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Sample records for cd2019 overcomes inhibition

  1. The mechanism study on overcoming oxygen inhibition of polyether type multifunctional acrylate

    International Nuclear Information System (INIS)

    The high reactive polyester type multifunctional acrylic resin and polyether type multifunctional acrylate was prepared and used for EB cured coatings. The experimental results have showed that when the absorbed dose reaches 60 KGy, the hardness kept to 80%. In order to overcome oxygen inhibition the authors also performed further mechanism study of anti-oxidation

  2. 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)

  3. Gambogic acid inhibits growth, induces apoptosis, and overcomes drug resistance in human colorectal cancer cells.

    Science.gov (United States)

    Wen, Chuangyu; Huang, Lanlan; Chen, Junxiong; Lin, Mengmeng; Li, Wen; Lu, Biyan; Rutnam, Zina Jeyapalan; Iwamoto, Aikichi; Wang, Zhongyang; Yang, Xiangling; Liu, Huanliang

    2015-11-01

    The emergence of chemoresistance is a major limitation of colorectal cancer (CRC) therapies and novel biologically based therapies are urgently needed. Natural products represent a novel potential anticancer therapy. Gambogic acid (GA), a small molecule derived from Garcinia hanburyi Hook. f., has been demonstrated to be highly cytotoxic to several types of cancer cells and have low toxicity to the hematopoietic system. However, the potential role of GA in colorectal cancer and its ability to overcome the chemotherapeutic resistance in CRC cells have not been well studied. In the present study, we showed that GA directly inhibited proliferation and induced apoptosis in both 5-fluorouracil (5-FU) sensitive and 5-FU resistant colorectal cancer cells; induced apoptosis via activating JNK signaling pathway. The data, therefore, suggested an alternative strategy to overcome 5-FU resistance in CRC and that GA could be a promising medicinal compound for colorectal cancer therapy. PMID:26397804

  4. Deammonification for digester supernatant pretreated with thermal hydrolysis: overcoming inhibition through process optimization.

    Science.gov (United States)

    Zhang, Qi; De Clippeleir, Haydée; Su, Chunyang; Al-Omari, Ahmed; Wett, Bernhard; Vlaeminck, Siegfried E; Murthy, Sudhir

    2016-06-01

    The thermal hydrolysis process (THP) has been proven to be an excellent pretreatment step for an anaerobic digester (AD), increasing biogas yield and decreasing sludge disposal. The goal of this work was to optimize deammonification for efficient nitrogen removal despite the inhibition effects caused by the organics present in the THP-AD sludge filtrate (digestate). Two sequencing batch reactors were studied treating conventional digestate and THP-AD digestate, respectively. Improved process control based on higher dissolved oxygen set-point (1 mg O2/L) and longer aeration times could achieve successful treatment of THP-AD digestate. This increased set-point could overcome the inhibition effect on aerobic ammonium-oxidizing bacteria (AerAOB), potentially caused by particulate and colloidal organics. Moreover, based on the mass balance, anoxic ammonium-oxidizing bacteria (AnAOB) contribution to the total nitrogen removal decreased from 97 ± 1 % for conventional to 72 ± 5 % for THP-AD digestate treatment, but remained stable by selective AnAOB retention using a vibrating screen. Overall, similar total nitrogen removal rates of 520 ± 28 mg N/L/day at a loading rate of 600 mg N/L/day were achieved in the THP-AD reactor compared to the conventional digestate treatment operating at low dissolved oxygen (DO) (0.38 ± 0.10 mg O2/L). PMID:26893142

  5. Arsenite-loaded nanoparticles inhibit PARP-1 to overcome multidrug resistance in hepatocellular carcinoma cells.

    Science.gov (United States)

    Liu, Hanyu; Zhang, Zongjun; Chi, Xiaoqin; Zhao, Zhenghuan; Huang, Dengtong; Jin, Jianbin; Gao, Jinhao

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the highest incidences in cancers; however, traditional chemotherapy often suffers from low efficiency caused by drug resistance. Herein, we report an arsenite-loaded dual-drug (doxorubicin and arsenic trioxide, i.e., DOX and ATO) nanomedicine system (FeAsOx@SiO2-DOX, Combo NP) with significant drug synergy and pH-triggered drug release for effective treatment of DOX resistant HCC cells (HuH-7/ADM). This nano-formulation Combo NP exhibits the synergistic effect of DNA damage by DOX along with DNA repair interference by ATO, which results in unprecedented killing efficiency on DOX resistant cancer cells. More importantly, we explored the possible mechanism is that the activity of PARP-1 is inhibited by ATO during the treatment of Combo NP, which finally induces apoptosis of HuH-7/ADM cells by poly (ADP-ribosyl) ation suppression and DNA lesions accumulation. This study provides a smart drug delivery strategy to develop a novel synergistic combination therapy for effectively overcome drug- resistant cancer cells. PMID:27484730

  6. Arsenite-loaded nanoparticles inhibit PARP-1 to overcome multidrug resistance in hepatocellular carcinoma cells

    Science.gov (United States)

    Liu, Hanyu; Zhang, Zongjun; Chi, Xiaoqin; Zhao, Zhenghuan; Huang, Dengtong; Jin, Jianbin; Gao, Jinhao

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the highest incidences in cancers; however, traditional chemotherapy often suffers from low efficiency caused by drug resistance. Herein, we report an arsenite-loaded dual-drug (doxorubicin and arsenic trioxide, i.e., DOX and ATO) nanomedicine system (FeAsOx@SiO2-DOX, Combo NP) with significant drug synergy and pH-triggered drug release for effective treatment of DOX resistant HCC cells (HuH-7/ADM). This nano-formulation Combo NP exhibits the synergistic effect of DNA damage by DOX along with DNA repair interference by ATO, which results in unprecedented killing efficiency on DOX resistant cancer cells. More importantly, we explored the possible mechanism is that the activity of PARP-1 is inhibited by ATO during the treatment of Combo NP, which finally induces apoptosis of HuH-7/ADM cells by poly (ADP-ribosyl) ation suppression and DNA lesions accumulation. This study provides a smart drug delivery strategy to develop a novel synergistic combination therapy for effectively overcome drug- resistant cancer cells. PMID:27484730

  7. Positively charged oligonucleotides overcome potassium-mediated inhibition of triplex DNA formation.

    OpenAIRE

    Dagle, J M; Weeks, D L

    1996-01-01

    The formation of triplex DNA using unmodified, purine-rich oligonucleotides (ODNs) is inhibited by physiologic levels of potassium. Changing negative phosphodiester bonds in a triplex forming oligonucleotide (TFO) to neutral linkages causes a small increase in triplex formation. When phosphodiester bonds in a TFO are converted to positively-charged linkages the formation of triplex DNA increases dramatically. In the absence of KCl, a 17mer TFO containing 11 positively-charged linkages at a co...

  8. Overcoming the Constraints of Anti-HIV/CD89 Bispecific Antibodies That Limit Viral Inhibition

    Directory of Open Access Journals (Sweden)

    Xiaocong Yu

    2016-01-01

    Full Text Available Innovative strategies are necessary to maximize the clinical application of HIV neutralizing antibodies. To this end, bispecific constructs of human antibody F240, reactive with well-conserved gp41 epitope and antibody 14A8, reactive with the IgA receptor (CD89 on effector cells, were constructed. A F240 × 14A8 bispecific single chain variable region (scFv molecule was constructed by linking two scFvs using a conventional GGGGS linker. Despite immunoreactivity with HIV gp41 and neutrophils, this bispecific scFv failed to inhibit HIV infection. This is in sharp contrast to viral inhibition using a chemical conjugate of the Fab of these two antibodies. Therefore, we constructed two novel Fab-like bispecific antibody molecules centered on fusion of the IgG1 CH1 domain or CH1-hinge domain to the C-terminus of F240scFv and fusion of the kappa chain CL domain to the C-terminus of 14A8scFv. Both Bi-Fab antibodies showed significant ADCVI activity for multiple clade B and clade C isolates by arming the neutrophils to inhibit HIV infection. The approach presented in this study is unique for HIV immunotherapy in that the impetus of neutralization is to arm and mobilize PMN to destroy HIV and HIV infected cells.

  9. Overcoming the Constraints of Anti-HIV/CD89 Bispecific Antibodies That Limit Viral Inhibition.

    Science.gov (United States)

    Yu, Xiaocong; Duval, Mark; Gawron, Melissa; Posner, Marshall R; Cavacini, Lisa A

    2016-01-01

    Innovative strategies are necessary to maximize the clinical application of HIV neutralizing antibodies. To this end, bispecific constructs of human antibody F240, reactive with well-conserved gp41 epitope and antibody 14A8, reactive with the IgA receptor (CD89) on effector cells, were constructed. A F240 × 14A8 bispecific single chain variable region (scFv) molecule was constructed by linking two scFvs using a conventional GGGGS linker. Despite immunoreactivity with HIV gp41 and neutrophils, this bispecific scFv failed to inhibit HIV infection. This is in sharp contrast to viral inhibition using a chemical conjugate of the Fab of these two antibodies. Therefore, we constructed two novel Fab-like bispecific antibody molecules centered on fusion of the IgG1 CH1 domain or CH1-hinge domain to the C-terminus of F240scFv and fusion of the kappa chain CL domain to the C-terminus of 14A8scFv. Both Bi-Fab antibodies showed significant ADCVI activity for multiple clade B and clade C isolates by arming the neutrophils to inhibit HIV infection. The approach presented in this study is unique for HIV immunotherapy in that the impetus of neutralization is to arm and mobilize PMN to destroy HIV and HIV infected cells. PMID:27419146

  10. Novel targets in HPV-negative head and neck cancer: overcoming resistance to EGFR inhibition.

    Science.gov (United States)

    Burtness, Barbara; Bauman, Julie E; Galloway, Thomas

    2013-07-01

    Cancers of the head and neck that arise from habitual exposure to carcinogens have lower cure rates than those that arise from infection with human papillomavirus (HPV), and intensification of cytotoxic chemotherapy and radiation has not improved outcomes. HPV-negative head and neck cancers abundantly express EGFR, and the monoclonal antibody cetuximab, directed against EGFR, is the only targeted therapy that has improved disease survival so far. However, response rates to single-agent cetuximab are lower than 15%, and cetuximab given with chemotherapy or radiation leads to only a modest effect on survival. Thus, investigating the mechanisms of resistance to EGFR inhibition in HPV-negative head and neck cancer might help identify novel and active therapies. In this Review, we focus on therapies in development that target redundant receptor tyrosine kinases (eg, HER2 and MET), reduce or abrogate nuclear functions of EGFR, affect cellular trafficking by inhibition of histone deacetylase, or treatments that might address resistance that arises in the EGFR signalling stream (eg, aurora-kinase inhibitors and STAT decoys). PMID:23816296

  11. MET inhibition overcomes radiation resistance of glioblastoma stem-like cells.

    Science.gov (United States)

    De Bacco, Francesca; D'Ambrosio, Antonio; Casanova, Elena; Orzan, Francesca; Neggia, Roberta; Albano, Raffaella; Verginelli, Federica; Cominelli, Manuela; Poliani, Pietro L; Luraghi, Paolo; Reato, Gigliola; Pellegatta, Serena; Finocchiaro, Gaetano; Perera, Timothy; Garibaldi, Elisabetta; Gabriele, Pietro; Comoglio, Paolo M; Boccaccio, Carla

    2016-01-01

    Glioblastoma (GBM) contains stem-like cells (GSCs) known to be resistant to ionizing radiation and thus responsible for therapeutic failure and rapidly lethal tumor recurrence. It is known that GSC radioresistance relies on efficient activation of the DNA damage response, but the mechanisms linking this response with the stem status are still unclear. Here, we show that the MET receptor kinase, a functional marker of GSCs, is specifically expressed in a subset of radioresistant GSCs and overexpressed in human GBM recurring after radiotherapy. We elucidate that MET promotes GSC radioresistance through a novel mechanism, relying on AKT activity and leading to (i) sustained activation of Aurora kinase A, ATM kinase, and the downstream effectors of DNA repair, and (ii) phosphorylation and cytoplasmic retention of p21, which is associated with anti-apoptotic functions. We show that MET pharmacological inhibition causes DNA damage accumulation in irradiated GSCs and their depletion in vitro and in GBMs generated by GSC xenotransplantation. Preclinical evidence is thus provided that MET inhibitors can radiosensitize tumors and convert GSC-positive selection, induced by radiotherapy, into GSC eradication. PMID:27138567

  12. Serum can overcome contact inhibition in confluent human pulmonary artery smooth muscle cells.

    Directory of Open Access Journals (Sweden)

    Victor Solodushko

    Full Text Available Pulmonary artery endothelial cells (PAEC in an intact vessel are continually exposed to serum, but unless injured, do not proliferate, constrained by confluence. In contrast, pulmonary artery smooth muscle cells (PASMC attain, and maintain, confluence in the presence of minimal serum, protected from serum's stimulatory effects except when the endothelial barrier becomes more permeable. We hypothesized therefore, that confluent PASMC may be less constrained by contact inhibition in the presence of serum than PAEC and tested this idea by exposing confluent non-transformed human PAEC and PASMC to media containing increasing concentrations of fetal bovine serum (FBS and determining cell growth over 7 days. PAEC that had attained confluence in low serum did not proliferate even when exposed to 5% serum, the highest concentration tested. In contrast, PASMC that attained confluence in low serum did proliferate once serum levels were increased, an effect that was dose dependent. Consistent with this observation, PASMC had more BrdU incorporation and a greater percentage of cells in S phase in 5% compared to 0.2% FBS, whereas no such difference was seen in PAEC. These results suggest that confluent human PAEC are resistant to the stimulatory effects of serum, whereas confluent PASMC can proliferate when serum levels are increased, an effect mediated in part by differences in phosphoinositide 3-kinase activation. This observation may be relevant to understanding the PASMC hyperplasia observed in humans and animals with pulmonary hypertension in which changes in endothelial permeability due to hypoxia or injury expose the underlying smooth muscle to serum.

  13. 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.

  14. Overcoming Amino-Nogo-induced Inhibition of Cell Spreading and Neurite Outgrowth by 12-O-Tetradecanoylphorbol-13-acetate-type Tumor Promoters

    OpenAIRE

    Deng, Kangwen; Gao, Ying; Cao, Zixuan; Graziani, Edmund I.; Wood, Andrew; Doherty, Patrick; Walsh, Frank S.

    2009-01-01

    The N-terminal domain of NogoA, called amino-Nogo, inhibits axonal outgrowth and cell spreading via a largely unknown mechanism. In the present study, we show that amino-Nogo decreases Rac1 activity and inhibits fibroblast spreading. 12-O-Tetradecanoylphorbol-13-acetate-type tumor promoters, such as phorbol 12-myristate 13-acetate (PMA) and teleocidin, increase Rac1 activity and overcome the amino-Nogo-induced inhibition of cell spreading. The stimulating effect of tumor promoters on cell spr...

  15. 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.

  16. 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.

  17. Overcoming Addiction

    Medline Plus

    Full Text Available ... as an addiction. And it seems to be one of the hardest addictions to overcome. Bill Saxby: ... who smoke are first and foremost individuals and one thing we've learned is that there's not ...

  18. Overcoming Addiction

    Medline Plus

    Full Text Available ... but it was only ten years ago that the Surgeon General identified cigarette smoking as an addiction. And it seems to be one of the hardest addictions to overcome. Bill Saxby: My name ...

  19. Thyroglobulin in smoking mothers and their newborns at delivery suggests autoregulation of placental iodide transport overcoming thiocyanate inhibition

    DEFF Research Database (Denmark)

    Andersen, Stine L; Backman Nøhr, Susanne; Wu, Chun S; Olsen, Jørn; Pedersen, Klaus M; Laurberg, Peter

    2013-01-01

    BACKGROUND: Placental transport of iodide is required for fetal thyroid hormone production. The sodium iodide symporter (NIS) mediates active iodide transport into the thyroid and the lactating mammary gland and is also present in placenta. NIS is competitively inhibited by thiocyanate from...... maternal smoking, but compensatory autoregulation of iodide transport differs between organs. The extent of autoregulation of placental iodide transport remains to be clarified. OBJECTIVE: To compare the impact of maternal smoking on thyroglobulin (Tg) levels in maternal serum at delivery and in cord serum......: Maternal smoking increased the degree of iodine deficiency in parallel in the mother and the fetus, as reflected by increased Tg levels. However, placental iodide transport seemed unaffected despite high thiocyanate levels, suggesting that thiocyanate-insensitive iodide transporters alternative to NIS are...

  20. Overcoming RNA inhibition in the fluorescent polymerase chain reaction assay to enhance detection of bovine DNA in cattle feeds.

    Science.gov (United States)

    Sawyer, Mary; Rensen, Gabriel; Smith, Wayne; Yee, Melanie; Wong, Alice; Osburn, Bennie; Cullor, James

    2004-01-01

    The practice of incorporating mammalian protein in ruminant feeds was banned in the United States in 1997 as a measure to avoid transmission of bovine spongiform encephalopathy (BSE). A sensitive means of identifying the banned additives in feeds would be by detection of species-specific DNA using the polymerase chain reaction (PCR). However, problems may arise in the PCR due to the presence of inhibitory substances. Using human DNA as an internal PCR control, inhibitory substances were evident in the DNA extraction products of cattle feeds. The results of heating experiments excluded enzymes as a cause of inhibition, and spectrophotometric calculations suggested the possibility of RNA contamination. Co-electrophoresis of untreated and RNAse digested extracts confirmed the presence of RNA in the undigested product. Seven cattle feeds were spiked with predetermined amounts of bovine meat and bone meal (BMBM). The DNA extracted products were treated with RNAse and the bovine specific mitochondrial DNA (B-mtDNA) was amplified by PCR. The minimum level of detection of B-mtDNA was influenced by RNAse treatment and feed composition. RNAse treatment decreased false-negative results overall by 75%. False-negative results were decreased 100% in the higher BMBM concentrations and 50% in the lower BMBM concentrations. Also, each cattle feed was spiked to attain a 2% wt/wt concentration with each swine, fish, sheep, or poultry product, or cattle dried blood. Amplification of B-mtDNA occurred only with the cattle dried blood and only in three feeds in which B-mtDNA was detected at the only level tested (2%). A commercial immunochromotographic assay (Neogen) detected the spiked BMBM in only one of the seven feeds and only at the upper concentration (1%). PMID:15992269

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

    International Nuclear Information System (INIS)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Chunlan [Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan, 602-714 (Korea, Republic of); Department of Physiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058 (China); Oh, Joon Seok; Yoo, Seung Hee; Lee, Jee Suk [Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan, 602-714 (Korea, Republic of); Yoon, Young Geol [Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan, 602-714 (Korea, Republic of); Department of Biomedical Science, Institute for Biomedical and Health Sciences, Jungwon University, Chungbuk, 367-805 (Korea, Republic of); Oh, Yoo Jin; Jang, Min Seok [Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan, 602-714 (Korea, Republic of); Lee, Sang Yeob [Department of Rheumatology, Dong-A University College of Medicine, Busan, 602-714 (Korea, Republic of); Yang, Jun [Department of Toxicology, Hangzhou Normal University School of Public Health, Hangzhou, Zhejiang, 310036 China (China); Lee, Sang Hwa [Department of Microbiology and, Dong-A University College of Medicine, Busan, 602-714 (Korea, Republic of); Kim, Hye Young [Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan, 602-714 (Korea, Republic of); Yoo, Young Hyun, E-mail: yhyoo@dau.ac.kr [Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan, 602-714 (Korea, Republic of)

    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

  3. Overcoming Addiction

    Medline Plus

    Full Text Available ... be one of the hardest addictions to overcome. Bill Saxby: My name is Bill Saxby. I'm 63 years old and I've smoked for 50 years, at least. Announcer: Bill is an electrician. He has tried to quit ...

  4. Overcoming Addiction

    Medline Plus

    Full Text Available ... overcome. Bill Saxby: My name is Bill Saxby. I'm 63 years old and I've smoked for 50 years, at least. Announcer: ... This is my famous tunafish-can ashtray. Because I've been going to quit smoking for a ...

  5. 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. PMID:25573956

  6. 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. PMID:12293758

  7. Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling

    OpenAIRE

    Baer, A.; Syed, Y; Kang, S.; Mitteregger, D; Vig, R; Ffrench-Constant, C; Franklin, R.; Altmann, F; Lubec, G; Kotter, M.

    2009-01-01

    Failure of oligodendrocyte precursor cell (OPC) differentiation contributes significantly to failed myelin sheath regeneration (remyelination) in chronic demyelinating diseases. Although the reasons for this failure are not completely understood, several lines of evidence point to factors present following demyelination that specifically inhibit differentiation of cells capable of generating remyelinating oligodendrocytes. We have previously demonstrated that myelin debris generated by demyel...

  8. 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.

  9. Simultaneous Inhibition of CXCR4 and VLA-4 Exhibits Combinatorial Effect in Overcoming Stroma-Mediated Chemotherapy Resistance in Mantle Cell Lymphoma Cells.

