers valuable mental support. The patients find help to overcome an initial anxiety and move forward towards a physically active life featuring a feeling of improved health and new......, and it seems to be crucial to further emphasise the individuals lived experiences when exercise-based cardiac rehabilitation is followed. Hence this study aims to investigate how patients experience exercise-based cardiac rehabilitation in a hospital setting. Methods. This study, which included nine men...... interviews were performed 1-2 months later. A phenomenological hermeneutic interpretation was conducted, comprising three methodological steps: naïve reading, structural analysis and comprehensive interpretation. Results. The preliminary findings are that although physically and especially mentally...

  9. PATIENTS OVERCOME ANXIETY AND ARE ENCOURAGED TO BE PHYSICAL ACTIVETHROUGH EXERCISE-BASED CARDIAC REHABILITATION

    DEFF Research Database (Denmark)

    Simonÿ, Charlotte; Dreyer, Pia; Pedersen, Birthe D.

    2015-01-01

    into that the heart endures physical activity. In addition to serving as physical guidance, exercise-based cardiac rehabilitation offers valuable mental support. The patients find help to overcome an initial anxiety and move forward towards a physically active life featuring a feeling of improved health and new......, and it seems to be crucial to further emphasise the individuals lived experiences when exercise-based cardiac rehabilitation is followed. Hence this study aims to investigate how patients experience exercise-based cardiac rehabilitation in a hospital setting. Methods. This study, which included nine men...... interviews were performed 1-2 months later. A phenomenological hermeneutic interpretation was conducted, comprising three methodological steps: naïve reading, structural analysis and comprehensive interpretation. Results. The preliminary findings are that although physically and especially mentally...

  10. Black Sea Cooperation: a Difficult Path to Overcoming Divisions and Marginalization

    Directory of Open Access Journals (Sweden)

    Panagiota Manoli

    2013-12-01

    Full Text Available The Black Sea area is mostly discussed for its security relevance to Europe and to the rest of the international community. Suffering from a long transition period to market economy and parliamentary democracy, the peoples living in the area have been struggling to overcome the new divisions of the post Soviet era and join the European community of stability and prosperity. Regionalism has been used as a means towards this end. Embraced already by the early 1990s by local political elites of the newly established countries in the region, regionalism became a fashionable policy tool responding to needs of sovereignty boosting, global integration and good neighbourly relations. Primarily used as a foreign policy tool, regionalism has followed a difficult path. This chapter presents an overview of the evolution of Black Sea regionalism, looking at actors, interests and processes. Then it discusses its achievements and shortcomings.

  11. Microbial advanced biofuels production: overcoming emulsification challenges for large-scale operation.

    Science.gov (United States)

    Heeres, Arjan S; Picone, Carolina S F; van der Wielen, Luuk A M; Cunha, Rosiane L; Cuellar, Maria C

    2014-04-01

    Isoprenoids and alkanes produced and secreted by microorganisms are emerging as an alternative biofuel for diesel and jet fuel replacements. In a similar way as for other bioprocesses comprising an organic liquid phase, the presence of microorganisms, medium composition, and process conditions may result in emulsion formation during fermentation, hindering product recovery. At the same time, a low-cost production process overcoming this challenge is required to make these advanced biofuels a feasible alternative. We review the main mechanisms and causes of emulsion formation during fermentation, because a better understanding on the microscale can give insights into how to improve large-scale processes and the process technology options that can address these challenges. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Complementary Health Approaches: Overcoming Barriers to Open Communication During Cancer Therapy
.

    Science.gov (United States)

    Wanchai, Ausanee; Armer, Jane M; Smith, Kandis M; Rodrick, Julia

    2017-12-01

    Complementary health approaches (CHAs) have been widely used by patients with cancer for many reasons. However, some patients choose not to disclose their use of CHAs to their nurses, fearing that this use will be viewed as unacceptable. Nurses may be uncomfortable talking about CHAs because of a lack of evidence-based research on the subject.
. This article promotes ways in which nurses can overcome barriers to open communication about CHAs with patients during cancer therapy.
. The literature related to CHAs and communication was reviewed.
. To encourage open communication between nurses and patients regarding the use of CHAs, nurses need to be more knowledgeable about CHAs through training or by conducting research related to CHAs.

  13. Overcoming challenges to gender equality in the workplace leadership and innovation

    CERN Document Server

    Flynn, Patricia M; Kilgour, Maureen A

    2016-01-01

    Many businesses and organizations are increasingly aware of the case for promoting gender equality, both within and outside their organizational boundaries. Evidence suggests that gender equality in the workplace boosts performance, and legal frameworks in many countries mandate specific action on gender inequality in the workplace. However, despite organizational policies on promoting equality and equal opportunities, there remain challenges to be overcome in many businesses, including throughout their supply chains. The book provides research rationales as to why responsible organizations must address the issue of gender equality in the workplace. It also presents case studies, action research and examples of good practices, describing how businesses and organizations are working to promote gender equality in various contexts. The book is designed to support the rationale for gender equality in business and organizations, provide evidence of implementation of gender equality in the workplace, and how to dea...

  14. Retelling the educational pathways of Black women physicists: Stories of experiencing and overcoming obstacles in life

    Science.gov (United States)

    Mensah, Felicia

    This is an empirical study on the underrepresentation of people of color in scientific careers. Grounded in critical race theory, the paper examines the lived experiences of six Black women physicists and addresses obstacles faced in their career paths and strategies used to overcome these obstacles. Data for this study were collected through semi-structured interviews and coded for emergent themes. The findings reveal that college recruitment and funding were fundamental for these women to choose physics over other STEM fields. In addition, Black women experience unique challenges of socialization in STEM, particularly by exclusion of study groups. We suggest physics departments provide a more inclusive environment to support Black women in science. CAPES, the Fulbright Program, Comissão Fulbright Brasil, and the Office of Diversity at Teachers College, Columbia University.