    Science.gov (United States)

    Kim, Yu-Ri; Eom, Ki-Seong

    2014-12-01

    There is growing evidence that crosstalk between mantle cell lymphoma (MCL) cells and stromal microenvironments, such as bone marrow and secondary lymphoid tissues, promotes tumor progression by enhancing survival and growth as well as drug resistance of MCL cells. Recent advances in the understanding of lymphoma microenvironment have led to the identification of crucial factors involved in the crosstalk and subsequent generation of their targeted agents. In the present study, we evaluated the combinatory effect of blocking antibodies (Ab) targeting CXCR4 and VLA-4, both of which were known to play significant roles in the induction of environment-mediated drug resistance (EMDR) in MCL cell line, Jeko-1. Simultaneous treatment with anti-CXCR4 and anti-VLA-4 Ab not only reduced the migration of Jeko-1 cells into the protective stromal cells, but also enhanced sensitivity of Jeko-1 to a chemotherapeutic agent to a greater degree than with either Ab alone. These combinatorial effects were associated with decreased phosphorylation of ERK1/2, AKT and NF-κB. Importantly, drug resistance could not be overcome once the adhesion of Jeko-1 to the stromal occurred despite the combined use of Abs, suggesting that the efforts to mitigate migration of MCLs should be attempted as much as possible. Our results provide a basis for a future development of therapeutic strategies targeting both CXCR4 and VLA-4, such as Ab combinations or bispecific antibodies, to improve treatment outcomes of MCL with grave prognosis. PMID:25550696

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

    OpenAIRE

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

    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 N...

  11. Chemogenomic Study of Carboplatin in Saccharomyces cerevisiae: Inhibition of the NEDDylation Process Overcomes Cellular Resistance Mediated by HuR and Cullin Proteins

    Science.gov (United States)

    Custodio, Débora Fernandes; Freitas, Vanessa Morais; Monteiro, Gisele

    2015-01-01

    The use of carboplatin in cancer chemotherapy is limited by the emergence of drug resistance. To understand the molecular basis for this resistance, a chemogenomic screen was performed in 53 yeast mutants that had previously presented strong sensitivity to this widely used anticancer agent. Thirty-four mutants were responsive to carboplatin, and from these, 21 genes were selected for further studies because they have human homologues. Sixty percent of these yeast genes possessed human homologues which encoded proteins that interact with cullin scaffolds of ubiquitin ligases, or whose mRNA are under the regulation of Human antigen R (HuR) protein. Both HuR and cullin proteins are regulated through NEDDylation post-translational modification, and so our results indicate that inhibition of this process should sensitise resistant tumour cells to carboplatin. We showed that treatment of a tumour cell line with MLN4924, a NEDDylation inhibitor, overcame the resistance to carboplatin. Our data suggest that inhibition of NEDDylation may be a useful strategy to resensitise tumour cells in patients that have acquired carboplatin resistance. PMID:26692264

  12. 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

    Full Text Available BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.

  13. Overcoming Breastfeeding Challenges

    Medline Plus

    Full Text Available ... on Women's Health Skip Navigation Skip top navigation Home A-Z Health Topics ePublications News About Us ... Only Natural email updates. Enter email address Submit Home > It's Only Natural > Overcoming challenges Overcoming breastfeeding challenges ...

  14. Overcoming Breastfeeding Challenges

    Medline Plus

    Full Text Available ... size | Print | Skip left navigation It's Only Natural Planning ahead Overcoming challenges Overcoming breastfeeding challenges Dealing with lack of family support Is my baby getting enough milk? Breastfeeding ...

  15. Overcoming Breastfeeding Challenges

    Medline Plus

    Full Text Available ... and Human Services Office on Women's Health Skip Navigation Skip top navigation Home A-Z Health Topics ePublications News About Us Contact Us Text size | Print | Skip left navigation It's Only Natural Planning ahead Overcoming challenges Overcoming ...

  16. Overcoming Breastfeeding Challenges

    Medline Plus

    Full Text Available ... size | Print | Skip left navigation It's Only Natural Planning ahead Overcoming challenges Overcoming breastfeeding challenges Dealing with ... it into your life My breastfeeding story Partner resources Subscribe ... at the U.S. Department of Health and Human Services 200 Independence Avenue, S.W. • Washington, DC 20201 ...

  17. Overcoming breastfeeding problems

    Science.gov (United States)

    Plugged milk ducts; Nipple soreness when breastfeeding; Breastfeeding - overcoming problems; Let-down reflex ... Breastfeeding (nursing) your baby can be a good experience for both the mother and the baby. It ...

  18. Overcoming Breastfeeding Challenges

    Medline Plus

    Full Text Available A project of the U.S. Department of Health and Human Services Office on Women's Health Skip Navigation ... challenges Overcoming breastfeeding challenges Dealing with lack of family support Is my baby getting enough ...

  19. 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 ...

  20. Overcoming Roadblocks to Healthy Eating

    Science.gov (United States)

    ... Free Stuff Be a Partner Overcoming Roadblocks to Healthy Eating Sometimes it’s hard to make smart food choices . ... from Go4Life to help you overcome barriers to healthy eating . Does food taste different? Your sense of taste ...

  1. Bone marrow stroma-induced resistance of chronic lymphocytic leukemia cells to arsenic trioxide involves Mcl-1 upregulation and is overcome by inhibiting the PI3Kδ or PKCβ signaling pathways.

    Science.gov (United States)

    Amigo-Jiménez, Irene; Bailón, Elvira; Aguilera-Montilla, Noemí; Terol, María José; García-Marco, José A; García-Pardo, Angeles

    2015-12-29

    CLL remains an incurable disease in spite of the many new compounds being studied. Arsenic trioxide (ATO) induces apoptosis in all CLL cell types and could constitute an efficient therapy. To further explore this, we have studied the influence of stromal cells, key components of the CLL microenvironment, on the response of CLL cells to ATO. Bone marrow stromal cells induced CLL cell resistance to 2 μM ATO and led to activation of Lyn, ERK, PI3K and PKC, as well as NF-κB and STAT3. Mcl-1, Bcl-xL, and Bfl-1 were also upregulated after the co-culture. Inhibition experiments indicated that PI3K and PKC were involved in the resistance to ATO induced by stroma. Moreover, idelalisib and sotrastaurin, specific inhibitors for PI3Kδ and PKCβ, respectively, inhibited Akt phosphorylation, NF-κB/STAT3 activation and Mcl-1 upregulation, and rendered cells sensitive to ATO. Mcl-1 was central to the mechanism of resistance to ATO, since: 1) Mcl-1 levels correlated with the CLL cell response to ATO, and 2) blocking Mcl-1 expression or function with specific siRNAs or inhibitors overcame the protecting effect of stroma. We have therefore identified the mechanism involved in the CLL cell resistance to ATO induced by bone marrow stroma and show that idelalisib or sotrastaurin block this mechanism and restore sensibility to ATO. Combination of ATO with these inhibitors may thus constitute an efficient treatment for CLL. PMID:26540567

  2. Osthole shows the potential to overcome P-glycoprotein‑mediated multidrug resistance in human myelogenous leukemia K562/ADM cells by inhibiting the PI3K/Akt signaling pathway.

    Science.gov (United States)

    Wang, Hong; Jia, Xiu-Hong; Chen, Jie-Ru; Wang, Jian-Yong; Li, You-Jie

    2016-06-01

    P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) has been reported to play a pivotal role in tumor chemotherapy failure. Study after study has illustrated that the phosphoinositide 3-kinase (PI3K)/Akt signaling cascade is involved in the MDR phenotype and is correlated with P-gp expression in many human malignancies. In the present study, osthole, an O-methylated coumarin, exhibited potent reversal capability of MDR in myelogenous leukemia K562/ADM cells. Simultaneously, the uptake and efflux of Rhodamine-123 (Rh-123) and the accumulation of doxorubicin assays combined with flow cytometric analysis suggested that osthole could increase intracellular drug accumulation. Furthermore, osthole decreased the expression of multidrug resistance gene 1 (MDR1) at both the mRNA and protein levels. Further experiments elucidated that osthole could suppress P-gp expression by inhibiting the PI3K/Akt signaling pathway which might be the main mechanism accounting for the reversal potential of osthole in the MDR in K562/ADM cells. In conclusion, osthole combats MDR and could be a promising candidate for the development of novel MDR reversal modulators. PMID:27109742

  3. 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.

  4. 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.

  5. 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. PMID:25549408

  6. ICT helps to overcome disabilities

    Directory of Open Access Journals (Sweden)

    P. Benda

    2011-12-01

    Full Text Available As a result of technological progress ICT (Information and Communication Technologies has created the so-called „digital divide“. Some people are unable to individually respond to this progress, but the proper use of ICT can help them overcome this handicap. One of the possibilities is to create accessible and usable applications depending on the character and level of disability. In accordance with the European CertiAgri project, e-learning tools are used for integrating people with disabilities into the horticultural area. The paper specifically describes examples of simple teaching aids from the practical „green care“ course, which focus on the skills of people with mental disabilities.

  7. Heating plant overcomes coal crisis

    International Nuclear Information System (INIS)

    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)

  8. Overcoming Barriers to Shared Decision Making

    Science.gov (United States)

    ... team to break it down. Barriers to shared decision making and solutions to overcome them include: Barrier: Fear, anger, stress or other emotions Solution: Strong emotions can interfere with your ability ...

  9. Overcome Cancer Cell Drug Resistance Using Natural Products

    Directory of Open Access Journals (Sweden)

    Pu Wang

    2015-01-01

    Full Text Available Chemotherapy is one of the major treatment methods for cancer. However, failure in chemotherapy is not uncommon, mainly due to dose-limiting toxicity associated with drug resistance. Management of drug resistance is important towards successful chemotherapy. There are many reports in the Chinese literature that natural products can overcome cancer cell drug resistance, which deserve sharing with scientific and industrial communities. We summarized the reports into four categories: (1 in vitro studies using cell line models; (2 serum pharmacology; (3 in vivo studies using animal models; and (4 clinical studies. Fourteen single compounds were reported to have antidrug resistance activity for the first time. In vitro, compounds were able to overcome drug resistance at nontoxic or subtoxic concentrations, in a dose-dependent manner, by inhibiting drug transporters, cell detoxification capacity, or cell apoptosis sensitivity. Studies in vivo showed that single compounds, herbal extract, and formulas had potent antidrug resistance activities. Importantly, many single compounds, herbal extracts, and formulas have been used clinically to treat various diseases including cancer. The review provides comprehensive data on use of natural compounds to overcome cancer cell drug resistance in China, which may facilitate the therapeutic development of natural products for clinical management of cancer drug resistance.

  10. Cabozantinib overcomes crizotinib resistance in ROS1 fusion positive cancer

    Science.gov (United States)

    Katayama, Ryohei; Kobayashi, Yuka; Friboulet, Luc; Lockerman, Elizabeth. L.; Koike, Sumie; Shaw, Alice T.; Engelman, Jeffrey A.; Fujita, Naoya

    2014-01-01

    Purpose ROS1 rearrangement leads to constitutive ROS1 activation with potent transforming activity. In an ongoing phase 1 trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib shows remarkable initial responses in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusions; however, cancers eventually develop crizotinib resistance due to acquired mutations such as G2032R in ROS1. Thus, understanding the crizotinib resistance mechanisms in ROS1 rearranged NSCLC and identification of therapeutic strategies to overcome the resistance are required. Experimental Design The sensitivity of CD74-ROS1-transformed Ba/F3 cells to multiple ALK inhibitors was examined. Acquired ROS1 inhibitor resistant mutations in CD74-ROS1 fusion were screened by N-ethyl-N-nitrosourea mutagenesis with Ba/F3 cells. To overcome the resistance mutation, we performed high throughput drug screening with small molecular inhibitors and anticancer drugs used in clinical practice or being currently tested in clinical trials. The effect of the identified drug was assessed in the CD74-ROS1 mutant Ba/F3 cells and crizotinib resistant patient-derived cancer cells (MGH047) harboring G2032R mutated CD74-ROS1. Results We identified multiple novel crizotinib resistance mutations in the ROS1 kinase domain including the G2032R mutation. As the result of high-throughput drug screening, we found that the cMET/RET/VEGFR inhibitor cabozantinib (XL184) effectively inhibited the survival of CD74-ROS1-WT and resistant mutants harboring Ba/F3 and MGH047 cells. Furthermore, cabozantinib could overcome all the resistance by all newly identified secondary mutations. Conclusions We developed a comprehensive model of acquired resistance to ROS1 inhibitors in NSCLC with ROS1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance. PMID:25351743

  11. Superlenses to overcome the diffraction limit.

    Science.gov (United States)

    Zhang, Xiang; Liu, Zhaowei

    2008-06-01

    The imaging resolution of conventional lenses is limited by diffraction. Artificially engineered metamaterials now offer the possibility of building a superlens that overcomes this limit. We review the physics of such superlenses and the theoretical and experimental progress in this rapidly developing field. Superlenses have great potential in applications such as biomedical imaging, optical lithography and data storage. PMID:18497850

  12. 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…

  13. Learn to Avoid or Overcome Leadership Obstacles

    Science.gov (United States)

    D'Auria, John

    2015-01-01

    Leadership is increasingly recognized as an important factor in moving schools forward, yet we have been relatively random in how we prepare and support them. Four obstacles often block or diminish their effectiveness. Avoiding or overcoming each of these requires an underlying set of skills and knowledge that we believe can be learned and…

  14. Overcoming the triple hurdle of diversity management

    OpenAIRE

    Ruigrok, Winfried

    2012-01-01

    Diversity management is a key instrument to position a company as a preferred employer. Fail to recite this mantra and you risk losing the attention of the majority of young graduates in Europe today. Explore the triple hurdle of diversity management that companies need to overcome in order to successfully develop their diversity management policies.

  15. Helping Chinese Overcome Stereotypes about American Culture

    Institute of Scientific and Technical Information of China (English)

    杜洁

    2014-01-01

    This research paper, from the perspective of cross-cultural communication, intends to analyze the cultural misconcep⁃tions Chinese have about North American culture. Inspired by the data the author collected through the semester-long project with three subjects from different background, the topic of helping Chinese people overcome stereotypes about American culture stands out to claim the practical value in terms of enhancing Chinese people’s cultural awareness and ability to distinguish cultural perspectives and recognize the complexity of cross-cultural communication. Also, recommendations like to know yourself, to de⁃velop cross-cultural communication competence are provided for overcoming the formation of stereotypes and to decrease possi⁃ble cultural incidents since people of both cultures are increasingly interacting with each other in various aspects in the situation of globalization.

  16. Overcoming Affective Barriers in College English Learning

    Institute of Scientific and Technical Information of China (English)

    任永东

    2014-01-01

    Nowadays, the development of economy as well as the progress of society requires better English competence of col-lege students. As a result, a large number of college students are obsessedby affective barriers in their English learning, especially when they have to cope with CET 4 or CET 6, which is more and more difficult. This paper focuses on how to help college stu-dents overcome their affective barriers more effectively to improve their English learning.

  17. Bacterial strategies to overcome insect defences.

    OpenAIRE

    Vallet-Gely, Isabelle; Lemaitre, Bruno; Boccard, Frédéric

    2008-01-01

    Recent genetic and molecular analyses have revealed how several strategies enable bacteria to persist and overcome insect immune defences. Genetic and genomic tools that can be used with Drosophila melanogaster have enabled the characterization of the pathways that are used by insects to detect bacterial invaders and combat infection. Conservation of bacterial virulence factors and insect immune repertoires indicates that there are common strategies of host invasion and pathogen eradication. ...

  18. Overcoming internal barriers to implement strategy effectively

    OpenAIRE

    Dutka, Arturs

    2013-01-01

    Degree programme: International Business Administration Writer(s): Arturs Dutka Thesis title: Overcoming internal barriers to implement strategy effectively Pages (of which appendices): 102 (46) Date: May 27, 2013 Thesis instructor(s): Esa Jauhola A changing environment is a fact today and organisations shall cope with changes, no matter if the organisation is a business unit, educational or social unit. To be successful in changing business environment it is mandatory for ...

  19. Overcoming Sequence Misalignments with Weighted Structural Superposition

    OpenAIRE

    Khazanov, Nickolay A.; Damm-Ganamet, Kelly L.; Quang, Daniel X.; Carlson, Heather A.

    2012-01-01

    An appropriate structural superposition identifies similarities and differences between homologous proteins that are not evident from sequence alignments alone. We have coupled our Gaussian-weighted RMSD (wRMSD) tool with a sequence aligner and seed extension (SE) algorithm to create a robust technique for overlaying structures and aligning sequences of homologous proteins (HwRMSD). HwRMSD overcomes errors in the initial sequence alignment that would normally propagate into a standard RMSD ov...

  20. Overcoming drug resistance by regulating nuclear receptors

    OpenAIRE

    Chen, Taosheng

    2010-01-01

    Drug resistance involves multiple mechanisms. Multidrug resistance (MDR) is the leading cause of treatment failure in cancer therapy. Elevated levels of MDR proteins [members of the ATP-binding cassette (ABC) transporter family] increase cellular efflux and decrease the effectiveness of chemotherapeutic agents. As a salvage approach to overcome drug resistance, inhibitors of MDR proteins have been developed, but have had limited success mainly due to undesired toxicities. Nuclear receptors (N...

  1. Overcoming Subcultural Barriers in Educational Technology Support

    OpenAIRE

    Zellweger, Franziska

    2005-01-01

    Various higher education institutions in German speaking Europe are in the process of establishing educational technology support structures. Educational technology support brings together a variety of academics as well as administrative units such as IT services, multimedia shops, faculty development, or the libraries. The following contribution describes academic and support subcultures, unfolds areas of conflict and suggests strategies to overcome cultural barriers in edtech support. Th...

  2. 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....... However, high customer dissatisfaction and low key performance indicators followed. This led to the need to reframe the task into one of creating a new, better process. This led to satisfactory outcomes. Six key elements facilitated the transfer or creation of experiential knowledge: defining content of...

  3. 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.

  4. Overcome IMF crisis with idea and invention

    International Nuclear Information System (INIS)

    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 Scalability Challenges for Tool Daemon Launching

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, D H; Arnold, D C; de Supinski, B R; Lee, G L; Miller, B P; Schulz, M

    2008-02-15

    Many tools that target parallel and distributed environments must co-locate a set of daemons with the distributed processes of the target application. However, efficient and portable deployment of these daemons on large scale systems is an unsolved problem. We overcome this gap with LaunchMON, a scalable, robust, portable, secure, and general purpose infrastructure for launching tool daemons. Its API allows tool builders to identify all processes of a target job, launch daemons on the relevant nodes and control daemon interaction. Our results show that Launch-MON scales to very large daemon counts and substantially enhances performance over existing ad hoc mechanisms.

  6. Bacterial strategies to overcome insect defences.

    Science.gov (United States)

    Vallet-Gely, Isabelle; Lemaitre, Bruno; Boccard, Frédéric

    2008-04-01

    Recent genetic and molecular analyses have revealed how several strategies enable bacteria to persist and overcome insect immune defences. Genetic and genomic tools that can be used with Drosophila melanogaster have enabled the characterization of the pathways that are used by insects to detect bacterial invaders and combat infection. Conservation of bacterial virulence factors and insect immune repertoires indicates that there are common strategies of host invasion and pathogen eradication. Long-term interactions of bacteria with insects might ensure efficient dissemination of pathogens to other hosts, including humans. PMID:18327270

  7. Overcoming Old in Age-Friendliness

    DEFF Research Database (Denmark)

    Lindenberg, J; Westendorp, Rudi GJ

    2015-01-01

    participants constructed ideal dwelling places that closely resembled a senior home, but at the same time they rejected wishing to live in a place that was identified as a senior home. We explain this paradox by the representation of such a space as being for old people, i.e. needy older individuals, which was...... not how the older participants wished to be identified. We conclude that the conception of age-friendly environments will have to face the difficult challenge of overcoming the association with old age, while simultaneously taking into account adjustments that signify and relate to the ageing process...... and that seem inescapably tied to oldness....

  8. 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. PMID:26348789

  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...

  10. Reshaping transport operations to overcome new challenges

    International Nuclear Information System (INIS)

    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

  11. Overcoming maladaptive plasticity through plastic compensation

    Institute of Scientific and Technical Information of China (English)

    Matthew R.J.MORRIS; Sean M.ROGERS

    2013-01-01

    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.

  12. T7 replisome directly overcomes DNA damage

    Science.gov (United States)

    Sun, Bo; Pandey, Manjula; Inman, James T.; Yang, Yi; Kashlev, Mikhail; Patel, Smita S.; Wang, Michelle D.

    2015-12-01

    Cells and viruses possess several known `restart' pathways to overcome lesions during DNA replication. However, these `bypass' pathways leave a gap in replicated DNA or require recruitment of accessory proteins, resulting in significant delays to fork movement or even cell division arrest. Using single-molecule and ensemble methods, we demonstrate that the bacteriophage T7 replisome is able to directly replicate through a leading-strand cyclobutane pyrimidine dimer (CPD) lesion. We show that when a replisome encounters the lesion, a substantial fraction of DNA polymerase (DNAP) and helicase stay together at the lesion, the replisome does not dissociate and the helicase does not move forward on its own. The DNAP is able to directly replicate through the lesion by working in conjunction with helicase through specific helicase-DNAP interactions. These observations suggest that the T7 replisome is fundamentally permissive of DNA lesions via pathways that do not require fork adjustment or replisome reassembly.

  13. 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. PMID:24575886

  14. Sorafenib overcomes irinotecan resistance in colorectal cancer by inhibiting the ABCG2 drug-efflux pump. : Sorafenib inhibits ABCG2 and overcome irinotecan resistance.

    OpenAIRE

    Mazard, Thibault; Causse, Annick; Simony, Joelle; Leconet, Wilhem; Vezzio-Vie, Nadia; Torro, Adeline; Jarlier, Marta; Evrard, Alexandre; Del Rio, Maguy; Assenat, Eric; Martineau, Pierre; Ychou, Marc; Robert, Bruno; Gongora, Celine

    2013-01-01

    Despite recent advances in the treatment of colorectal cancer (CRC), tumor resistance is a frequent cause of chemotherapy failure. Therefore, new treatment options are needed to improve survival of patients with irinotecan-refractory CRCs, particularly those bearing KRAS mutations that preclude the use of anti-EGFR therapies. In this study, we investigated whether sorafenib could reverse irinotecan resistance, thereby enhancing the therapeutic efficacy of routinely used irinotecan-based chemo...

  15. Free surfaces overcome superheating in simulated melting of isotactic polypropylene

    Science.gov (United States)

    Chen, Qin; Sirota, Eric B.; Zhang, Min; Chung, T. C. Mike; Milner, Scott T.

    The equilibrium melting point (Tm) is a challenging experimental benchmark for molecular dynamics simulation of polymer melting and crystallization. Tm obtained from melting simulation of α phase isotactic polypropylene (iPP) can exhibit superheating of over 100°C. Superheating has been attributed to the use of periodic boundary conditions and ultrafast simulated heating rates, both of which inhibit melting. We have developed a simple method to overcome superheating; we replace the periodic crystal structure with a periodic array of finite thickness slabs, separated by vacuum gaps. Thermal disorder at the slab surface promotes nucleation of the melt phase. Above Tm, we observe that the melting front advances into the crystal with a velocity proportional to T -Tm . This correspond to a quadratic rise in the system energy versus temperature, at constant heating rate. We obtain Tm as the onset of this quadratic rise in energy, which give values consistent with experimental melting points for iPP oligomers. The same simulations allow reasonable estimates of the crystal-vacuum interfacial free energy, from the energy difference between crystalline slabs and periodic crystals. The authors acknowledge support from National Science Foundation DMR-1507980.

  16. Evaluative pressure overcomes perceptual load effects.

    Science.gov (United States)

    Normand, Alice; Autin, Frédérique; Croizet, Jean-Claude

    2015-06-01

    Perceptual load has been found to be a powerful bottom-up determinant of distractibility, with high perceptual load preventing distraction by any irrelevant information. However, when under evaluative pressure, individuals exert top-down attentional control by giving greater weight to task-relevant features, making them more distractible from task-relevant distractors. One study tested whether the top-down modulation of attention under evaluative pressure overcomes the beneficial bottom-up effect of high perceptual load on distraction. Using a response-competition task, we replicated previous findings that high levels of perceptual load suppress task-relevant distractor response interference, but only for participants in a control condition. Participants under evaluative pressure (i.e., who believed their intelligence was assessed) showed interference from task-relevant distractor at all levels of perceptual load. This research challenges the assumptions of the perceptual load theory and sheds light on a neglected determinant of distractibility: the self-relevance of the performance situation in which attentional control is solicited. PMID:25233881

  17. 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.

  18. 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.

  19. Change In Strategy - The Answer To Overcome Global Downturn

    OpenAIRE

    Siddhartha Ghosh

    2012-01-01

    In terms of overcoming the global downturn, innovative business strategy has three major dimensions namely, ‘Innovative Promotional Practices’, ‘Social and Organizational welfare’, and ‘Ethical behavior’. Fortunately most strategic dimensions in business and management are measurable so as to facilitate development ratings in order to compare and highlight the different levels of overcoming the global downturn. My research paper on the role of innovative business strategy in overcoming the re...

  20. Targeting hypoxic tumour cells to overcome metastasis

    International Nuclear Information System (INIS)

    The microenvironment within solid tumours can influence the metastatic dissemination of tumour cells, and recent evidence suggests that poorly oxygenated (hypoxic) cells in primary tumours can also affect the survival and proliferation of metastatic tumour cells in distant organs. Hypoxic tumour cells have been historically targeted during radiation therapy in attempts to improve loco-regional control rates of primary tumours since hypoxic cells are known to be resistant to ionizing radiation-induced DNA damage. There are, therefore, a number of therapeutic strategies to directly target hypoxic cells in primary (and metastatic) tumours, and several compounds are becoming available to functionally inhibit hypoxia-induced proteins that are known to promote metastasis. This mini-review summarizes several established and emerging experimental strategies to target hypoxic cells in primary tumours with potential clinical application to the treatment of patients with tumour metastases or patients at high risk of developing metastatic disease. Targeting hypoxic tumour cells to reduce metastatic disease represents an important advance in the way scientists and clinicians view the influence of tumour hypoxia on therapeutic outcome

  1. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition

    OpenAIRE

    Weigert, Oliver; Bird, Liat; Kopp, Nadja; van Bodegom, Diederik; Marubayashi, Sachie; Christie, Amanda L.; Paranal, Ronald M.; Gaul, Christoph; Vangrevelinghe, Eric; Romanet, Vincent; Murakami, Masato; Tiedt, Ralph; Ebel, Nicolas; Evrot, Emeline; De Pover, Alain

    2012-01-01

    Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor–like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with ...

  2. ABCG2 Inhibition as a Therapeutic Approach for Overcoming Multidrug Resistance in Cancer

    Indian Academy of Sciences (India)

    Maryam Hosseini Hasanabady; Fatemeh Kalalinia

    2016-06-01

    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 and harmful agents in the intestine, as well as through the blood-brain barrier and placental. ABCG2 recognizes and transports numerous anticancer drugs including conventional chemotherapeutic and new targeted small therapeutic molecules in clinical usage. Development of ABCG2 inhibitors for clinical usage may allow increased penetration of therapeutic agents into sanctuary sites and increased their intestinal absorption. In this report, we review the mechanisms that modulate MDR mediated by the ABC transporter ABCG2 in normal and cancer cells by different levels including, epigenetic modifications, transcriptional, posttranscriptional, translation and posttranslational regulation. Some clinical applications of ABCG2 inhibitors, also is explained.

  3. A new approach to overcome potassium-mediated inhibition of triplex formation.

    OpenAIRE

    Svinarchuk, F; Cherny, D; Debin, A; Delain, E; Malvy, C

    1996-01-01

    G,A-containing purine oligonucleotides of various lengths form extremely stable and specific triplexes with the purine-pyrimidine stretch of the vpx gene [Svinarchuk,F., Monnot,M., Merle,A., Malvy,C. and Fermandjian,S. (1995) Nucleic Acids Res., 22, 3742--3747]. The potential application of triple-helix-forming oligonucleotides (TFO) in gene-targeted therapy has prompted us to study triplex formation mimicking potassium concentrations and temperatures in cells. Triplex formation was tested by...

  4. Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibition.

    Science.gov (United States)

    Wilson, Catherine; Nicholes, Katrina; Bustos, Daisy; Lin, Eva; Song, Qinghua; Stephan, Jean-Philippe; Kirkpatrick, Donald S; Settleman, Jeff

    2014-09-15

    Epithelial to mesenchymal transition (EMT) is a key process in embryonic development and has been associated with cancer metastasis and drug resistance. For example, in EGFR mutated non-small cell lung cancers (NSCLC), EMT has been associated with acquired resistance to the EGFR inhibitor erlotinib. Moreover, "EGFR-addicted" cancer cell lines induced to undergo EMT become erlotinib-resistant in vitro. To identify potential therapeutic vulnerabilities specifically within these mesenchymal, erlotinib-resistant cells, we performed a small molecule screen of ~200 established anti-cancer agents using the EGFR mutant NSCLC HCC827 cell line and a corresponding mesenchymal derivative line. The mesenchymal cells were more resistant to most tested agents; however, a small number of agents showed selective growth inhibitory activity against the mesenchymal cells, with the most potent being the Abl/Src inhibitor, dasatinib. Analysis of the tyrosine phospho-proteome revealed several Src/FAK pathway kinases that were differentially phosphorylated in the mesenchymal cells, and RNAi depletion of the core Src/FAK pathway components in these mesenchymal cells caused apoptosis. These findings reveal a novel role for Src/FAK pathway kinases in drug resistance and identify dasatinib as a potential therapeutic for treatment of erlotinib resistance associated with EMT. PMID:25193862

  5. Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibition

    OpenAIRE

    Wilson, Catherine; Nicholes, Katrina; Bustos, Daisy; Lin, Eva; Song, Qinghua; Stephan, Jean-Philippe; Kirkpatrick, Donald S.; Settleman, Jeff

    2014-01-01

    Epithelial to mesenchymal transition (EMT) is a key process in embryonic development and has been associated with cancer metastasis and drug resistance. For example, in EGFR mutated non-small cell lung cancers (NSCLC), EMT has been associated with acquired resistance to the EGFR inhibitor erlotinib. Moreover, “EGFR-addicted” cancer cell lines induced to undergo EMT become erlotinib-resistant in vitro. To identify potential therapeutic vulnerabilities specifically within these mesenchymal, erl...

  6. Commentaries on Overcoming Challenges in Operational Forecasting Projects

    OpenAIRE

    Patrick Wader; Mark A. Moon

    2008-01-01

    In separate articles, Wader and Moon comment on Ian Watson-Jones' article (issue 11 of Foresight) on overcoming challenges in operational forecast projects. Copyright International Institute of Forecasters, 2008

  7. Addressing and overcoming barriers for energy savings in business

    DEFF Research Database (Denmark)

    Dirckinck-Holmfeld, Kasper

    Energy savings are generally viewed as an effective way to cut GHG emissions, as there are huge potentials for improvements because of several barriers and constraining factors for implementing otherwise profitable solutions. Several different polity tools have been applied to overcome these...... authorities (and other intermediates in the energy saving area) for how they can interact with companies to assist them overcome different barriers and constrains taking a role and approach as a “reflective dialogue partner”....

  8. 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.......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....

  9. Developing an effective strategic leadership for learning working overcomes

    OpenAIRE

    Miceski, Trajko

    2010-01-01

    To overcome the unpredictable problems and dangers related with economic and other trends that may fall in future period in the existence of this world. as a necessary factor appears the effective strategic leadership. The effective strategic leadership imposes ability for prediction of the events. anticipating the opportunities. maintaining the flexibility and power of professionals to create strategic change. It uses seven components for building a model for overcoming the unmasterable incl...

  10. Organizational barriers to effective communication and how to overcome them

    Institute of Scientific and Technical Information of China (English)

    何一民

    2013-01-01

    Effective communication has long been credited as a prime factor in achieving high levels of organizational effective-ness. In this essay, the author will discuss the five barriers to or-ganizational communication and the resolutions to overcome them. the author concludes that the overall ways to overcome communication barriers are communication audits and establish differentiated communication cultures to ensure two-way com-munication.

  11. Nanomedicine therapeutic approaches to overcome cancer drug resistance.

    Science.gov (United States)

    Markman, Janet L; Rekechenetskiy, Arthur; Holler, Eggehard; Ljubimova, Julia Y

    2013-11-01

    Nanomedicine is an emerging form of therapy that focuses on alternative drug delivery and improvement of the treatment efficacy while reducing detrimental side effects to normal tissues. Cancer drug resistance is a complicated process that involves multiple mechanisms. Here we discuss the major forms of drug resistance and the new possibilities that nanomedicines offer to overcome these treatment obstacles. Novel nanomedicines that have a high ability for flexible, fast drug design and production based on tumor genetic profiles can be created making drug selection for personal patient treatment much more intensive and effective. This review aims to demonstrate the advantage of the young medical science field, nanomedicine, for overcoming cancer drug resistance. With the advanced design and alternative mechanisms of drug delivery known for different nanodrugs including liposomes, polymer conjugates, micelles, dendrimers, carbon-based, and metallic nanoparticles, overcoming various forms of multi-drug resistance looks promising and opens new horizons for cancer treatment. PMID:24120656

  12. 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…

  13. 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…

  14. Career Barriers: How People Experience, Overcome, and Avoid Failure.

    Science.gov (United States)

    London, Manuel

    This book defines career barriers, considers how people react to them, and offers ways to overcome and prevent them. It is geared towards people experiencing career barriers; for students at the start of their careers; for seasoned employees wanting to avoid or be prepared to deal with career barriers; and for managers, human resource…

  15. On Overcoming Sexism in Schooling: To Marginalize or Mainstream.

    Science.gov (United States)

    Willis, Sue; Kenway, Jane

    1986-01-01

    The argument in favor of single-sex schooling as a means of overcoming sexist educational practices is refuted, a less optimistic scenario of the results of single-sex schooling is offered, and a more appropriate means of improving girls' educational experiences is suggested. (MSE)

  16. Overcoming tumour radiation resistance resulting from acute hypoxia

    International Nuclear Information System (INIS)

    Radioresistant hypoxic cells in tumours are believed to compromise the success of clinical radiotherapy. This brief article discusses three methods of overcoming acute hypoxia in tumours, all of which are applicable in clinical radiotherapy. Of these nicotinamide probably has the greatest clinical potential. (UK)

  17. Overcoming Organizational Fixation: Creating and Sustaining an Innovation Culture

    Science.gov (United States)

    Stempfle, Joachim

    2011-01-01

    Fixation on established paradigms and practices can severely limit the capability of organizations to change, thereby jeopardizing the ability of organizations to keep up with changes in their environment and new technological developments. Overcoming organizational fixation is therefore a requirement for any organization that strives to achieve…

  18. 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

    Cyanogenic glucosides (CNglcs) are widespread plant defence compounds that release toxic hydrogen cyanide by plant bglucosidase activity after tissue damage. Specialised insect herbivores have evolved counter strategies and some sequester CNglcs, but the underlying mechanisms to keep CNglcs intact...... 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...

  19. 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.

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

    International Nuclear Information System (INIS)

    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

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

    International Nuclear Information System (INIS)

    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.

  2. 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.

  3. Overcoming Learning Time And Space Constraints Through Technological Tool

    OpenAIRE

    Nafiseh Zarei; Supyan Hussin; Taufik Rashid

    2015-01-01

    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 E...

  4. OVERCOMING TECHNICAL DESPOTISM IN THE UPLAND RICE PRODUCTIVE CHAIN

    OpenAIRE

    Ferreira, Carlos Magri

    2010-01-01

    This paper presents an experiment aimed at developing sustainable rice production in the State of Mato Grosso (Brazil). It shows results from the Perception Method of Upland Rice Cropping System' Sustainability (MPSAT), which is a tool for joint analysis of technicians and stakeholders considering sustainability of upland rice productive chain within a region. It highlights the relevance of this method to overcome some undesirable practices and attitudes of many technicians in conducting rese...

  5. Methods for overcoming dormancy of Parkinsonia aculeata L. seeds

    OpenAIRE

    Pollyanna Freire Montenegro Agra; Roberta Sales Guedes; Maria Lúcia Maurício da Silva; Vênia Camelo de Souza; Leonaldo Alves de Andrade; Edna Ursulino Alves

    2015-01-01

    The Parkinsonia aculeata L seeds have tegumentary dormancy, which makes them last for a long period in the seed bank of the earth so that their germination occurs in favorable conditions. Our aim was to evaluate the influence of pregermination treatments for overcoming the dormancy of P. aculeata seeds. The seeds were submitted to the following treatments: sample – intact seeds (T1); mechanical scarification with water sandpaper no. 80, followed by room temperature water soaking for 12 and 24...

  6. An action research to overcome undergraduates’ laboratory anxiety

    OpenAIRE

    Acar Şeşen, Burçin; Mutlu (Karadaş), Ayfer

    2014-01-01

    In this study, it was aimed to determine and overcome undergraduates’ laboratory anxiety. For this purpose, Laboratory Anxiety Questionnaire (LAQ) was developed by researchers. LAQ was applied to 92 undergraduates as a pre-test and focus group interviews were performed to determine their laboratory anxiety. An action research was conducted by researchers. After instruction was accomplished in ten weeks, LAQ was applied as post-test. According to results, it was found that undergradua...

  7. Strategies for overcoming gender stereotypes in cognitive representations

    OpenAIRE

    Finnegan, Eimear

    2014-01-01

    Gender stereotypes are activated spontaneously and unintentionally when certain role nouns are read. For example, people expect a builder to be male and a beautician to be female. Such gender inferences lead to processing difficulties when violations of stereotypical gender occur. The aim of this thesis was to devise strategies aimed at overcoming the activation of gender stereotype biases in English. Across nine studies, a variety of stereotype reduction strategies were investigated in ...

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

    OpenAIRE

    James Fitzsimons; Michael Heiner; Bruce McKenney; Kei Sochi; Joseph Kiesecker

    2014-01-01

    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 cha...

  9. Overcoming dormancy in seeds of cotton-silk tree

    OpenAIRE

    Irinaldo Lima do Nascimento

    2012-01-01

    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,...

  10. Medical Students' Personal Determinants of Overcoming Strategies in Difficult Situations

    OpenAIRE

    Veretelnikova Yu.Ya.; Chernyshkova E.V.; Belyakov A.Ye.

    2013-01-01

    Goal of the research was to study conditionality of overcoming strategies in difficult situations of social interaction by personal representations of attitude to others among medical students. Material and methods. 134 first-year students of Saratov State Medical University n.a. V. I. Razumovsky took part in the comparative diagnostic study. Results. Comparison of average indices of various strategies evidence in coping behaviour allowed revealing statistically significant dependence of copi...

  11. Overcoming localization of knowledge: The role of professional service firms

    OpenAIRE

    Wagner, Stefan; Hoisl, Karin; Thoma, Grid

    2013-01-01

    The literature on organizational learning asserts that external learning is often limited geographically and technologically. We scrutinize to what extent organizations acquire external knowledge by accessing external knowledge repositories. We argue that professional service firms (PSFs) grant access to nonlocalized knowledge repositories and thereby not only facilitate external learning but also help to overcome localization. Focusing on patent law firms, we test our predictions using a uni...

  12. Decision Aiding to Overcome Biases in Object Identification

    OpenAIRE

    Mary Fendley; Narayanan, S.

    2012-01-01

    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 ide...

  13. Sesquiterpenes with TRAIL-resistance overcoming activity from Xanthium strumarium.

    Science.gov (United States)

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

    2015-08-01

    The ability of TRAIL to selectively induce apoptosis in cancer cells while sparing normal cells makes it an attractive target for the development of new cancer therapy. In search of bioactive natural products for overcoming TRAIL-resistance from natural resources, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionations of the extract of Xanthium strumarium led to the isolation of five sesquiterpene compounds (1-5). 11α,13-dihydroxanthinin (2) and 11α,13-dihydroxanthuminol (3) were first isolated from natural resources and xanthinosin (1), desacetylxanthanol (4), and lasidiol p-methoxybenzoate (5) were known compounds. All compounds (1-5) showed potent TRAIL-resistance overcoming activity at 8, 20, 20, 16, and 16 μM, respectively, in TRAIL-resistant AGS cells. Compounds 1 and 5 enhanced the levels of apoptosis inducing proteins DR4, DR5, p53, CHOP, Bax, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 and also decreased the levels of cell survival protein Bcl-2 in TRAIL-resistant AGS cells in a dose-dependent manner. Compound 1 also enhanced the levels of DR4 and DR5 proteins in a time-dependent manner. Thus, compounds 1 and 5 were found to induce both extrinsic and intrinsic apoptotic cell death. Compound 1 also exhibit TRAIL-resistance overcoming activity in DLD1, DU145, HeLa, and MCF7 cells but did not decrease viability in non-cancer HEK293 cells up to 8 μM. PMID:26081757

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

    International Nuclear Information System (INIS)

    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.

  15. The use of ICT to overcome the handicap

    OpenAIRE

    Fleyberková, Zuzana

    2014-01-01

    In this bachelor´s thesis entitled “The use of ICT to overcome the handicap” are analyzed and researched companies employing people with disabilities and the use of information and communication technology to carry out their work. The aim is to demonstrate the use of special information technologies for the disabled in employment. If the companies with disabled employees use this special information and communication technologies. If the job is much more easier with mobility aids. The ...

  16. Behavior of Overcoming graduate degree in nursing Cienfuegos

    Directory of Open Access Journals (Sweden)

    Vladimir Barco Díaz

    2010-08-01

    Full Text Available Background: Graduate overcoming represents the continuous process to achieve the updated development of professionals. Objective: To determine the behavior of overcoming graduate degree in nursing from Cienfuegos. Methods: A retrospective descriptive study of 72 nursing graduates working in Primary Health Care, selected by random combination, first each of the areas of health was considered a stratum and then the professionals were selected by simple random method. We included the years from 2000 to 2008. A survey that collected the variables: years of graduate, postgraduate courses received, amount of research, publication of research and scientific events that have participated over the eight years studied. Results: More than a third made no postgraduate course or other form of improvement over the eight years studied. Almost half did not conduct scientific research and those who did not perform more than three investigations. Half did not participate in any scientific event. Conclusions: Overcoming graduate nursing graduates working in Primary Health Care in Cienfuegos municipality is insufficient.

  17. 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.

  18. Change In Strategy - The Answer To Overcome Global Downturn

    Directory of Open Access Journals (Sweden)

    Siddhartha Ghosh

    Full Text Available In terms of overcoming the global downturn, innovative business strategy has three major dimensions namely, ‘Innovative Promotional Practices’, ‘Social and Organizational welfare’, and ‘Ethical behavior’. Fortunately most strategic dimensions in business and management are measurable so as to facilitate development ratings in order to compare and highlight the different levels of overcoming the global downturn. My research paper on the role of innovativebusiness strategy in overcoming the recession and succeeding in the postrecessionary period basically focus on the different categorical elements of business strategies and its direct or indirect impact on the medium and small scale organizations. For the better understanding of the term ‘INNOVATION’ I have carried out a letter by letter scrutinization of this golden term. It goes like this:I-IdeasN-New Plan or DesignN-Noticeable changesO-Optimum change valuationV-VarietyA-Adaptation to the New Environment/New BusinessT-Thought Process for Planned ChangesI-Ideological Developments in BusinessO-Optimization of the changesN-Numero Uno (How Innovation helps in Securing the topmostposition.In order to understand the impact of innovative business strategies n combating the downturn I have formulated four important and innovative strategies. Thesestrategies are:1. HBS Strategy (Holistic Business Strategy.2. PBS Strategy (Polymorphic Business Strategy.3. GBS Strategy (Green Business Strategy.4. CCBS Strategy. (Country-club Business Strategy.By following these innovative strategies an enterprise can reach the zeniths of success and successfully combat the global downturn.