  15. The nature of socio-psychological barriers to peaceful conflict resolution and ways to overcome them

    Directory of Open Access Journals (Sweden)

    Daniel Bar-Tal

    2013-10-01

    Full Text Available The many devastating, violent inter-group conflicts raging in different parts of the world are very current and actual. Such conflicts arise from disputes over incompatible goals and interests in different domains that must be addressed in seeking to find a solution. It is well established that these conflicts might be resolved were it not for strong socio-psychological barriers that help to sustain them. These barriers block progress toward peaceful conflict settlement. They pertain to the integrated operation of cognitive, emotional and motivational processes combined with a pre-existing repertoire of rigid supporting beliefs, worldviews and emotions that favor selective, biased and distorted information processing. This paper elaborates on the nature of socio-psychological barriers and proposes ways to overcome them.

  16. Change in CNE boiler control level and stepback to overcome strong grid transients

    International Nuclear Information System (INIS)

    Lorenzetti, J.; Sablic, J.C.

    1991-01-01

    In Argentina the grid distribution is organized in such a way that the Embalse Power Plant is located in a place where power is produced. The most important places of power consumption are located near Buenos Aires city. Just one line connects Embalse with the consumption places. As a result of that condition the power is flowing through the interconnection line in such a way that every time a disturb cuts the line a strong power transient affects the Nuclear Power Plant. The changes in the boiler level control were done in order to avoid reactor trip, reactor stepback or turbine trip based on boiler level upsets. After several years of operation it was possible to verify that the new algorithm reduces the chances of plant outage increasing the confidence in the plant to overcome with success such transient. Every transient in the plant is analyzed in order to improve the control algorithm

  17. Overcoming the sign problem in 1-dimensional QCD by new integration rules with polynomial exactness

    Energy Technology Data Exchange (ETDEWEB)

    Ammon, A. [IVU-Traffic Technologies AG, Berlin (Germany); Hartung, T. [King' s College London (United Kingdom). Dept. of Mathematics; Jansen, K.; Volmer, J. [Deutsches Elektronen-Synchrotron (DESY), Zeuthen (Germany). John von Neumann-Inst. fuer Computing NIC; Leoevey, H. [Humboldt-Universitaet, Berlin (Germany). Inst. fuer Mathematik

    2016-08-15

    In this paper we describe a new integration method for the groups U(N) and SU(N), for which we verified numerically that it is polynomially exact for N≤3. The method is applied to the example of 1-dimensional QCD with a chemical potential. We explore, in particular, regions of the parameter space in which the sign problem appears due the presence of the chemical potential. While Markov Chain Monte Carlo fails in this region, our new integration method still provides results for the chiral condensate on arbitrary precision, demonstrating clearly that it overcomes the sign problem. Furthermore, we demonstrate that our new method leads to orders of magnitude reduced errors also in other regions of parameter space.

  18. The Role of Serbian Higher Business Education in Overcoming the Challenges of SME Managers

    Directory of Open Access Journals (Sweden)

    Maja Kočevar

    2014-06-01

    Full Text Available In this exploratory study, in-depth interviews with Serbian managers of small and medium-sized enterprises (SMEs were conducted to identify their main work-related challenges and the extent to which formal higher business education has helped them to overcome these challenges. Serbian SME managers find the main challenges to be related to HR- and marketing-related issues, followed by country-specific problems, such as dealing with bureaucracy, difficulties in obtaining financial resources, and coping with delayed payments. They see considerable deficits in the current system of higher business education, specifically referring to a lack of practice-oriented teaching methods and insufficient cooperation between the universities and the business sector.

  19. Overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application.

    Science.gov (United States)

    Maione, Paolo; Sacco, Paola Claudia; Sgambato, Assunta; Casaluce, Francesca; Rossi, Antonio; Gridelli, Cesare

    2015-09-01

    The discovery that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by druggable protein kinases has led to a revolutionary change in nonsmall cell lung cancer (NSCLC) treatment. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are the targets of several tyrosine kinase inhibitors (TKIs), some of them approved for treatment and others currently in clinical development. First-generation agents offer, in target populations, a substantial improvement of outcomes compared with standard chemotherapy in the treatment of advanced NSCLC. Unfortunately, drug resistance develops after initial benefit through a variety of mechanisms. Novel generation EGFR and ALK inhibitors are currently in advanced clinical development and are producing encouraging results in patients with acquired resistance to previous generation agents. The search for new drugs or strategies to overcome the TKI resistance in patients with EGFR mutations or ALK rearrangements is to be considered a priority for the improvement of outcomes in the treatment of advanced NSCLC.

  20. Pretreatment and fermentation strategies to overcome the toxicity of acetic acid in hemicellulosic hydrolysates

    DEFF Research Database (Denmark)

    Mussatto, Solange I.

    Acetic acid is one of the most important toxic compounds present in hemicellulosic hydrolysates. In order to overcome this problem, several strategies were studied for both biomass pretreatment and fermentation steps. Biomass deacetylation by mild alkaline pretreatment or using high pressure CO2...... were considered interesting strategies to selectively remove acetic acid from biomass structure. In addition, the selective removal of acetic acid from biomass as a first step in the whole biomass conversion chain, contribute for the development and implementation of competitive biorefinery platforms...... where acetic acid can also be integrated as a valuable final product. For the fermentation step, it is well known that hemicellulosic hydrolysates usually need to be detoxified prior use as fermentation medium in order to improve the performance of the microorganism to convert sugars in the product...