  19. 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...

  20. Wind energy: Overcoming inadequate wind and modeling uncertainties

    Energy Technology Data Exchange (ETDEWEB)

    Kane, Vivek

    2010-09-15

    'Green Energy' is the call of the day, and significance of Wind Energy can never be overemphasized. But the key question here is - What if the wind resources are inadequate? Studies reveal that the probability of finding favorable wind at a given place on land is only 15%. Moreover, there are inherent uncertainties associated with wind business. Can we overcome inadequate wind resources? Can we scientifically quantify uncertainty and model it to make business sense? This paper proposes a solution, by way of break-through Wind Technologies, combined with advanced tools for Financial Modeling, enabling vital business decisions.

  1. 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.

  2. Old people and new technologies: a gap to overcome

    OpenAIRE

    Amaro, Fausto; Gil, Henrique

    2010-01-01

    This paper aims to reflect and discuss the main problems concerning the use of ICT (Information and Communication) and AT (Assistive Technologies) by old people. Some obstacles and constraints were identified as well as some proposals to overcome those difficulties the old people faced when they tried to use ICT/AT. Taking in account that Portugal is a country with a high rate of old people this paper also aims to become a reference for the implementation of policies towards the increased use...

  3. Overcoming multidrug resistance(MDR) in cancer by nanotechnology

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The emerging nanotechnology-based drug delivery holds tremendous potential to deliver chemotherapeutic drugs for treatment of multidrug resistance(MDR) cancer.This drug delivery system could improve the pharmacokinetic behavior of antitumor drugs,deliver chemotherapeutic drugs to target sites,control release of drugs,and reduce the systemic toxicity of drugs in MDR cancer.This review addresses the use of nanotechnology to overcome MDR classified on the bases of the fundamental mechanisms of MDR and various approaches to deliver drugs for treatment of MDR cancer.

  4. Overcoming Design Fixation Through Education and Creativity Methods

    DEFF Research Database (Denmark)

    Howard, Thomas J.; Maier, Anja; Onarheim, Balder; Friis-Olivarius, Morten

    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...... of ideas produced per group and the groups' fixation ratios, adding to the quantity breads novelty debate. Finally, the study also provided further evidence of the hypothesis by Agogué et al (2011) that example solutions constructed from restrictive partitions have a greater fixation affect....

  5. How can we overcome tumor hypoxia in radiation therapy?

    International Nuclear Information System (INIS)

    Local recurrence and distant metastasis frequently occur after radiation therapy for cancer and can be fatal. Evidence obtained from radiochemical and radiobiological studies has revealed these problems to be caused, at least in part, by a tumor-specific microenvironment, hypoxia. Moreover, a transcription factor, hypoxia-inducible factor 1 (HIF-1), was identified as pivotal to hypoxia-mediated radioresistance. To overcome the problems, radiation oncologists have recently obtained powerful tools, such as 'simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT), which enables a booster dose of radiation to be delivered to small target fractions in a malignant tumor', 'hypoxia-selective cytotoxins/drugs', and 'HIF-1 inhibitors' etc. In order to fully exploit these innovative and interdisciplinary strategies in cancer therapy, it is critical to unveil the characteristics, intratumoral localization, and dynamics of hypoxia/HIF-1-active tumor cells during tumor growth and after radiation therapy. We have performed optical imaging experiments using tumor-bearing mice and revealed that the locations of HIF-1-active tumor cells changes dramatically as tumors grow. Moreover, HIF-1 activity changes markedly after radiation therapy. This review overviews fundamental problems surrounding tumor hypoxia in current radiation therapy, the function of HIF-1 in tumor radioresistance, the dynamics of hypoxic tumor cells during tumor growth and after radiation therapy, and how we should overcome the difficulties with radiation therapy using innovative interdisciplinary technologies. (author)

  6. 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. PMID:23366358

  7. Overcoming Learning Aversion in Evaluating and Managing Uncertain Risks.

    Science.gov (United States)

    Cox, Louis Anthony Tony

    2015-10-01

    Decision biases can distort cost-benefit evaluations of uncertain risks, leading to risk management policy decisions with predictably high retrospective regret. We argue that well-documented decision biases encourage learning aversion, or predictably suboptimal learning and premature decision making in the face of high uncertainty about the costs, risks, and benefits of proposed changes. Biases such as narrow framing, overconfidence, confirmation bias, optimism bias, ambiguity aversion, and hyperbolic discounting of the immediate costs and delayed benefits of learning, contribute to deficient individual and group learning, avoidance of information seeking, underestimation of the value of further information, and hence needlessly inaccurate risk-cost-benefit estimates and suboptimal risk management decisions. In practice, such biases can create predictable regret in selection of potential risk-reducing regulations. Low-regret learning strategies based on computational reinforcement learning models can potentially overcome some of these suboptimal decision processes by replacing aversion to uncertain probabilities with actions calculated to balance exploration (deliberate experimentation and uncertainty reduction) and exploitation (taking actions to maximize the sum of expected immediate reward, expected discounted future reward, and value of information). We discuss the proposed framework for understanding and overcoming learning aversion and for implementing low-regret learning strategies using regulation of air pollutants with uncertain health effects as an example. PMID:26491992

  8. Methods for overcoming dormancy of Parkinsonia aculeata L. seeds

    Directory of Open Access Journals (Sweden)

    Pollyanna Freire Montenegro Agra

    2015-06-01

    Full Text Available The Parkinsonia aculeata L seeds have tegumentary dormancy, which makes them last for a long period in the seed bank of the earth so that their germination occurs in favorable conditions. Our aim was to evaluate the influence of pregermination treatments for overcoming the dormancy of P. aculeata seeds. The seeds were submitted to the following treatments: sample – intact seeds (T1; mechanical scarification with water sandpaper no. 80, followed by room temperature water soaking for 12 and 24 hours (T3 e T4, respectively; immersion in sulfuric acid for 5, 10, 15 and 20 minutes (T5, T6, T7 e T8, respectively; immersion in water in 60ºC, 70ºC, 80ºC and 90ºC for one minute (T9, T10, T11 e T12, respectively. The characteristics evaluated were: percentage of emergence, emergence first count, emergence speed index, height and dry weight of seedlings. In the treatments that involved immersion in water in 60ºC, 70ºC, 80ºC and 90ºC, a low percentage of emergence was obtained. The P. aculeate seeds tegumentary dormancy is overcome with maximum efficiency by the mechanical scarification with sandpaper, suggesting that, in natural environment the movement of contraction and expansion of the soil results in a mechanical scarification of the tegument of the seeds, thus, allowing a high percentage of germination with distribution as time passes.

  9. A novel nanoparticle formulation overcomes multiple types of membrane efflux pumps in human breast cancer cells.

    Science.gov (United States)

    Prasad, Preethy; Cheng, Ji; Shuhendler, Adam; Rauth, Andrew M; Wu, Xiao Yu

    2012-04-01

    Multidrug resistance (MDR) in cancer cells can involve overexpression of different types of membrane drug efflux pumps and other drug resistance mechanisms. Hence, inhibition of one resistance mechanism may not be therapeutically effective. Previously we demonstrated a new polymer lipid hybrid nanoparticle (PLN) system was able to circumvent drug resistance of P-glycoprotein (P-gp) overexpressing breast cancer cells. The objectives of the present study were 2-fold: (1) to evaluate the ability of the PLN system to overcome two other membrane efflux pumps-multidrug resistance protein 1 (MRP1+) and breast cancer resistance protein (BCRP+) overexpressed on human breast cancer cell lines MCF7 VP (MRP1+) and MCF7 MX (BCRP+); and (2) to evaluate possible synergistic effects of doxorubicin (Dox)-mitomycin C (MMC) in these cell lines. These objectives were accomplished by measuring in vitro cellular uptake, intracellular trafficking, and cytotoxicity (using a clonogenic assay and median effect analysis), of Dox, MMC, or Dox-MMC co-loaded PLN. Treatment of MDR cells with PLN encapsulating single anticancer agents significantly enhanced cell kill compared to free Dox or MMC solutions. Dox-MMC co-loaded PLN were 20-30-folds more effective in killing MDR cells than free drugs. Co-encapsulated Dox-MMC was more effective in killing MDR cells than single agent-encapsulated PLN. Microscopic images showed perinuclear localization of fluorescently labelled PLN in all cell lines. These results are consistent with our previous results for P-gp overexpressing breast cancer cells suggesting the PLN system can overcome multiple types of membrane efflux pumps increasing the cytotoxicity of Dox-MMC at significantly lower doses than free drugs. PMID:25786718

  10. 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.

  11. 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 elucid

  12. Collective overcoming of point defects by dislocations in the dynamic region

    Science.gov (United States)

    Malashenko, V. V.

    2014-08-01

    A mechanism of collective overcoming of point defects by dislocations during the over-barrier slip has been proposed. It has been shown that the interaction between dislocations promotes the overcoming of point defects at a high dislocation density.

  13. How insects overcome two-component plant chemical defence

    DEFF Research Database (Denmark)

    Pentzold, Stefan; Zagrobelny, Mika; Rook, Frederik;

    2014-01-01

    , before and during feeding as well as during digestion, and at several levels such as the insects’ feeding behaviour, physiology and metabolism. Insect adaptations frequently circumvent or counteract the activity of the plant β-glucosidases, bioactivating enzymes that are a key element in the plant’s two......-component chemical defence. These adaptations include host plant choice, non-disruptive feeding guilds and various physiological adaptations as well as metabolic enzymatic strategies of the insect’s digestive system. Furthermore, insect adaptations often act in combination, may exist in both generalists and...... studies are suggested to investigate in detail how insect adaptations act in combination to overcome plant chemical defences and to allow ecologically relevant conclusions....

  14. Overcoming tumor resistance by heterologous adeno-poxvirus combination therapy

    Science.gov (United States)

    Vähä-Koskela, Markus; Tähtinen, Siri; Grönberg-Vähä-Koskela, Susanna; Taipale, Kristian; Saha, Dipongkor; Merisalo-Soikkeli, Maiju; Ahonen, Marko; Rouvinen-Lagerström, Noora; Hirvinen, Mari; Veckman, Ville; Matikainen, Sampsa; Zhao, Fang; Pakarinen, Päivi; Salo, Jarmo; Kanerva, Anna; Cerullo, Vincenzo; Hemminki, Akseli

    2015-01-01

    Successful cancer control relies on overcoming resistance to cell death and on activation of host antitumor immunity. Oncolytic viruses are particularly attractive in this regard, as they lyse infected tumor cells and trigger robust immune responses during the infection. However, repeated injections of the same virus promote antiviral rather than antitumor immunity and tumors may mount innate antiviral defenses to restrict oncolytic virus replication. In this article, we have explored if alternating the therapy virus could circumvent these problems. We demonstrate in two virus-resistant animal models a substantial delay in antiviral immune- and innate cellular response induction by alternating injections of two immunologically distinct oncolytic viruses, adenovirus, and vaccinia virus. Our results are in support of clinical development of heterologous adeno-/vaccinia virus therapy of cancer. PMID:27119097

  15. Overcoming Intrinsic Spin Resonances with an rf Dipole

    International Nuclear Information System (INIS)

    A coherent spin resonance excited by an rf dipole was used to overcome depolarization due to intrinsic spin resonances at the Alternating Gradient Synchrotron (AGS) at Brookhaven National Laboratory. We found that our data are consistent with a full spin flip of a polarized proton beam, without emittance growth, at Gγ=12+νz and 36-νz , by adiabatically exciting a vertical coherent betatron oscillation using a single rf dipole magnet. The interference pattern observed between the intrinsic spin resonance and the coherent spin resonance agrees well with multiparticle spin simulations based on a simple two-resonance model. The interference pattern can be used for beam diagnostics. copyright 1998 The American Physical Society

  16. Overcoming tumor resistance by heterologous adeno-poxvirus combination therapy.

    Science.gov (United States)

    Vähä-Koskela, Markus; Tähtinen, Siri; Grönberg-Vähä-Koskela, Susanna; Taipale, Kristian; Saha, Dipongkor; Merisalo-Soikkeli, Maiju; Ahonen, Marko; Rouvinen-Lagerström, Noora; Hirvinen, Mari; Veckman, Ville; Matikainen, Sampsa; Zhao, Fang; Pakarinen, Päivi; Salo, Jarmo; Kanerva, Anna; Cerullo, Vincenzo; Hemminki, Akseli

    2015-01-01

    Successful cancer control relies on overcoming resistance to cell death and on activation of host antitumor immunity. Oncolytic viruses are particularly attractive in this regard, as they lyse infected tumor cells and trigger robust immune responses during the infection. However, repeated injections of the same virus promote antiviral rather than antitumor immunity and tumors may mount innate antiviral defenses to restrict oncolytic virus replication. In this article, we have explored if alternating the therapy virus could circumvent these problems. We demonstrate in two virus-resistant animal models a substantial delay in antiviral immune- and innate cellular response induction by alternating injections of two immunologically distinct oncolytic viruses, adenovirus, and vaccinia virus. Our results are in support of clinical development of heterologous adeno-/vaccinia virus therapy of cancer. PMID:27119097

  17. Overcoming design fixation through education and creativity methods

    DEFF Research Database (Denmark)

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

    2013-01-01

    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......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......' 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...

  18. 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

  19. Satellite Communication: Overcoming the Challenges of Capacity, Connectivity and Cost.

    Directory of Open Access Journals (Sweden)

    Engr E. C. Arihilam

    2013-11-01

    Full Text Available The economics of the digital age has made the Information Technology Domain (ITD the battle field of all human activities (current and future-configured and connected to the Internet. Communication Satellites acquisition and ownership are fundamental prerequisites for sustainable nation-building and survivability. While fibre technology may be the main infrastructure currently being utilized, satellite technologies are often used as the last mile solution. In areas where terrestrial infrastructure is not well developed, satellite solutions overcome the infrastructure gap to provide rural areas with the last pipe solution directly. Using Ka- band transponders, they offer frequencies in the 18-31GHz range and promise high power and multi-spot beams for targeted mass connectivity. This paper reviews the deployment of satellites in the Ka- band as they have more capacity to deliver internet connectivity than any other presently in the C- or Ku- bands.

  20. Strategies to overcome seasonal anestrus in water buffalo.

    Science.gov (United States)

    de Carvalho, Nelcio Antonio Tonizza; Soares, Julia Gleyci; Baruselli, Pietro Sampaio

    2016-07-01

    Reproductive seasonality in buffalo (Bubalus bubalis) is characterized by behavioral, endocrine, and reproductive changes that occur over distinct periods of the year. During the nonbreeding season (spring and summer), the greater light-dark ratio (long days) suppresses estrus behavior and the occurrence of ovulation. Anestrous buffaloes have insufficient pulsatile of LH to support the final stages of follicular development, and subsequently, estrus behavior and ovulation do not occur, limiting reproductive efficiency, especially in artificial insemination (AI) programs. A number of therapeutic strategies designed to synchronize follicular wave emergence and ovulation have allowed for the use of AI throughout the year, overcoming seasonal anestrus in buffalo. These therapies also improve reproductive performance by increasing the service rate and pregnancy per AI in buffalo herds, regardless of reproductive seasonality. PMID:27157389

  1. Medical Students' Personal Determinants of Overcoming Strategies in Difficult Situations

    Directory of Open Access Journals (Sweden)

    Veretelnikova Yu.Ya.

    2013-03-01

    Full Text Available Goal of the research was to study conditionality of overcoming strategies in difficult situations of social interaction by personal representations of attitude to others among medical students. Material and methods. 134 first-year students of Saratov State Medical University n.a. V. I. Razumovsky took part in the comparative diagnostic study. Results. Comparison of average indices of various strategies evidence in coping behaviour allowed revealing statistically significant dependence of coping behaviour modi in difficult situations of social interaction upon types of personal representations of attitude toward others and gender features of forming effective strategies of coping behaviour among medical students. Conclusion. Correlation between coping behaviour modi in difficult situations of social interaction and typology of personal representations of attitudes toward others among medical students was marked.

  2. 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.

  3. Overcoming barriers to public understanding of nuclear waste management

    International Nuclear Information System (INIS)

    Communication with the public to promote public understanding of, and participation in, nuclear waste issues is crucial. However, such communication with the public is falling short. One of the major reasons for this failure is that the public feels it cannot trust the motivations or actions of USDOE. The biggest barrier to public involvement in nuclear waste issues is the lack of trust in those who invite us to be involved. Many methods could be employed to increase communication and public involvement in complex and technical nuclear matters. This paper discusses the authors' observations of how USDOE's loss of credibility has affected the high-level nuclear waste repository siting process and suggests methods to overcome this primary barrier

  4. Genecialist manifesto: overcoming the "class struggle" in medicine.

    Science.gov (United States)

    Iwata, Kentaro

    2013-01-01

    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. PMID:23596354

  5. 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

  6. Overcoming obstacles to colour-kinematics duality at two loops

    Science.gov (United States)

    Mogull, Gustav; O'Connell, Donal

    2015-12-01

    The discovery of colour-kinematics duality has allowed great progress in our understanding of the UV structure of gravity. However, it has proven difficult to find numerators which satisfy colour-kinematics duality in certain cases. We discuss obstacles to building a set of such numerators in the context of the five-gluon amplitude with all helicities positive at two loops. We are able to overcome the obstacles by adding more loop momentum to our numerator to accommodate tension between the values of certain cuts and the symmetries of certain diagrams. At the same time, we maintain control over the size of our ansatz by identifying a highly constraining but desirable symmetry property of our master numerator. The resulting numerators have twelve powers of loop momenta rather than the seven one would expect from the Feynman rules.

  7. Overcoming the limits of the growth of nuclear power

    International Nuclear Information System (INIS)

    It is now well recognised that nuclear energy can play an important, perhaps vital, role in de-carbonising the electricity production sector and significantly reducing the emission of greenhouse gases. However, there appear to be limits to the growth of nuclear power as a global response based on issues of government policy, financing, supply chain constraints, resources (human, institutional and physical), public acceptability and industrial capability. Examples of factors that may limit the growth of nuclear power include: -) Uncertainties among governments about the level of intervention needed to support investment in nuclear capacity, especially in liberalized electricity markets; -) The high investment cost of nuclear power, which may require innovative ways of reducing financing costs, through better risk sharing, long term supply contracts or action by world financing organizations to enable newcomer countries to introduce the technology; -) Supply chain limits due to the long period without significant nuclear growth in many regions, the consequent lack of capacity for fabrication of some key components, and the complexity that arises because much of the supply chain is now out-sourced; -) The need to ensure that human and material resources are available to construct and operate nuclear power plants; -) The requirement for public involvement in decision-making and the imperative to show that high level waste can be disposed of safely; and -) The need for industry to prove that it can overcome first of a kind issues and construct nuclear power plants to time and budget in different parts of the world. This paper will use recent NEA work in these areas to analyse the constraints and suggest ways by which they can be overcome, based on the need to achieve significant nuclear growth by 2050 to respond to the current non-sustainability of energy production. (authors)

  8. 'Hidden poverty' of teachers: Status, consequences and overcoming strategies

    Directory of Open Access Journals (Sweden)

    Bogunović Blanka

    2008-01-01

    Full Text Available The consequences of reduced financial and other possibilities in the period of social transition are reflected on the quality of life and work of teachers, and thereby indirectly on education of pupils as well. Aims: (1 to determine teachers' estimation of their own financial status and subjective perception of teachers' poverty; (2 to examine in which way the personal perception of poverty of teachers is linked with the quality of their engagement in curricular and extracurricular activities; (3 to examine which economic and psychological strategies teachers use in overcoming stress because of the lower financial status; (4 to examine whether there are differences between teachers with regard to socio-demographic variables and the previously established goals. Sample consists of 141 teachers of music and general education schools in Belgrade and the interior of the country. Method: research is explorative and uses qualitative and psychometric methods of analysis. Results point out to the structure of 'hidden poverty' of teachers: average and poor financial status, financial and logistic support of the extended family, additional job, unfulfilled financial expectations regarding the educational status and ungratified higher needs. Teachers estimate that real poverty of educational system and 'hidden poverty' of teachers are reflected on the quality of certain aspects of educational process as a whole and in certain elements: teacher's personal life and work motivation, authority in school, quality of teacher's engagement in tuition and the possibility of professional specialization. Teachers use financial and psychological strategies for overcoming stress that can be determined as: moralist compensatory, evasive, inappropriate, emotional, relying on family and friendly supportive systems and activist. Conclusion: primarily subjective and spiritual impoverishment of the stratum of highly educated people, who are, in addition to this, the bearers

  9. 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

  10. 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...

  11. 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

  12. 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. PMID:25349422

  13. 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

  14. Overcoming phytoremediation limitations. A case study of Hg contaminated soil

    Science.gov (United States)

    Barbafieri, Meri

    2013-04-01

    Phytoremediation is a broad term that comprises several technologies to clean up water and soil. Despite the numerous articles appearing in scientific journals, very few field applications of phytoextraction have been successfully realized. The research here reported on Phytoextraction, the use the plant to "extract" metals from contaminated soil, is focused on implementations to overcome two main drawbacks: the survival of plants in unfavorable environmental conditions (contaminant toxicity, low fertility, etc.) and the often lengthy time it takes to reduce contaminants to the requested level. Moreover, to overcome the imbalance between the technology's potential and its drawbacks, there is growing interest in the use of plants to reduce only the fraction that is the most hazardous to the environment and human health, that is to target the bioavailable fractions of metals in soil. Bioavailable Contaminant Stripping (BCS) would be a remediation approach focused to remove the bioavailable metal fractions. BCS have been used in a mercury contaminated soil from Italian industrial site. Bioavailable fractions were determined by sequential extraction with H2O and NH4Cl.Combined treatments of plant hormone and thioligand to strength Hg uptake by crop plants (Brassica juncea and Helianthus annuus) were tested. Plant biomass, evapotranspiration, Hg uptake and distribution following treatments were compared. Results indicate the plant hormone, cytokinine (CK) foliar treatment, increased evapotranspiration rate in both tested plants. The Hg uptake and translocation in both tested plants increased with simultaneous addition of CK and TS treatments. B. juncea was the most effective in Hg uptake. Application of CK to plants grown in TS-treated soil lead to an increase in Hg concentration of 232% in shoots and 39% in roots with respect to control. While H. annuus gave a better response in plant biomass production, the application of CK to plants grown in TS-treated soil lead to

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. San Jacinto scheme overcomes geological and other difficulties

    Energy Technology Data Exchange (ETDEWEB)

    Kempf, D.T.; Calderon, G.R.; Tardieu, B.; Felix, P. de; Zappi, U. (Associacio San Jacinto, Tarija (BO) ENDE, Cochabamba (B) Coyne et Bellier, Paris (FR))

    1991-12-01

    The Bolivian San Jacinto multipurpose hydroscheme was completed in 1990. It includes a 47 m-high arch dam on the Tolomosa river, a headrace pressure tunnel, surface penstocks, and a power station, as well as an irrigation starter pipe to be connected to a second stage irrigation system, now under construction. A long embankment (La Tablada) along the left flank of the reservoir, protects highly erosive soils on its dry side. A power line connects the 7.4 MW powerhouse with the city of Tarija, capital of the region, in the southernmost part of Bolivia which borders Argentina. It is of interest not only from a technical point of view, but also from a constructional and historical one. It is a typical example of a project using standard technology built in a developing country; however, it had to overcome not only normal difficulties like complex local geological conditions, but also the burden of a cumbersome type of financing (with credit for the supply of goods necessitating the importation of all materials and equipment from Argentina). In addition, the project was developed in the context of Bolivia's troubled path towards a stable political and economic system at the beginning, and of the Argentinian economic crisis at the end. (author).

  20. 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.

  1. Attributions and affirmations for overcoming anxiety and depression.

    Science.gov (United States)

    Kinnier, Richard T; Hofsess, Christy; Pongratz, Rick; Lambert, Christina

    2009-06-01

    Individuals who struggle with anxiety or depression often turn to experts for help in overcoming these disorders. In this study, we consult three expert 'populations': the popular self-help literature, well-respected therapists, and individuals who believe that they have successfully recovered from either anxiety or depression for their recommendations to those who are currently anxious or depressed. In Part I, we content-analyse recommendations from 10 current self-help books on anxiety and 10 on depression. In Part II, we asked 17 respected therapists and 18 individuals who believed that they have recovered from anxiety and 23 individuals who believe they have recovered from depression what they believe are the 'keys' for recovery. We also asked them to rate the efficacy of seven popular affirmations. Through content analysis and descriptive statistics, we summarize their collective wisdom. Among the main findings are the recommendations for anxious and depressed individuals to actively seek help from multiple people and interventions, as well as to being open to trying innovative self-tailored interventions. Affirmations relating to 'not being crazy' in relation to anxiety and that the depression will subside in time were deemed most helpful for recovery. Discussion focuses on practical application. PMID:19091166

  2. 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.

  3. Continuous evolution of Bacillus thuringiensis toxins overcomes insect resistance.

    Science.gov (United States)

    Badran, Ahmed H; Guzov, Victor M; Huai, Qing; Kemp, Melissa M; Vishwanath, Prashanth; Kain, Wendy; Nance, Autumn M; Evdokimov, Artem; Moshiri, Farhad; Turner, Keith H; Wang, Ping; Malvar, Thomas; Liu, David R

    2016-05-01

    The Bacillus thuringiensis δ-endotoxins (Bt toxins) are widely used insecticidal proteins in engineered crops that provide agricultural, economic, and environmental benefits. The development of insect resistance to Bt toxins endangers their long-term effectiveness. Here we have developed a phage-assisted continuous evolution selection that rapidly evolves high-affinity protein-protein interactions, and applied this system to evolve variants of the Bt toxin Cry1Ac that bind a cadherin-like receptor from the insect pest Trichoplusia ni (TnCAD) that is not natively bound by wild-type Cry1Ac. The resulting evolved Cry1Ac variants bind TnCAD with high affinity (dissociation constant Kd = 11-41 nM), kill TnCAD-expressing insect cells that are not susceptible to wild-type Cry1Ac, and kill Cry1Ac-resistant T. ni insects up to 335-fold more potently than wild-type Cry1Ac. Our findings establish that the evolution of Bt toxins with novel insect cell receptor affinity can overcome insect Bt toxin resistance and confer lethality approaching that of the wild-type Bt toxin against non-resistant insects. PMID:27120167

  4. Targeting heparanase overcomes chemoresistance and diminishes relapse in myeloma.

    Science.gov (United States)

    Ramani, Vishnu C; Zhan, Fenghuang; He, Jianbo; Barbieri, Paola; Noseda, Alessandro; Tricot, Guido; Sanderson, Ralph D

    2016-01-12

    In most myeloma patients, even after several rounds of intensive therapy, drug resistant tumor cells survive and proliferate aggressively leading to relapse. In the present study, gene expression profiling of tumor cells isolated from myeloma patients after sequential rounds of chemotherapy, revealed for the first time that heparanase, a potent promoter of myeloma growth and progression, was elevated in myeloma cells that survived therapy. Based on this clinical data, we hypothesized that heparanase was involved in myeloma resistance to drug therapy. In several survival and viability assays, elevated heparanase expression promoted resistance of myeloma tumor cells to chemotherapy. Mechanistically, this enhanced survival was due to heparanase-mediated ERK signaling. Importantly, use of the heparanase inhibitor Roneparstat in combination with chemotherapy clearly diminished the growth of disseminated myeloma tumors in vivo. Moreover, use of Roneparstat either during or after chemotherapy diminished regrowth of myeloma tumors in vivo following therapy. These results provide compelling evidence that heparanase is a promising, novel target for overcoming myeloma resistance to therapy and that targeting heparanase has the potential to prevent relapse in myeloma and possibly other cancers. PMID:26624982

  5. Photonic ADC: overcoming the bottleneck of electronic jitter.

    Science.gov (United States)

    Khilo, Anatol; Spector, Steven J; Grein, Matthew E; Nejadmalayeri, Amir H; Holzwarth, Charles W; Sander, Michelle Y; Dahlem, Marcus S; Peng, Michael Y; Geis, Michael W; DiLello, Nicole A; Yoon, Jung U; Motamedi, Ali; Orcutt, Jason S; Wang, Jade P; Sorace-Agaskar, Cheryl M; Popović, Miloš A; Sun, Jie; Zhou, Gui-Rong; Byun, Hyunil; Chen, Jian; Hoyt, Judy L; Smith, Henry I; Ram, Rajeev J; Perrott, Michael; Lyszczarz, Theodore M; Ippen, Erich P; Kärtner, Franz X

    2012-02-13

    Accurate conversion of wideband multi-GHz analog signals into the digital domain has long been a target of analog-to-digital converter (ADC) developers, driven by applications in radar systems, software radio, medical imaging, and communication systems. Aperture jitter has been a major bottleneck on the way towards higher speeds and better accuracy. Photonic ADCs, which perform sampling using ultra-stable optical pulse trains generated by mode-locked lasers, have been investigated for many years as a promising approach to overcome the jitter problem and bring ADC performance to new levels. This work demonstrates that the photonic approach can deliver on its promise by digitizing a 41 GHz signal with 7.0 effective bits using a photonic ADC built from discrete components. This accuracy corresponds to a timing jitter of 15 fs - a 4-5 times improvement over the performance of the best electronic ADCs which exist today. On the way towards an integrated photonic ADC, a silicon photonic chip with core photonic components was fabricated and used to digitize a 10 GHz signal with 3.5 effective bits. In these experiments, two wavelength channels were implemented, providing the overall sampling rate of 2.1 GSa/s. To show that photonic ADCs with larger channel counts are possible, a dual 20-channel silicon filter bank has been demonstrated. PMID:22418205

  6. Women’s language: a struggle to overcome inequality

    Directory of Open Access Journals (Sweden)

    Bolaños Cuellar Sergio

    2006-06-01

    Full Text Available This paper attempts to show that the intellectual construct women's language is entirely justified on a political, ideological, and economic basis that stresses the fact that women have historically been victims of overt (and covert discrimination and exploitation in our society. Linguistically speaking, however, a women's language seems not to exist in traditional strict terms, but rather as a rhetorical term used in the form of a synecdoche. Despite their incompleteness, two attempts of characterizing truly women languages, Nu Shu and Láadan, are discussed, underlining and recognizing their legitimate symbolic value as equalizing manoeuvres. Women have resorted to more subtle linguistic means to emerge as visible agents in our society. Linguistic resources go from a passive acceptance of the traditional all-inclusive generic masculine forms, through the equalizing use of both masculine and feminine markers, to the most progressive, liberal and controversial strategies of using feminizing forms, i.e. all-inclusive generic feminine forms. Women's struggle to overcome inequity and inequality is a legitimate endeavour which is leaving visible linguistic traces in our languages. Women are changing languages around the world.

  7. Electron beam direct write: shaped beam overcomes resolution concerns

    Science.gov (United States)

    Stolberg, Ines; Pain, Laurent; Kretz, Johannes; Boettcher, Monika; Doering, Hans-Joachim; Gramss, Juergen; Hahmann, Peter

    2007-02-01

    In semiconductor industry time to market is one of the key success factors. Therefore fast prototyping and low-volume production will become extremely important for developing process technologies that are well ahead of the current technological level. Electron Beam Lithography has been launched for industrial use as a direct write technology for these types of applications. However, limited throughput rates and high tool complexity have been seen as the major concerns restricting the industrial use of this technology. Nowadays this begins to change. Variable Shaped Beam (VSB) writers have been established in Electron Beam Direct Write (EBDW) on Si or GaAs. In the paper semiconductor industry requirements to EBDW will be outlined. Behind this background the Vistec SB3050 lithography system will be reviewed. The achieved resolution enhancement of the VSB system down to the 22nm node exposure capability will be discussed in detail; application examples will be given. Combining EBDW in a Mix and Match technology with optical lithography is one way to utilize the high flexibility advantage of this technology and to overcome existing throughput concerns. However, to some extend a common Single Electron Beam Technology (SBT) will always be limited in throughput. Therefore Vistec's approach of a system that is based on the massive parallelisation of beams (MBT), which was initially pursued in a European Project, will also be discussed.

  8. Can WIMP dark matter overcome the nightmare scenario?

    International Nuclear Information System (INIS)

    Even if new physics beyond the standard model indeed exists, the energy scale of new physics might be beyond the reach at the Large Hadron Collider (LHC), and the LHC could find only the Higgs boson but nothing else. This is the so-called ''nightmare scenario.'' On the other hand, the existence of the dark matter has been established from various observations. One of the promising candidates for thermal relic dark matter is a stable and electric charge-neutral weakly interacting massive particle (WIMP) with mass below the TeV scale. In the nightmare scenario, we introduce a WIMP dark matter singlet under the standard model gauge group, which only couples to the Higgs doublet at the lowest order, and investigate the possibility that such WIMP dark matter can be a clue to overcome the nightmare scenario via various phenomenological tests such as the dark matter relic abundance, the direct detection experiments for the dark matter particle, and the production of the dark matter particle at the LHC.

  9. Can WIMP Dark Matter overcome the Nightmare Scenario?

    CERN Document Server

    Kanemura, Shinya; Nabeshima, Takehiro; Okada, Nobuchika

    2010-01-01

    Even if new physics beyond the Standard Model (SM) indeed exists, the energy scale of new physics might be beyond the reach at the Large Hadron Collider (LHC) and the LHC could find only the Higgs boson but nothing else. This is the so-called "nightmare scenario". On the other hand, the existence of the dark matter has been established from various observations. One of the promising candidates for thermal relic dark matter is a stable and electric charge-neutral Weakly Interacting Massive Particle (WIMP) with the mass below the TeV scale. In the nightmare scenario, we introduce a WIMP dark matter singlet under the SM gauge group, which only couples to the Higgs doublet at the lowest order, and investigate a possibility that such WIMP dark matter can be a clue to overcome the nightmare scenario via various phenomenological tests such as the dark matter relic abundance, the direct detection experiments for the dark matter particle, and the production of the dark matter particle at the LHC.

  10. Can WIMP dark matter overcome the nightmare scenario?

    Science.gov (United States)

    Kanemura, Shinya; Matsumoto, Shigeki; Nabeshima, Takehiro; Okada, Nobuchika

    2010-09-01

    Even if new physics beyond the standard model indeed exists, the energy scale of new physics might be beyond the reach at the Large Hadron Collider (LHC), and the LHC could find only the Higgs boson but nothing else. This is the so-called “nightmare scenario.” On the other hand, the existence of the dark matter has been established from various observations. One of the promising candidates for thermal relic dark matter is a stable and electric charge-neutral weakly interacting massive particle (WIMP) with mass below the TeV scale. In the nightmare scenario, we introduce a WIMP dark matter singlet under the standard model gauge group, which only couples to the Higgs doublet at the lowest order, and investigate the possibility that such WIMP dark matter can be a clue to overcome the nightmare scenario via various phenomenological tests such as the dark matter relic abundance, the direct detection experiments for the dark matter particle, and the production of the dark matter particle at the LHC.

  11. Overcoming bottlenecks in the membrane protein structural biology pipeline.

    Science.gov (United States)

    Hardy, David; Bill, Roslyn M; Jawhari, Anass; Rothnie, Alice J

    2016-06-15

    Membrane proteins account for a third of the eukaryotic proteome, but are greatly under-represented in the Protein Data Bank. Unfortunately, recent technological advances in X-ray crystallography and EM cannot account for the poor solubility and stability of membrane protein samples. A limitation of conventional detergent-based methods is that detergent molecules destabilize membrane proteins, leading to their aggregation. The use of orthologues, mutants and fusion tags has helped improve protein stability, but at the expense of not working with the sequence of interest. Novel detergents such as glucose neopentyl glycol (GNG), maltose neopentyl glycol (MNG) and calixarene-based detergents can improve protein stability without compromising their solubilizing properties. Styrene maleic acid lipid particles (SMALPs) focus on retaining the native lipid bilayer of a membrane protein during purification and biophysical analysis. Overcoming bottlenecks in the membrane protein structural biology pipeline, primarily by maintaining protein stability, will facilitate the elucidation of many more membrane protein structures in the near future. PMID:27284049

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. Midwives unable to overcome language barriers in prenatal care

    Directory of Open Access Journals (Sweden)

    Mirjam P. Fransen

    2012-09-01

    Full Text Available

    Background: 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 Dutch midwifery practices in Rotterdam completed a structured webbased questionnaire (n=57. Data were obtained on perceived ethnic-related differences and barriers in providing information on prenatal screening, preparedness to provide cultural competent care, and the use of translated materials and professional translators. A group interview was conducted to further explore the results emerging from the questionnaire (n=23.

    Results: almost all midwives (95% experienced barriers in informing women from non-Western ethnic backgrounds about prenatal screening. Midwives especially felt incompetent to provide information to pregnant women that hardly speak and understand Dutch. In total 58% of the midwives reported that they never used translated information materials and 88% never used professional interpreters in providing information on prenatal screening. The main reasons for this underutilization were unawareness of the availability of translated materials and unfamiliarity with the use of professional interpreters.

    Conclusions: although language barriers were reported to be the main difficulty in providing cultural competent care to patients from diverse ethnic backgrounds, only a minority of the midwives used translated materials or professional interpreters. In order to enable all pregnant women to make an informed decision whether or not to participate in prenatal screening, midwives’ competences to address language barriers should be increased.

  17. Survivin inhibition and DNA double-strand break repair: A molecular mechanism to overcome radioresistance in glioblastoma

    International Nuclear Information System (INIS)

    Background and purpose: Gliomas display prime examples of ionizing radiation (IR) resistant tumors. The IAP Survivin is reported to be critically involved in radiation resistance by anti-apoptotic and by caspase-independent mechanisms. The present study aimed to elucidate an interrelationship between Survivin’s cellular localization and DNA damage repair in glioma cells. Material and methods: Cellular distribution and nuclear complex formation were assayed by immunoblotting, immunofluorescence staining and co-immunoprecipitation of Survivin bound proteins in LN229 glioblastoma cells. Apoptosis induction, survival and DNA repair following IR were assayed by means of caspase3/7 activity, clonogenic assay, γ-H2AX/53BP1 foci formation, single cell gel electrophoresis assay, and DNA-PKcs kinase assay in the presence of Survivin siRNA or over expression of Survivin-GFP. Results: Following irradiation, we observed a nuclear accumulation and a direct interrelationship between Survivin, MDC1, γ-H2AX, 53BP1 and DNA-PKcs, which was confirmed by immunofluorescence co-localization. Survivin downregulation by siRNA resulted in an increased apoptotic fraction, decreased clonogenic survival and increased DNA-damage, as demonstrated by higher amount of DNA breaks and an increased amount of γ-H2AX/53BP1 foci post irradiation. Furthermore, we detected in Survivin-depleted LN229 cells a hampered S2056 (auto)phosphorylation and a significantly decreased DNA-PKcs kinase activity. Conclusion: Nuclear accumulation of Survivin and interaction with components of the DNA-double-strand break (DSB) repair machinery indicates Survivin to regulate DSB damage repair that leads to a significant improvement of survival of LN229 glioblastoma cells.

  18. Assets for policy making in health promotion: overcoming political barriers inhibiting women in difficult life situations to access sport facilities.

    Science.gov (United States)

    Rütten, Alfred; Abu-Omar, Karim; Frahsa, Annika; Morgan, Antony

    2009-12-01

    Although the need for intersectoral policy making in health promotion has been commonplace and a high priority for several decades, there is still a lack of appropriate methods available to assess the inputs, processes, and outcomes associated with the effectiveness of such approaches, particularly in relation to sectors outside of health. This paper demonstrates how asset based models to intersectoral policy making in health promotion can improve the effectiveness of projects aiming to improve health and related outcomes. In particular, it summarises how asset based approaches to the planning and implementation of health promotion programmes can be used to develop our methods for assessing intersectorial actions. The paper is based on the findings from a local neighbourhood project based in Erlangen, Germany, aiming to improve the opportunities for physical activity among women in difficult life situations. The neighbourhood was characterised by high rates of unemployment, social welfare recipients, and migrants. Ethnographic methods enabled us to highlight the range of health related assets available in the neighbourhood which could be activated to improve access to and uptake of physical activity amongst the target population. Results indicate that intersectoral policies seeking to improve health outcomes, are more likely to be successful if they maximise the opportunities for making the most of the assets that exist in individuals, communities and organisations. This study demonstrates how the asset model was used to create the supportive environments which facilitated women from the target population to work with policy makers on an equal footing. Their involvement in project planning and implementation helped to achieve the structural changes required to achieve the aims of the project. These included the establishment of a new job position at the city office for sports and improved access to sport facilities for women in difficult life situations. PMID:19800160

  19. Small-Molecule Inhibition of HIV pre-mRNA Splicing as a Novel Antiretroviral Therapy to Overcome Drug Resistance

    OpenAIRE

    Nadia Bakkour; Yea-Lih Lin; Sophie Maire; Lilia Ayadi; Florence Mahuteau-Betzer; Chi Hung Nguyen; Clément Mettling; Pierre Portales; David Grierson; Benoit Chabot; Philippe Jeanteur; Christiane Branlant; Pierre Corbeau; Jamal Tazi

    2007-01-01

    Author Summary Over the two decades highly active antiretroviral therapy (HAART) for the treatment of HIV infection has led to a significant decline in morbidity and mortality rates among HIV-infected individuals. HAART uses a combination of molecules that target the virus itself. However, naturally occurring and extensive genetic variation found in the virus allow the emergence of drug-resistant viruses, which rapidly render individuals untreatable. An alternative approach for effective anti...

  20. Improved PCR Performance Using Template DNA from Formalin-Fixed and Paraffin-Embedded Tissues by Overcoming PCR Inhibition

    OpenAIRE

    Dietrich, Dimo; Uhl, Barbara; Sailer, Verena; Holmes, Emily Eva; Jung, Maria; Meller, Sebastian; Kristiansen, Glen

    2013-01-01

    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 utili...

  1. 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

  2. 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.

  3. Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors.

    Science.gov (United States)

    Zhang, Gao; Frederick, Dennie T; Wu, Lawrence; Wei, Zhi; Krepler, Clemens; Srinivasan, Satish; Chae, Young Chan; Xu, Xiaowei; Choi, Harry; Dimwamwa, Elaida; Ope, Omotayo; Shannan, Batool; Basu, Devraj; Zhang, Dongmei; Guha, Manti; Xiao, Min; Randell, Sergio; Sproesser, Katrin; Xu, Wei; Liu, Jephrey; Karakousis, Giorgos C; Schuchter, Lynn M; Gangadhar, Tara C; Amaravadi, Ravi K; Gu, Mengnan; Xu, Caiyue; Ghosh, Abheek; Xu, Weiting; Tian, Tian; Zhang, Jie; Zha, Shijie; Liu, Qin; Brafford, Patricia; Weeraratna, Ashani; Davies, Michael A; Wargo, Jennifer A; Avadhani, Narayan G; Lu, Yiling; Mills, Gordon B; Altieri, Dario C; Flaherty, Keith T; Herlyn, Meenhard

    2016-05-01

    Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAFV600E melanoma. This approach is not curative, as some BRAF-mutated melanoma cells are intrinsically resistant to MAPK inhibitors (MAPKi). At the systemic level, our knowledge of how signaling pathways underlie drug resistance needs to be further expanded. Here, we have shown that intrinsically resistant BRAF-mutated melanoma cells with a low basal level of mitochondrial biogenesis depend on this process to survive MAPKi. Intrinsically resistant cells exploited an integrated stress response, exhibited an increase in mitochondrial DNA content, and required oxidative phosphorylation to meet their bioenergetic needs. We determined that intrinsically resistant cells rely on the genes encoding TFAM, which controls mitochondrial genome replication and transcription, and TRAP1, which regulates mitochondrial protein folding. Therefore, we targeted mitochondrial biogenesis with a mitochondrium-targeted, small-molecule HSP90 inhibitor (Gamitrinib), which eradicated intrinsically resistant cells and augmented the efficacy of MAPKi by inducing mitochondrial dysfunction and inhibiting tumor bioenergetics. A subset of tumor biopsies from patients with disease progression despite MAPKi treatment showed increased mitochondrial biogenesis and tumor bioenergetics. A subset of acquired drug-resistant melanoma cell lines was sensitive to Gamitrinib. Our study establishes mitochondrial biogenesis, coupled with aberrant tumor bioenergetics, as a potential therapy escape mechanism and paves the way for a rationale-based combinatorial strategy to improve the efficacy of MAPKi. PMID:27043285

  4. Corrosion inhibiting organic coatings

    Energy Technology Data Exchange (ETDEWEB)

    Sasson, E.

    1984-10-16

    A corrosion inhibiting coating comprises a mixture of waxes, petroleum jelly, a hardener and a solvent. In particular, a corrosion inhibiting coating comprises candelilla wax, carnauba wax, microcrystalline waxes, white petrolatum, an oleoresin, lanolin and a solvent.

  5. Overcoming Barriers in the Implementation of Environmental Remediation Projects

    International Nuclear Information System (INIS)

    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.

  6. Efficient Blockade of Akt signaling is a determinant factor to overcome resistance to Matuzumab

    Directory of Open Access Journals (Sweden)

    Meira Debora D

    2011-12-01

    Full Text Available Abstract Background Clinical studies have shown antineoplastic effectiveness of monoclonal antibodies (MAbs against EGFR for different indications. Several MAbs directed to EGFR were developed recently, such as matuzumab, but there is still lack of information on preclinical data on its combination with chemo-radiation. Thus, the present study intended to examine the molecular pathways triggered by matuzumab alone or associated to chemo-radiotherapy in gynecological cell lines and its impact on cell growth and signaling. Results Combination of matuzumab with radiation and cisplatin did not enhance its cytostatic effects on A431, Caski and C33A cells (high, intermediate and low EGFR expression, respectively in clonogenic assays, when compared to controls. The lack of effect was mediated by persistent signaling through EGFR due to its impaired degradation. In spite of the fact that matuzumab inhibited phosphorylation of EGFR, it had no effect upon cell viability. To analyze which downstream molecules would be involved in the EGFR signaling in the presence of matuzumab, we have tested it in combination with either PD98059 (MAPK inhibitor, or LY294002 (PI3K inhibitor. Matuzumab exhibited a synergic effect with LY294002, leading to a reduction of Akt phosphorylation that was followed by a decrease in A431 and Caski cells survival. The combination of PD98059 and matuzumab did not show the same effect suggesting that PI3K is an important effector of EGFR signaling in matuzumab-treated cells. Nonetheless, matuzumab induced ADCC in Caski cells, but not in the C33A cell line, suggesting that its potential therapeutic effects in vitro are indeed dependent on EGFR expression. Conclusions Matuzumab combined with chemoradiation did not induce cytotoxic effects on gynecological cancer cell lines in vitro, most likely due to impaired EGFR degradation. However, a combination of matuzumab and PI3K inhibitor synergistically inhibited pAkt and cell survival

  7. Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

    Science.gov (United States)

    Canonici, Alexandra; Gijsen, Merel; Mullooly, Maeve; Bennett, Ruth; Bouguern, Noujoude; Pedersen, Kasper; O'Brien, Neil A; Roxanis, Ioannis; Li, Ji-Liang; Bridge, Esther; Finn, Richard; Siamon, Dennis; McGowan, Patricia; Duffy, Michael J; O'Donovan, Norma; Crown, John; Kong, Anthony

    2013-10-01

    Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab. PMID:24009064

  8. Barriers to Effective Counseling with Blacks and Therapeutic Strategies for Overcoming Them.

    Science.gov (United States)

    Tucker, Carolyn M.; And Others

    1981-01-01

    Presents strategies for counselors working with Black clients. Suggests awareness of potential barriers to effective counseling enables the therapist to gear the initial sessions toward overcoming these obstacles and thus make early observations of tangible therapeutic gains. Proposes such advances are important in overcoming client skepticism and…

  9. Altered Cross-Linking of HSP27 by Zerumbone as a Novel Strategy for Overcoming HSP27-Mediated Radioresistance

    International Nuclear Information System (INIS)

    Purpose: HSP27 or HSP25 negatively regulates apoptosis pathways after radiation or chemotherapeutic agents. Abrogation of HSP27 function may be a candidate target for overcoming radio- and chemoresistance. Methods and Materials: Zerumbone (ZER), a cytotoxic component isolated from Zingiber zerumbet smith. Clonogenic survival assay and flow cytometry after Annexin V staining were performed to determine in vitro sensitization effects of ZER with ionizing radiation. A nude mouse xenografting system was also applied to detect in vivo radiosensitizing effects of ZER. Results: ZER produced cross-linking of HSP27, which was dependent on inhibition of the monomeric form of HSP27. ZER was directly inserted between the disulfide bond in the HSP27 dimer and modified normal HSP27 dimerization. Pretreatment with ZER before radiation inhibited the binding affinity between HSP27 and apoptotic molecules, such as cytochrome c and PKCδ, and induced sensitization in vitro and in an in vivo xenografted nude mouse system. Structural analogs lacking only the carbonyl group in ZER, such as α-humulene (HUM) and 8-hydroxy-humulen (8-OH-HUM), did not affect normal cross-linking of HSP27 and did not induce radiosensitization. Conclusions: We suggest that altered cross-linking of HSP27 by ZER is a good strategy for abolishing HSP27-mediated resistance.

  10. Polymeric micelles containing reversibly phospholipid-modified anti-survivin siRNA: a promising strategy to overcome drug resistance in cancer

    OpenAIRE

    Salzano, G; Riehle, R.; Navarro, Gemma; Perche, Federico; Rosa, G.; Torchilin, VT

    2013-01-01

    The discovery that survivin, a small anti-apoptotic protein, is involved in chemoresistance, opens a new scenario to overcome the drug resistance in cancer. It was shown that siRNA can efficiently inhibit the expression of survivin in cancer cells. However, the clinical use of siRNA is still hampered by an unfavorable pharmacokinetic profile. To address this problem, earlier we developed a novel system to deliver siRNA into cancer cells. Namely, we reversibly modified the survivin siRNA with ...

  11. A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor β-induced cell-cycle arrest

    OpenAIRE

    Claassen, Gisela F.; Hann, Stephen R.

    2000-01-01

    c-Myc plays a vital role in cell-cycle progression. Deregulated expression of c-Myc can overcome cell-cycle arrest in order to promote cellular proliferation. Transforming growth factor β (TGFβ) treatment of immortalized human keratinocyte cells inhibits cell-cycle progression and is characterized by down-regulation of c-Myc followed by up-regulation of p21CIP1. A direct role of c-Myc in this pathway was demonstrated by the observation that ectopic expression of c-Myc overcame the cell-cycle ...

  12. Inhibition in multiclass classification

    OpenAIRE

    Huerta, Ramón; Vembu, Shankar; Amigó, José M.; Nowotny, Thomas; Elkan, Charles

    2012-01-01

    The role of inhibition is investigated in a multiclass support vector machine formalism inspired by the brain structure of insects. The so-called mushroom bodies have a set of output neurons, or classification functions, that compete with each other to encode a particular input. Strongly active output neurons depress or inhibit the remaining outputs without knowing which is correct or incorrect. Accordingly, we propose to use a classification function that embodies unselective inhibition and ...

  13. Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance.

    Science.gov (United States)

    Heinrich, Anne-Kathrin; Lucas, Henrike; Schindler, Lucie; Chytil, Petr; Etrych, Tomáš; Mäder, Karsten; Mueller, Thomas

    2016-05-01

    The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging-based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. ©2016 AACR. PMID:26939698

  14. Inhibition of selectin binding

    Energy Technology Data Exchange (ETDEWEB)

    Nagy, Jon O. (Rodeo, CA); Spevak, Wayne R. (Albany, CA); Dasgupta, Falguni (New Delhi, IN); Bertozzi, Caroline (Albany, CA)

    2001-10-09

    This invention provides compositions for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10.sup.6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, these composition scan be used to palliate certain inflammatory and immunological conditions.

  15. Inhibition of selectin binding

    Energy Technology Data Exchange (ETDEWEB)

    Nagy, J.O.; Spevak, W.R.; Dasgupta, F.; Bertozzi, C.

    1999-10-05

    This invention provides a system for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10{sup 6} fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, this system can be used to palliate certain inflammatory and immunological conditions.

  16. Inhibition of selectin binding

    Energy Technology Data Exchange (ETDEWEB)

    Nagy, Jon O. (Rodeo, CA); Spevak, Wayne R. (Albany, CA); Dasgupta, Falguni (New Delhi, IN); Bertozzi, Caroline (Albany, CA)

    1999-01-01

    This invention provides compositions for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10.sup.6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, these composition scan be used to palliate certain inflammatory and immunological conditions.

  17. Inhibition of selectin binding

    Energy Technology Data Exchange (ETDEWEB)

    Nagy, J.O.; Spevak, W.R.; Dasgupta, F.; Bertozzi, C.

    1999-11-16

    This invention provides compositions for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10{sup 6} fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, these composition scan be used to palliate certain inflammatory and immunological conditions.

  18. Inhibition of selectin binding

    Energy Technology Data Exchange (ETDEWEB)

    Nagy, Jon O. (Rodeo, CA); Spevak, Wayne R. (Albany, CA); Dasgupta, Falguni (New Delhi, IN); Bertozzi, Carolyn (Albany, CA)

    1999-10-05

    This invention provides a system for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10.sup.6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, this system can be used to palliate certain inflammatory and immunological conditions.

  19. Overcoming Addiction

    Medline Plus

    Full Text Available ... Fiore of the Center for Tobacco Research and Intervention at the University of Wisconsin is helping Bill ... Fiore at the Center for Tobacco Research and Intervention in Madison, Wisconsin had prescribed the non-nicotine, ...

  20. Overcoming Addiction

    Medline Plus

    Full Text Available ... Bill is pinning his hopes on. It's an anti-depressant which for some smokers can soothe nicotine ... in Madison, Wisconsin had prescribed the non-nicotine, anti-depressant Zyban. Two months later, Bill was unhappy ...

  1. Overcoming Addiction

    Medline Plus

    Full Text Available ... Bill that his carbon monoxide level is over three times higher than a non-smoker's, which would ... helping. After a week, Bill is smoking only three cigarettes, as compared to his usual pack a ...

  2. Overcoming Addiction

    Medline Plus

    Full Text Available ... already. Now he smokes over a pack a day. Bill Saxby: This is my famous tunafish-can ... in their appetite and within a matter of days, may actually start to gain weight. Bill: It's ...

  3. Overcoming Addiction

    Medline Plus

    Full Text Available ... Within seven seconds of inhaling, nicotine enters the brain through the nervous system. Neural receptors, responding to the nicotine, stimulate parts of the brain which release the chemical dopamine. When a smoker ...

  4. Overcoming Addiction

    Medline Plus

    Full Text Available ... is bad for your health, but it was only ten years ago that the Surgeon General identified ... be helping. After a week, Bill is smoking only three cigarettes, as compared to his usual pack ...

  5. Overcoming Addiction

    Medline Plus

    Full Text Available ... Within a few hours after you quit, that will start to come down. Bill: Is that what ... to handle that. I'm hoping this drug will help. Announcer: Zyban is the drug Bill is ...

  6. Overcoming Addiction

    Medline Plus

    Full Text Available ... totally collapsed -- all I want to do is sleep. And then right after I get through a ... anger, irritability, frustration, people have problems concentrating, their sleep gets knocked out of whack. They often feel ...

  7. Overcoming Addiction

    Medline Plus

    Full Text Available ... for your health, but it was only ten years ago that the Surgeon General identified cigarette smoking ... My name is Bill Saxby. I'm 63 years old and I've smoked for 50 years, ...

  8. Overcoming Addiction

    Medline Plus

    Full Text Available ... difficult. Dr. Michael Fiore of the Center for Tobacco Research and Intervention at the University of Wisconsin ... Bill, Dr. Michael Fiore at the Center for Tobacco Research and Intervention in Madison, Wisconsin had prescribed ...

  9. Overcoming Addiction

    Medline Plus

    Full Text Available ... will start to come down. Bill: Is that what makes you feel woozy? Dr. Jorenby: Yeah, some ... have their first shot of nicotine to replace what they lost. I don't know how I' ...

  10. Overcoming Addiction

    Medline Plus

    Full Text Available ... psychologist Doug Jorenby explains to Bill that his carbon monoxide level is over three times higher than ... heavy smokers you're getting a lot more oxygen to your brain than it's used to. Announcer: ...

  11. Overcoming Addiction

    Medline Plus

    Full Text Available ... inhaling, nicotine enters the brain through the nervous system. Neural receptors, responding to the nicotine, stimulate parts ... a smoker quits, the changes in the dopamine system disrupt the entire nervous system. Withdrawal symptoms can ...

  12. Overcoming Addiction

    Medline Plus

    Full Text Available ... level is over three times higher than a non-smoker's, which would register less than 10. Dr. ... and Intervention in Madison, Wisconsin had prescribed the non-nicotine, anti-depressant Zyban. Two months later, Bill ...

  13. Overcoming Addiction

    Medline Plus

    Full Text Available ... system. Withdrawal symptoms can be very difficult. Dr. Michael Fiore of the Center for Tobacco Research and ... Wisconsin is helping Bill prepare to quit. Dr. Michael Fiore: Yeah, they sound like the lungs of ...

  14. Overcoming Addiction

    Medline Plus

    Full Text Available ... been well-known for a long time that smoking is bad for your health, but it was ... years ago that the Surgeon General identified cigarette smoking as an addiction. And it seems to be ...

  15. Overcoming Addiction

    Medline Plus

    Full Text Available ... smoking at least 20 times already. Now he smokes over a pack a day. Bill Saxby: This ... perfect program or any magic bullet. People who smoke are first and foremost individuals and one thing ...

  16. Overcoming Addiction

    Medline Plus

    Full Text Available ... are getting in bad condition. When I get up in the morning, I cough and I hack and spit up junk and goo. Technician: Exhale -- all the way, ... Jorenby: 35 parts per million. Yeah, that's definitely up there. Within a few hours after you quit, ...

  17. Overcoming Addiction

    Medline Plus

    Full Text Available ... a habit, it's addictive. The sad part is after you've smoked as long as I do you ... that's definitely up there. Within a few hours after you quit, that will start to come down. Bill: ...

  18. Overcoming Addiction

    Medline Plus

    Full Text Available ... Dr. Michael Fiore of the Center for Tobacco Research and Intervention at the University of Wisconsin is ... Dr. Michael Fiore at the Center for Tobacco Research and Intervention in Madison, Wisconsin had prescribed the ...

  19. Overcoming Addiction

    Medline Plus

    Full Text Available ... knocked out of whack. They often feel an increase in their appetite and within a matter of ... handle that. I'm hoping this drug will help. Announcer: Zyban is the drug Bill is pinning ...

  20. Overcoming Addiction

    Medline Plus

    Full Text Available ... Dr. Michael Fiore of the Center for Tobacco Research and Intervention at the University of Wisconsin is helping Bill prepare to quit. Dr. Michael Fiore: Yeah, they sound like the lungs of a 90-year-old. About how old were you when you started ...

  1. Overcoming Addiction

    Medline Plus

    Full Text Available Announcer: It's been well-known for a long time that smoking is bad for your health, but it was only ten years ago that the Surgeon General identified cigarette smoking as an addiction. And it seems to be one of the hardest addictions ...

  2. Overcoming Addiction

    Medline Plus

    Full Text Available ... be very difficult. Dr. Michael Fiore of the Center for Tobacco Research and Intervention at the University ... we saw Bill, Dr. Michael Fiore at the Center for Tobacco Research and Intervention in Madison, Wisconsin ...

  3. Overcoming Addiction

    Medline Plus

    Full Text Available ... of inhaling, nicotine enters the brain through the nervous system. Neural receptors, responding to the nicotine, stimulate parts ... changes in the dopamine system disrupt the entire nervous system. Withdrawal symptoms can be very difficult. Dr. Michael ...

  4. Overcoming Addiction

    Medline Plus

    Full Text Available Announcer: It's been well-known for a long time that smoking is bad for your health, but it was only ten years ago ... Bill was unhappy with the results. Dr. Fiore: Well, first, I don't think there's any perfect ...

  5. Overcoming Addiction

    Medline Plus

    Full Text Available ... Well, first, I don't think there's any perfect program or any magic bullet. People who smoke ... not a simple recipe that's going to be perfect for every patient who wants to quit. Bill: ...

  6. Overcoming Addiction

    Medline Plus

    Full Text Available ... and within a matter of days, may actually start to gain weight. Bill: It's like an alcoholic -- you know, when the first thing they do when they get up in the morning is have a drink, you ...

  7. Overcoming Addiction

    Medline Plus

    Full Text Available ... fast as you can. Announcer: Testing Bill's pulmonary function shows the damage years of smoking can do. ... Dr. Michael Fiore at the Center for Tobacco Research and Intervention in Madison, Wisconsin had prescribed the ...

  8. 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”?

  9. Methods of Telomerase Inhibition

    OpenAIRE

    Andrews, Lucy G.; Tollefsbol, Trygve O.

    2008-01-01

    Telomerase is central to cellular immortality and is a key component of most cancer cells although this enzyme is rarely expressed to significant levels in normal cells. Therefore, the inhibition of telomerase has garnered considerable attention as a possible anticancer approach. Many of the methods applied to telomerase inhibition focus on either of the two major components of the ribonucleoprotein holoenzyme, that is, the telomerase reverse transcriptase (TERT) catalytic subunit or the telo...

  10. Cetuximab-modified mesoporous silica nano-medicine specifically targets EGFR-mutant lung cancer and overcomes drug resistance.

    Science.gov (United States)

    Wang, Yuetong; Huang, Hsin-Yi; Yang, Liu; Zhang, Zhanxia; Ji, Hongbin

    2016-01-01

    Drug resistance to tyrosine kinase inhibitor (TKI) is the main obstacle for efficient treatment of epidermal growth factor receptor (EGFR)-mutant lung cancer patients. Here we design a cetuximab-capped mesoporous silica nanoparticle (MP-SiO2 NP) as the drug carrier to specifically target EGFR-mutant lung cancer cells and efficiently release loaded drugs including doxorubicin and gefitinib. This innovative nano-medicine can specifically target lung cancer cells with high EGFR expression rather than those with low EGFR level. Treatment of a gefitinib-resistant cell line derived from PC9 cell (PC9-DR) with the gefitinib-loaded cetuximab-capped MP-SiO2 NP showed a significant inhibition of cell growth. Moreover, this nano-medicine successfully suppressed the progression of PC9-DR xenograft tumors. This tumor suppression was due to the endocytosis of large amount of nano-medicine and the effective gefitinib release induced by high glutathione (GSH) level in PC9-DR cells. Collectively, our study provides a novel approach to overcome EGFR-TKI resistance using cetuximab modified MP-SiO2 NP, which holds strong potential for effective management of EGFR-mutant lung cancer. PMID:27151505

  11. Expression of rabbit IL-4 by recombinant myxoma viruses enhances virulence and overcomes genetic resistance to myxomatosis.

    Science.gov (United States)

    Kerr, P J; Perkins, H D; Inglis, B; Stagg, R; McLaughlin, E; Collins, S V; Van Leeuwen, B H

    2004-06-20

    Rabbit IL-4 was expressed in the virulent standard laboratory strain (SLS) and the attenuated Uriarra (Ur) strain of myxoma virus with the aim of creating a Th2 cytokine environment and inhibiting the development of an antiviral cell-mediated response to myxomatosis in infected rabbits. This allowed testing of a model for genetic resistance to myxomatosis in wild rabbits that have undergone 50 years of natural selection for resistance to myxomatosis. Expression of IL-4 significantly enhanced virulence of both virulent and attenuated virus strains in susceptible (laboratory) and resistant (wild) rabbits. SLS-IL-4 completely overcame genetic resistance in wild rabbits. The pathogenesis of SLS-IL-4 was compared in susceptible and resistant rabbits. The results support a model for resistance to myxomatosis of an enhanced innate immune response controlling virus replication and allowing an effective antiviral cell-mediated immune response to develop in resistant rabbits. Expression of IL-4 did not overcome immunity to myxomatosis induced by immunization. PMID:15183059

  12. Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma.

    Science.gov (United States)

    Kuhn, Deborah J; Berkova, Zuzana; Jones, Richard J; Woessner, Richard; Bjorklund, Chad C; Ma, Wencai; Davis, R Eric; Lin, Pei; Wang, Hua; Madden, Timothy L; Wei, Caimiao; Baladandayuthapani, Veerabhadran; Wang, Michael; Thomas, Sheeba K; Shah, Jatin J; Weber, Donna M; Orlowski, Robert Z

    2012-10-18

    Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no β5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)-1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA-mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib-resistant cell lines and patient samples to bortezomib. Importantly, OSI-906 in combination with bortezomib also overcame bortezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic. PMID:22932796

  13. 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. PMID:27114303

  14. A Study on Overcoming Misconceptions of 6th Graders About Equations

    Directory of Open Access Journals (Sweden)

    Gözde AKYÜZ

    2014-01-01

    Full Text Available The aim of this study is to determine and overcome misconceptions of 6th graders about first degree equations with one unknown. The study has a mixed research design and was conducted with 25 sixth graders in a public school during the spring semester of the 2011-2012 academic year. Data were collected through a test of 20 open-ended items developed by the researcher. The misconceptions were detected through descriptive analysis of the test. Then, students were being taught based on activity-based instructional methods for eight hours. The test was also given at the end of the instruction as a post-test to examine the effectiveness of the activity-based instruction with overcoming their misconceptions. Data were analyzed by paired samples t test through SPSS 16.0. Findings indicated that activity-based instruction was effective in overcoming students’ misconceptions.

  15. Overcoming drug efflux-based multidrug resistance in cancer with nanotechnology

    Institute of Scientific and Technical Information of China (English)

    Xue Xue; Xing-Jie Liang

    2012-01-01

    Multidrug resistance (MDR),which significantly decreases the efficacy of anticancer drugs and causes tumor recurrence,has been a major challenge in clinical cancer treatment with chemotherapeutic drugs for decades.Several mechanisms of overcoming drug resistance have been postulated.Well known Pglycoprotein (P-gp) and other drug efflux transporters are considered to be critical in pumping anticancer drugs out of cells and causing chemotherapy failure.Innovative theranostic (therapeutic and diagnostic)strategies with nanoparticles are rapidly evolving and are anticipated to offer opportunities to overcome these limits.In this review,we discuss the mechanisms of drug efflux-mediated resistance and the application of multiple nanoparticle-based platforms to overcome chemoresistance and improve therapeutic outcome.

  16. Charybdotoxin inhibits proliferation and interleukin 2 production in human peripheral blood lymphocytes.

    OpenAIRE

    Price, M; Lee, S. C.; Deutsch, C.

    1989-01-01

    We demonstrate that blockade of the lymphocyte voltage-gated K+ channel by charybdotoxin (CTX) inhibits lymphocyte mitogenesis. Charybdotoxin blocks conductance with a Ki of 0.3 nM and inhibits mitogen- and antigen-stimulated proliferation with a Ki of 0.5 nM. As opposed to the other blockers of the lymphocyte K+ channel, the inhibition of mitogenesis by CTX can be overcome selectively by exogenous recombinant interleukin 2 (IL-2); endogenous levels of IL-2 in the culture supernatants of stim...

  17. Inhibition of Klebsiella β-Lactamases (SHV-1 and KPC-2) by Avibactam: A Structural Study

    OpenAIRE

    Nikhil P Krishnan; Nguyen, Nhu Q.; Papp-Wallace, Krisztina M.; Robert A Bonomo; van den Akker, Focco

    2015-01-01

    β-Lactamase inhibition is an important clinical strategy in overcoming β-lactamase-mediated resistance to β-lactam antibiotics in Gram negative bacteria. A new β-lactamase inhibitor, avibactam, is entering the clinical arena and promising to be a major step forward in our antibiotic armamentarium. Avibactam has remarkable broad-spectrum activity in being able to inhibit classes A, C, and some class D β-lactamases. We present here structural investigations into class A β-lactamase inhibition b...

  18. Overcoming dormancy and determining optimal temperature for slender serradella seed germination

    OpenAIRE

    Rodrigo Ramos Lopes; Cleber Henrique Lopes de Souza; Patricia Bertoncelli; Lucia Brandão Franke

    2015-01-01

    ABSTRACT The objective of this study was to identify the most efficient method for overcoming coat-imposed dormancy and determine the optimal germination temperature for Ornithopus pinnatus seeds. Treatments to overcome dormancy were: intact seeds; immersion in hot water at 60 ºC, followed by soaking in the same water (unheated)/24 h; immersion in hot water at 90 ºC, followed by soaking in the same water (unheated)/24 h; mechanical scarification; chemical scarification, H2SO4/5 min; and chemi...

  19. Service use among low-income minority elderly: strategies for overcoming barriers.

    Science.gov (United States)

    Yeatts, D E; Crow, T; Folts, E

    1992-02-01

    The 1987 amendments to the Older Americans Act mandate a special effort to serve low-income minority elderly persons. A literature review showed that "practice-oriented" research on service use has focused primarily on identifying barriers with much less attention to identification of strategies for overcoming the barriers. This paper identifies and describes strategies used throughout Texas. Strategies addressing the "lack of knowledge" barrier included use of influential groups, working with significant individuals, and the media. Strategies addressing the "lack of access" barrier included transportation, affordability, and availability. Strategies addressing the "lack of intent" barrier focused on cultural differences, making services attractive, and overcoming negative attitudes toward service use. PMID:1740252

  20. Arsenic trioxide overcomes rapamycin-induced feedback activation of AKT and ERK signaling to enhance the anti-tumor effects in breast cancer.

    Directory of Open Access Journals (Sweden)

    Cynthia Guilbert

    Full Text Available Inhibitors of the mammalian target of rapamycin (mTORi have clinical activity; however, the benefits of mTOR inhibition by rapamycin and rapamycin-derivatives (rapalogs may be limited by a feedback mechanism that results in AKT activation. Increased AKT activity resulting from mTOR inhibition can be a result of increased signaling via the mTOR complex, TORC2. Previously, we published that arsenic trioxide (ATO inhibits AKT activity and in some cases, decreases AKT protein expression. Therefore, we propose that combining ATO and rapamycin may circumvent the AKT feedback loop and increase the anti-tumor effects. Using a panel of breast cancer cell lines, we find that ATO, at clinically-achievable doses, can enhance the inhibitory activity of the mTORi temsirolimus. In all cell lines, temsirolimus treatment resulted in AKT activation, which was decreased by concomitant ATO treatment only in those cell lines where ATO enhanced growth inhibition. Treatment with rapalog also results in activated ERK signaling, which is decreased with ATO co-treatment in all cell lines tested. We next tested the toxicity and efficacy of rapamycin plus ATO combination therapy in a MDA-MB-468 breast cancer xenograft model. The drug combination was well-tolerated, and rapamycin did not increase ATO-induced liver enzyme levels. In addition, combination of these drugs was significantly more effective at inhibiting tumor growth compared to individual drug treatments, which corresponded with diminished phospho-Akt and phospho-ERK levels when compared with rapamycin-treated tumors. Therefore, we propose that combining ATO and mTORi may overcome the feedback loop by decreasing activation of the MAPK and AKT signaling pathways.

  1. Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer.

    Science.gov (United States)

    Nakagawa, Takayuki; Takeuchi, Shinji; Yamada, Tadaaki; Nanjo, Shigeki; Ishikawa, Daisuke; Sano, Takako; Kita, Kenji; Nakamura, Takahiro; Matsumoto, Kunio; Suda, Kenichi; Mitsudomi, Tetsuya; Sekido, Yoshitaka; Uenaka, Toshimitsu; Yano, Seiji

    2012-10-01

    Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) erlotinib and gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression, thereafter relapsing. Thus, it is urgent to develop novel agents to overcome EGFR-TKI resistance. We have tested the effects of the mutant-selective EGFR-TKI WZ4002 and the mutant-selective Met-TKI E7050 on 3 EGFR mutant lung cancer cell lines resistant to erlotinib by different mechanisms: PC-9/HGF cells with an exon 19 deletion, H1975 with an L858R mutation, and HCC827ER with an exon 19 deletion, with acquired resistance to erlotinib because of HGF gene transfection, gatekeeper T790M mutation, and Met amplification, respectively. WZ4002 inhibited the growth of H1975 cells with a gatekeeper T790M mutation, but did not inhibit the growth of HCC827ER and PC-9/HGF cells. HGF triggered the resistance of H1975 cells to WZ4002, whereas E7050 sensitized HCC827ER, PC-9/HGF, and HGF-treated H1975 cells to WZ4002, inhibiting EGFR and Met phosphorylation and their downstream molecules. Combined treatment potently inhibited the growth of tumors induced in severe-combined immunodeficient mice by H1975, HCC827ER, and PC-9/HGF cells, without any marked adverse events. These therapeutic effects were associated with the inhibition of EGFR and Met phosphorylation in vivo. The combination of a mutant-selective EGFR-TKI and a Met-TKI was effective in suppressing the growth of erlotinib-resistant tumors caused by gatekeeper T790M mutation, Met amplification, and HGF overexpression. Further evaluations in clinical trials are warranted. PMID:22844075

  2. Overcoming the Child-Langmuir law via the magnetic mirror effect

    OpenAIRE

    Son, S.; Moon, Sung Joon

    2012-01-01

    The maximum current in a vacuum tube prescribed by the classical Child-Langmuir law can be overcome, when the space-charge effect of the induced potential is mitigated by the mirror effect in a spatially varying magnetic field. The current could exceed the Child-Langmuir value by as much as a few factors. The regime of practical interest is examined.

  3. 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...

  4. 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…

  5. Plasma-collection plant has to overcome tainted-blood fallout in search for donors

    OpenAIRE

    OReilly, M

    1998-01-01

    Canada's lack of self-sufficiency in blood products has led to the opening of a blood-plasma collection centre in Thunder Bay, Ont.--the first of its type in Canada. In convincing donors to donate plasma, the new centre had to overcome some lingering public concern about the safety of the blood-collection system.

  6. Dental Hygiene Entry-Level Program Administrators' Strategies for Overcoming Challenges of Distance Education

    Science.gov (United States)

    Buchanan, Bette A.

    2009-01-01

    The use of distance education by entry-level dental hygiene programs is increasing. The focus of this study was to determine the number of entry-level dental hygiene program administrators with experience developing and/or maintaining dental hygiene education by distance, the challenges encountered, and the strategies used to overcome the…

  7. 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.

  8. Cherokee Adaptation to the Landscape of the West and Overcoming the Loss of Culturally Significant Plants

    Science.gov (United States)

    Vick, R. Alfred

    2011-01-01

    Plant species utilized by Cherokees have been documented by several authors. However, many of the traditional uses of plants were lost or forgotten in the generations following the Trail of Tears. The pressures of overcoming the physical and psychological impact of the removal, adapting to a new landscape, rebuilding a government, rebuilding…

  9. Overcoming the Efficiency-Limiting Mechanisms in Commercial Si Solar Cells

    International Nuclear Information System (INIS)

    A brief review of performance-limiting processes in a commercial solar cell fabricated on low-cost substrate is given. Higher efficiencies require effective gettering of precipitated impurities present at the defect clusters, and improved cell and process designs. Overcoming these limitations is expected to lead to 18%-20 % cell efficiencies

  10. 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…

  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 Challenges of the Technological Age by Teaching Information Literacy Skills

    Science.gov (United States)

    Burke, Melynda

    2010-01-01

    The technological age has forever altered every aspect of life and work. Technology has changed how people locate and view information. However, the transition from print to electronic formats has created numerous challenges for individuals to overcome. These challenges include coping with the massive amounts of information bombarding people and…

  13. 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.

  14. 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. PMID:23046772

  15. Utility of Concept Cartoons in Diagnosing and Overcoming Misconceptions Related to Photosynthesis

    Science.gov (United States)

    Ekici, Fatma; Ekici, Erhan; Aydin, Fatih

    2007-01-01

    In this study, the effectiveness of concept cartoons in diagnosing and overcoming students' misconceptions related to photosynthesis subject was examined. Firstly, the literature has been thoroughly examined and misconceptions about photosynthesis subject have been listed and then grouped. Concept cartoons related to these groups have been…

  16. Overcoming classical measurement limits through entanglement in photon number: an introduction

    Directory of Open Access Journals (Sweden)

    Genovese M.

    2015-01-01

    Full Text Available We discuss the recent developments in exploiting Quantum Optical Correlations in order to overcome the classical limits on measurement. After a general introduction to the argument, we will consider in detail some specific and emblematic protocols, and focus in particular on applications to the holometer.

  17. 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…

  18. 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…

  19. Math Is Like a Scary Movie? Helping Young People Overcome Math Anxiety

    Science.gov (United States)

    Kulkin, Margaret

    2016-01-01

    Afterschool teachers who tutor students or provide homework help have a unique opportunity to help students overcome the social or emotional barriers that so often block learning. They can embrace a creative and investigative approach to math learning. Margaret Kulkin's interest in being a math attitude "myth-buster" led her to apply to…

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

    OpenAIRE

    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.

  1. 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...

  2. 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. PMID:25789542

  3. Quorum sensing inhibition

    DEFF Research Database (Denmark)

    Persson, T.; Givskov, Michael Christian; Nielsen, J.

    2005-01-01

    /receptor transcriptional regulator in some clinically relevant Gram-negative bacteria. The present review contains all reported compound types that are currently known to inhibit the QS transcriptional regulator in Gram-negative bacteria. These compounds are sub-divided into two main groups, one comprising structural...

  4. 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 with...

  5. An AS1411 aptamer-conjugated liposomal system containing a bubble-generating agent for tumor-specific chemotherapy that overcomes multidrug resistance.

    Science.gov (United States)

    Liao, Zi-Xian; Chuang, Er-Yuan; Lin, Chia-Chen; Ho, Yi-Cheng; Lin, Kun-Ju; Cheng, Po-Yuan; Chen, Ko-Jie; Wei, Hao-Ji; Sung, Hsing-Wen

    2015-06-28

    Recent research in chemotherapy has prioritized overcoming the multidrug resistance (MDR) of cancer cells. In this work, liposomes that contain doxorubicin (DOX) and ammonium bicarbonate (ABC, a bubble-generating agent) are prepared and functionalized with an antinucleolin aptamer (AS1411 liposomes) to target DOX-resistant breast cancer cells (MCF-7/ADR), which overexpress nucleolin receptors. Free DOX and liposomes without functionalization with AS1411 (plain liposomes) were used as controls. The results of molecular dynamic simulations suggest that AS1411 functionalization may promote the affinity and specific binding of liposomes to the nucleolin receptors, enhancing their subsequent uptake by tumor cells, whereas plain liposomes enter cells with difficulty. Upon mild heating, the decomposition of ABC that is encapsulated in the liposomes enables the immediate activation of generation of CO2 bubbles, creating permeable defects in their lipid bilayers, and ultimately facilitating the swift intracellular release of DOX. In vivo studies in nude mice that bear tumors demonstrate that the active targeting of AS1411 liposomes can substantially increase the accumulation of DOX in the tumor tissues relative to free DOX or passively targeted plain liposomes, inhibiting tumor growth and reducing systemic side effects, including cardiotoxicity. The above findings indicate that liposomes that are functionalized with AS1411 represent an attractive therapeutic alternative for overcoming the MDR effect, and support a potentially effective strategy for cancer therapy. PMID:25637705

  6. 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.;

    , 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...... 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...... 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...

  7. SUCCESSFUL ACTIONS TO OVERCOME EXCLUSION THROUGH COMMUNITY INVOLVEMENT. THE TRANSFORMATION OF THE GHETTO

    Directory of Open Access Journals (Sweden)

    Antonio Muñoz Amador

    2013-06-01

    Full Text Available In a neighborhood of Albacete with strong indicators of exclusion, is currently undertaking a transformation in all social areas. Becoming in Europe as a reference model to overcome the ghetto. This process has been mainly due two key aspects which will deepen the article. First, the introduction of successful actions based on scientific evidences to overcome social inequality and the transformation of the ghetto. Second, the inclusion of all the voices in the design of policies that will be implemented, in order that the target groups take active part in the decision making process. In this process of reflection and decision which has brought together a wide range of people, highlights the role of social workers and the nodal point of an intense network of interactions that connects the real needs of the population with the resources and existing services. That will be done in an individual level as well as in a communitarian level through consensus.

  8. Intracellular Self-Assembly of Taxol Nanoparticles for Overcoming Multidrug Resistance.

    Science.gov (United States)

    Yuan, Yue; Wang, Lin; Du, Wei; Ding, Zhanling; Zhang, Jia; Han, Tao; An, Linna; Zhang, Huafeng; Liang, Gaolin

    2015-08-10

    Multidrug resistance (MDR) remains the biggest challenge in treating cancers. Herein we propose the intracellular self-assembly of nanodrugs as a new strategy for overcoming MDR. By employing a biocompatible condensation reaction, we rationally designed a taxol derivative Ac-Arg-Val-Arg-Arg-Cys(StBu)-Lys(taxol)-2-cyanobenzothiazole (CBT-Taxol) which could be subjected to furin-controlled condensation and self-assembly of taxol nanoparticles (Taxol-NPs). In vitro and in vivo studies indicated that, compared with taxol, CBT-Taxol showed a 4.5-fold or 1.5-fold increase in anti-MDR effects, respectively, on taxol-resistant HCT 116 cancer cells or tumors without being toxic to the cells or the mice. Our results demonstrate that structuring protease-susceptible agents and assembling them intracellularly into nanodrugs could be a new optimal strategy for overcoming MDR. PMID:26118539

  9. Tivantinib (ARQ 197) exhibits antitumor activity by directly interacting with tubulin and overcomes ABC transporter-mediated drug resistance.

    Science.gov (United States)

    Aoyama, Aki; Katayama, Ryohei; Oh-Hara, Tomoko; Sato, Shigeo; Okuno, Yasushi; Fujita, Naoya

    2014-12-01

    Tivantinib (ARQ197) was first reported as a highly selective inhibitor of c-MET and is currently being investigated in a phase III clinical trial. However, as recently reported by us and another group, tivantinib showed cytotoxic activity independent of cellular c-MET status and also disrupted microtubule dynamics. To investigate if tivantinib exerts its cytotoxic activity by disrupting microtubules, we quantified polymerized tubulin in cells and xenograft tumors after tivantinib treatment. Consistent with our previous report, tivantinib reduced tubulin polymerization in cells and in mouse xenograft tumors in vivo. To determine if tivantinib directly binds to tubulin, we performed an in vitro competition assay. Tivantinib competitively inhibited colchicine but not vincristine or vinblastine binding to purified tubulin. These results imply that tivantinib directly binds to the colchicine binding site of tubulin. To predict the binding mode of tivantinib with tubulin, we performed computer simulation of the docking pose of tivantinib with tubulin using GOLD docking program. Computer simulation predicts tivantinib fitted into the colchicine binding pocket of tubulin without steric hindrance. Furthermore, tivantinib showed similar IC50 values against parental and multidrug-resistant cells. In contrast, other microtubule-targeting drugs, such as vincristine, paclitaxel, and colchicine, could not suppress the growth of cells overexpressing ABC transporters. Moreover, the expression level of ABC transporters did not correlate with the apoptosis-inducing ability of tivantinib different from other microtubule inhibitor. These results suggest that tivantinib can overcome ABC transporter-mediated multidrug-resistant tumor cells and is potentially useful against various tumors. PMID:25313010

  10. Enabling Older Homeless Minority Women to Overcome Homelessness by Using a Life Management Enhancement Group Intervention

    OpenAIRE

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

    2009-01-01

    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...

  11. Co-delivery of siRNA and therapeutic agents using nanocarriers to overcome cancer resistance

    OpenAIRE

    Creixell, Mar; Peppas, Nicholas A.

    2012-01-01

    There are two main mechanisms by which cells become multidrug resistant (MDR): by increasing drug efflux pumps on the cell membrane and by increasing anti-apoptotic pathways. The use of nanotechnology to develop nanodelivery systems has allowed researchers to overcome limitations of antineoplastic drugs by increasing the solubility of the drug and decreasing the toxicity to healthy tissues. By encapsulating drugs into nanoparticles that bypass the efflux pumps, drug efflux is reduced, hence i...

  12. Overcoming the gap between academic and pratical knowledge about CSR : a methodological framework

    OpenAIRE

    Avenier, M. J.; Barin Cruz, L.

    2009-01-01

    Overcoming the Gap Between Academic and Practical Knowledge about CSR: A Methodological Framework Whenever researchers contemplate constructing knowledge from practice and managers' experience, they are faced with a number of questions which have not yet been satisfactorily answered in the literature. Although the gap between academia and practice has already been addressed by some scholars, potential solutions are still being discussed. Therefore, this paper has two main objectives: first, t...

  13. Book review: iDisorder: understanding our obsession with technology and overcoming its hold on us

    OpenAIRE

    Conroy, Melanie

    2013-01-01

    "iDisorder: Understanding our Obsession with Technology and Overcoming its Hold on Us." Larry Rosen, Nancy Cheever, and Mark Carrier. Palgrave Macmillan. May 2013. --- How is your daily use of media and technology changing your brain’s ability to process information and your ability to relate to the world, resulting in stress, sleeplessness, and a compulsive need to check in with all of your technology? iDisorder considers the creeping psychological and neurological impacts that technology is...

  14. OVERCOMING OBSTACLES TO IMPLEMENTING THE UN DECLARATION ON THE RIGHTS OF INDIGENOUS PEOPLES IN CANADA

    OpenAIRE

    Brenda L Gunn

    2015-01-01

    The majority vote by the General Assembly, which brought the UN Declaration on the Rights of Indigenous Peoples into existence as an international instrument, was just the first step.  Now the long and difficult road of implementation begins.  Implementation requires the application of international law in a specific national context.  This article explores the potential obstacles to implement the UN Declaration in Canada and suggest avenues to overcome these obstacles.  This article conclude...

  15. Overcoming the Diffraction Limit Using Multiple Light Scattering in a Highly Disordered Medium

    OpenAIRE

    Choi, Youngwoon; Yang, Taeseok Daniel; Fang-Yen, Christopher; Kang, Pilsung; Lee, Kyoung Jin; Dasari, Ramachandra R.; Feld, Michael S.; Choi, Wonshik

    2011-01-01

    We report that disordered media made of randomly distributed nanoparticles can be used to overcome the diffraction limit of a conventional imaging system. By developing a method to extract the original image information from the multiple scattering induced by the turbid media, we dramatically increase a numerical aperture of the imaging system. As a result, the the resolution is enhanced by more than five times over the diffraction limit and a field of view is extended over the physical area ...

  16. Investement in people and change management priorities for the overcoming the current economic crisis

    OpenAIRE

    Pasnicu, Daniela; Cismigiu, Magda; Dragoiu, Codruta

    2009-01-01

    In line with the EU's goal of becoming a knowledge-based society, education and lifelong learning will also feature prominently on the agenda of the European Year. EU should use the current economic crisis to develop strategic goals both at European and national level and improve conditions for creativity and innovation. The Member States must invest more in the human capital in order to provide good tools to overcome environmental challenges. The target of the paper is to emphasize the impor...

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

    Science.gov (United States)

    Flug, Marshall; Scott, John F.

    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.

  18. Counter-stereotypical pictures as a strategy for overcoming spontaneous gender stereotypes

    OpenAIRE

    Finnegan, Eimear; Oakhill, Jane; Garnham, Alan

    2015-01-01

    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 judgment 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 bot...

  19. Does advertising overcome brand loyalty? Evidence from the breakfast-cereals market

    OpenAIRE

    Shum, Matthew

    2004-01-01

    In differentiated product markets where consumer preferences are characterized by brand loyalty, an important role for advertising may be to overcome brand loyalty by encouraging consumers to switch to less familiar brands. Using a scanner panel dataset of breakfast-cereal purchases, I find evidence consistent with the hypothesis that advertising counteracts the tendencies of brand loyalty toward repeat purchasing. Equivalently, advertising reduces switching costs in this market. Furthermore,...

  20. Overcoming low self-efficacy beliefs in teaching English to young learners

    OpenAIRE

    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 develop deeper practical knowledge and stronger self-efficacy beliefs with regard to the particular task, while supported by a constructivist teacher educ...

  1. Using Technology to Overcome the Tyranny of Space: Information Provision and Wayfinding

    OpenAIRE

    Julian Hine; Derek Swan; Judith Scott; David Binnie; John Sharp

    2000-01-01

    Urban wayfinding technology offers many possibilities by which older people and mobility-impaired users can overcome the barriers encountered on every-day journeys in the built environment. Previous work has highlighted the extent to which personal mobility and independence are significant determinants of the quality of life amongst both elderly and visually impaired groups. The paper outlines the development of the auditory location finder (ALF), which is a beacon-based local information sys...

  2. 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

  3. Studies of overcoming acquired resistance : molecular mechanisms and development of novel drugs

    OpenAIRE

    Wang, Xin

    2014-01-01

    Chemotherapeutic agents have become widely applied for treatment of various types of malignancies. Drug resistance unfortunately remains as a major obstacle for the effectiveness of chemotherapy. Cancer drug resistance includes two broad categories: intrinsic and acquired. In this thesis I have examined the problem of acquired drug resistance and have aimed to develop novel approaches to overcome acquired resistance. Clofarabine is a second-generation nucleoside analogue which has been ...

  4. Evaluation of methods to overcome dormancy in the germination of Ormosia arborea (Vell.) Harms

    OpenAIRE

    Walquíria Fernanda Teixeira; Evandro Binotto Fagan; Derblai Casaroli; Sabrina de Carvalho Canedo; Kamilla Alves Barbosa

    2011-01-01

    The work aimed to evaluate the effect of different methods to overcome dormancy in the germination of Ormosia arborea. The following treatments were used: 72h of water immersion; chemical scarification with 100% sulfuric acid; mechanical scarification + 24h of imbibing and group control, each treatment being carried out with 12h and 0h photoperiods. The seeds undertook luminosity treatments within the period of germination testing in two germination chambers, BOD model. A completely randomize...

  5. The discourse analysis in overcoming difficulties on teaching the literary translation

    OpenAIRE

    BOYKO STEPAN A.

    2014-01-01

    The problem of overcoming difficulties existing nowadays in methodical science on teaching literary translation is considered by application of cognitive discourse analysis of the literary text. The various methods of studying of the literary text, existing in modern methodical science are shown. The contribution of Russia''s and foreign science in determining approaches to the analysis of communicative and cognitive components of the text and application of interdisciplinary approaches and c...

  6. Devaluation as the instrument for recession overcoming in Bosnia and Herzegovina

    Directory of Open Access Journals (Sweden)

    Zeljko Maric

    2011-01-01

    Full Text Available Devaluation is the instrument of monetary policy which has been used very often during the 20th century. In recent time of globalization, the many limited factors (openness of the economy, capital movements, currency substitution, money illusion significantly reduce or completely make impossible the devaluation implementation as the measure for foreign trade deficit or recession overcoming in many countries. This paper discusses on positive and negative effects of devaluation in the case of Bosnia and Herzegovina economy.

  7. Signs of a crisis and ways of its overcoming in the system of government administration

    OpenAIRE

    SYTNIK L.S.; BERVENOVA T.N.

    2014-01-01

    The paper characterizes government administration as a way to implement the state power; signs, forms and methods, structure of the mechanism of government administration; factors of formation of the style of the government-administration activity. The authors distinguish essential signs of the crisis in the government administration, the sequence of stages of crises emergence and aggravation; types of conflicts on the territorial component, reasons for revolutions, principles of overcoming; ...

  8. Overcoming restrictive technologies in police call centres: A human agency perspective

    OpenAIRE

    Papazafeiropoulou, A; Spinelli, G; Sharma, B.

    2008-01-01

    Call centres in the police force are restrictive information systems which tend to present call operators with constraints that they need to overcome using their experience in order to offer better services to the public. This paper is looking at how elements of human agency come in to play and help users’ enactment against restrictive technologies. Information systems research on human agency has been mainly focused on the examination of whether agency lies within human or mac...

  9. Phase-oriented treatment of structural dissociation in complex traumatization: overcoming trauma-related phobias.

    Science.gov (United States)

    Steele, Kathy; van der Hart, Onno; Nijenhuis, Ellert R S

    2005-01-01

    The theory of structural dissociation of the personality proposes that patients with complex trauma-related disorders are characterized by a division of their personality into different prototypical parts, each with its own psychobiological underpinnings. As one or more apparently normal parts (ANPs), patients have a propensity toward engaging in evolutionary prepared action systems for adaptation to daily living to guide their actions. Two or more emotional parts (EPs) are fixated in traumatic experience. As EPs, patients predominantly engage action systems related to physical defense and attachment cry. ANP and EP are insufficiently integrated, but interact and share a number of dispositions of the personality (e.g., speaking). All parts are stuck in maladaptive action tendencies that maintain dissociation, including a range of phobias, which is a major focus of this article. Phase-oriented treatment helps patients gradually develop adaptive mental and behavioral actions, thus overcoming their phobias and structural dissociation. Phase 1, symptom reduction and stabilization, is geared toward overcoming phobias of mental contents, dissociative parts, and attachment and attachment loss with the therapist. Phase 2, treatment of traumatic memories, is directed toward overcoming the phobia of traumatic memories, and phobias related to insecure attachment to the perpetrator(s), particularly in EPs. In Phase 3, integration and rehabilitation, treatment is focused on overcoming phobias of normal life, healthy risk-taking and change, and intimacy. To the degree that the theory of structural dissociation serves as an integrative heuristic for treatment, it should be compatible with other theories that guide effective treatment of patients with complex dissociative disorders. PMID:16172081

  10. The Role of Serbian Higher Business Education in Overcoming the Challenges of SME Managers

    OpenAIRE

    Maja Kočevar; Dietmar Sternad

    2014-01-01

    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, a...

  11. Different sterilization methods for overcoming internal bacterial infection in sunflower seeds

    Directory of Open Access Journals (Sweden)

    Taški-Ajduković Ksenija J.

    2005-01-01

    Full Text Available During culture of protoplasts in agarose droplets, permanent problem was bacterial infection. It was assumed that the seeds are the origin of infection, so different sterilization methods were tested in order to overcome this problem. Germination, infection of seeds and hypocotyls and their growth were examined. Based on these parameters, the best result was obtained with the combined use of 5% commercial bleach and dry heating at 45°C.

  12. Conducting research with end-of-life populations: overcoming recruitment challenges when working with clinical agencies.

    Science.gov (United States)

    Fischer, Dena J; Burgener, Sandy C; Kavanaugh, Karen; Ryan, Catherine; Keenan, Gail

    2012-11-01

    Conducting end-of-life (EOL) research can present numerous challenges associated with recruitment and retention of research subjects. Such issues may result from working with a variety of clinical settings or the uniqueness of the patient population. The purposes of this article were to describe recruitment challenges in EOL research when collaborating with different types of clinical agencies and to discuss strategies that are being used to overcome these recruitment issues. PMID:21700424

  13. Overcoming barriers to hepatitis B immunisation by a dedicated hepatitis B immunisation service

    OpenAIRE

    Larcher, V.; Bourne, J; Aitken, C; Jeffries, D; Hodes, D; Sloan, D.; Ramsay, M; Goldberg, D.; BRAMLEY, C.

    2001-01-01

    AIMS—To determine the effectiveness of a selective hospital based hepatitis B immunisation programme and the barriers to be overcome in obtaining a successful outcome.
METHODS—Retrospective case note review of 265 infants born over a five year period to hepatitis B carrier mothers at a university affiliated hospital in Hackney, London.
RESULTS—A total of 242 infants (91%) were fully vaccinated; 217 (82%) had serology; 31 required booster doses. Percentages failing to reach s...

  14. A Novel Approach for Microencapsulation of Nanoemulsions to Overcome the Oxidation of Bioactives in Aqueous Phase

    OpenAIRE

    Haroon Jamshaid Qazi; Hamid Majeed; Waseem Safdar; John Antoniou; Zhong Fang

    2015-01-01

    Microencapsulation is a promising technique to retain the physical attributes of nanoemulsions and to overcome the oxidation of bioactives that become more available to aqueous phase during emulsification. Purity Gum Ultra (PGU) and Hi-CAP 100 (HiCap) emulsified nanoemulsions of Clove Oil (CO) co-encapsulated with Canola oil (CA) and Medium Chain Triglyceride (MCT) (5:5% v/v CO:CA and CO:MCT) were prepared through high pressure homogenization. Microencapsulation of nanoemulsions was performed...

  15. Overcoming the Solubility Limit with Solubility-Enhancement Tags: Successful Applications in Biomolecular NMR Studies

    OpenAIRE

    Zhou, Pei; Wagner, Gerhard

    2010-01-01

    Although the rapid progress of NMR technology has significantly expanded the range of NMR-trackable systems, preparation of NMR-suitable samples that are highly soluble and stable remains a bottleneck for studies of many biological systems. The application of solubility-enhancement tags (SETs) has been highly effective in overcoming solubility and sample stability issues and has enabled structural studies of important biological systems previously deemed unapproachable by solution NMR techniq...

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

    OpenAIRE

    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

    2014-01-01

    Inhibitors of the FGF receptors (FGFRs) are currently under clinical investigation for the treatment of various cancers. All currently approved kinase inhibitors eventually are rendered useless by the emergence of drug-resistant tumors. We used structure-based drug design to develop the first, to our knowledge, selective, next-generation covalent FGFR inhibitors that can overcome the most common form of kinase inhibitor resistance, the mutation of the so-called “gatekeeper” residue located in...

  17. High-dose adenosine overcomes the attenuation of myocardial perfusion reserve caused by caffeine.

    OpenAIRE

    Reyes, E.; Loong, C Y; Harbinson, Mark; Donovan, J; Anagnostopoulos, C.; Underwood, S. R.

    2008-01-01

    Objectives:We studied whether an increase in adenosine dose overcomes caffeine antagonism on adenosine-mediated coronary vasodilation.Background:Caffeine is a competitive antagonist at the adenosine receptors, but it is unclear whether caffeine in coffee alters the actions of exogenous adenosine, and whether the antagonism can be surmounted by increasing the adenosine dose.Methods:Myocardial perfusion scintigraphy (MPS) was used to assess adenosine-induced hyperemia in 30 patients before (bas...

  18. Scientific provision of the problems of overcoming the Chernobyl catastrophe consequences. Chapter 6

    International Nuclear Information System (INIS)

    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

  19. Scientific provision of the problems of overcoming the Chernobyl catastrophe consequences. Chapter 6

    International Nuclear Information System (INIS)

    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. (authors)

  20. Diels-Alder Reactions of Furans with Itaconic Anhydride: Overcoming Unfavorable Thermodynamics.

    Science.gov (United States)

    Pehere, Ashok D; Xu, Shu; Thompson, Severin K; Hillmyer, Marc A; Hoye, Thomas R

    2016-06-01

    Unfavorable thermodynamics often render furans reluctant to engage in high-yielding Diels-Alder (DA) cycloaddition reactions. Here, we report the highly efficient conversion of the biosourced reactants itaconic anhydride (IA) and furfuryl alcohol (FA) to a single DA adduct. The free energy advantages provided by anhydride ring opening and crystal lattice energy of the product overcome the loss of aromaticity of the furanoid diene. Detailed (1)H NMR studies provided valuable insights about relevant kinetic and thermodynamic features. PMID:27214494

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

    OpenAIRE

    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 and aroma, especially of non-fragrant rices, has not been given high priority. In this study, we utilised a multi-disciplinary approach to understand better quality traits of aroma and flavour in rice grains, and to ...

  2. 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.

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

    International Nuclear Information System (INIS)

    Varying concentrations of NAA and GA3 (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 GA3 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)

  4. Overcoming acquired drug resistance in colorectal cancer cells by targeted delivery of 5-FU with EGF grafted hollow mesoporous silica nanoparticles

    Science.gov (United States)

    Chen, Lijue; She, Xiaodong; Wang, Tao; He, Li; Shigdar, Sarah; Duan, Wei; Kong, Lingxue

    2015-08-01

    effect and mechanism of 5-FU loaded EGF grafted HMSNs (EGF-HMSNs-5-FU) in overcoming acquired drug resistance in SW480/ADR cells were studied. The EGF-HMSNs were demonstrated to be specifically internalized in EGFR overexpressed SW480/ADR cells via a receptor-mediated endocytosis and can escape from endo-lysosomes. The EGF-HMSNs-5-FU exhibited much higher cytotoxicity on SW480/ADR cells than HMSNs-5-FU and free 5-FU while the plain HMSNs did not show significant cytotoxicity. The mechanism of EGF-HMSNs-5-FU in overcoming drug resistance in SW480/ADR cells could be attributed to the specific internalization of EGF-HMSNs-5-FU in EGFR overexpressed cells which can lead to high intracellular drug accumulation and cause cell death through S phase arrest. Electronic supplementary information (ESI) available: TEM image of EGF-HMSNs, characterization of HMSNs, EGFR expression in colorectal cancer cells, flow cytometry results, inhibition of endocytosis, confocal microscopy images of endosome escape and cell cycle distribution in SW480 cells. See DOI: 10.1039/C5NR03527A

  5. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3.

    Science.gov (United States)

    Nelson, Erik A; Walker, Sarah R; Kepich, Alicia; Gashin, Laurie B; Hideshima, Teru; Ikeda, Hiroshi; Chauhan, Dharminder; Anderson, Kenneth C; Frank, David A

    2008-12-15

    Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival. PMID:18824601

  6. Fast online determination of surfactant inhibition in acidic phase bioreactors.

    Science.gov (United States)

    Feitkenhauer, H

    2004-01-01

    Surfactants have been shown to inhibit the anaerobic digestion process severely, with the methanogenic microorganisms being the most affected. The diverse nature of surfactants used even in one (e.g. textile finishing) plant makes an online determination of surfactants sometimes very difficult and expensive. Therefore a fast online determination of inhibitory effects on the acidogenic microorganisms (first step of the degradation cascade) can help to give an early warning signal or to calculate a "pseudo"-surfactant concentration. In a two-phase system this information can be used to protect the methanogenic reactor against surfactant overloading and its long term negative effects. In this paper it is shown that the inhibition is a consequence of microbial inhibition and is not caused by an inactivation of extracellular hydrolytic enzymes (released by the cells for biopolymer cleavage). A titration technique was successfully employed to measure the surfactant inhibition in a laboratory-scale acidification reactor. Additional experiments demonstrate (using sodium dodecyl sulfate as the model substance) how inhibitory effects (and strategies to overcome inhibitory effects) can be investigated efficiently. PMID:14979534

  7. Inhibition of trypsin expression in Lutzomyia longipalpis using RNAi enhances the survival of Leishmania

    OpenAIRE

    Sant'Anna Mauricio RV; Diaz-Albiter Hector; Mubaraki Murad; Dillon Rod J; Bates Paul A

    2009-01-01

    Abstract Background Leishmania parasites must overcome several barriers to achieve transmission by their sand fly vectors. One of the earliest threats is exposure to enzymes during blood meal digestion. Trypsin-like enzymes appear to be detrimental to parasite survival during the very early phase of development as amastigotes transform into promastigote stages. Here, we investigate whether parasites can affect trypsin secretion by the sand fly midgut epithelium and if inhibition of this proce...

  8. Vancomycin analogues active against vanA-resistant strains inhibit bacterial transglycosylase without binding substrate

    OpenAIRE

    Chen, Lan; Walker, Deborah; Sun, Binyuan; Hu, Yanan; Walker, Suzanne; Kahne, Daniel

    2003-01-01

    Bacterial transglycosylases are enzymes that couple the disaccharide subunits of peptidoglycan to form long carbohydrate chains. These enzymes are the target of the pentasaccharide antibiotic moenomycin as well as the proposed target of certain glycopeptides that overcome vancomycin resistance. Because bacterial transglycosylases are difficult enzymes to study, it has not previously been possible to evaluate how moenomycin inhibits them or to determine whether glycopeptide analogues directly ...

  9. Validation of Inhibition Effect in the Cellulose Hydrolysis: a Dynamic Modelling Approach

    DEFF Research Database (Denmark)

    Morales Rodriguez, Ricardo; Tsai, Chien-Tai; Meyer, Anne S.;

    2011-01-01

    Enzymatic hydrolysis is one of the main steps in the processing of bioethanol from lignocellulosic raw materials. However, complete understanding of the underlying phenomena is still under development. Hence, this study has focused on validation of the inhibition effects in the cellulosic biomass...... hydrolysis employing a dynamic mathematical model. A systematic framework for parameter estimation is used for model validation, which helps overcome the problem of parameter correlation. Data sets obtained from carefully designed enzymatic cellulose and cellobiose hydrolysis experiments, were used for...

  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. PMID:26801746

  11. 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

    2016-03-15

    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

  12. Overcoming the Diffraction Limit Using Multiple Light Scattering in a Highly Disordered Medium

    Science.gov (United States)

    Choi, Youngwoon; Yang, Taeseok Daniel; Fang-Yen, Christopher; Kang, Pilsung; Lee, Kyoung Jin; Dasari, Ramachandra R.; Feld, Michael S.; Choi, Wonshik

    2011-07-01

    We report that disordered media made of randomly distributed nanoparticles can be used to overcome the diffraction limit of a conventional imaging system. By developing a method to extract the original image information from the multiple scattering induced by the turbid media, we dramatically increase a numerical aperture of the imaging system. As a result, the resolution is enhanced by more than 5 times over the diffraction limit, and the field of view is extended over the physical area of the camera. Our technique lays the foundation to use a turbid medium as a far-field superlens.

  13. Overcoming doxorubicin resistance of cancer cells by Cas9-mediated gene disruption

    OpenAIRE

    Jong Seong Ha; Juyoung Byun; Dae-Ro Ahn

    2016-01-01

    In this study, Cas9 system was employed to down-regulate mdr1 gene for overcoming multidrug resistance of cancer cells. Disruption of the MDR1 gene was achieved by delivery of the Cas9-sgRNA plasmid or the Cas9-sgRNA ribonucleoprotein complex using a conventional gene transfection agent and protein transduction domain (PTD). Doxorubicin showed considerable cytotoxicity to the drug-resistant breast cancer cells pre-treated with the RNA-guided endonuclease (RGEN) systems, whereas virtually non-...

  14. [Molecular physiology of receptor mediated endocytosis and its role in overcoming multidrug resistance].

    Science.gov (United States)

    Severin, E S; Posypanova, G A

    2011-06-01

    Receptor-mediated endocytosis plays important role in the selective uptake of proteins at the plasma membrane of eukaryotic cells. Endocytosis regulates many processes of cell signalling by controlling the number of functional receptors on the cell surface. The article reviews the mechanism of clathrin-dependent endocytosis and the possibility of using this phenomenon for the targeted delivery of drugs. Use of certain proteins as targeting component of drug delivery systems can significantly improve the selectivity of this drug, as well as to overcome the multidrug resistance of cells resulting from the activity of the ABC-transporters. PMID:21874867

  15. 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

  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. Eyring equation and the second order rate law: Overcoming a paradox

    OpenAIRE

    Laurent, Bonnet

    2016-01-01

    The standard transition state theory (TST) of bimolecular reactions was recently shown to lead to a rate law in disagreement with the expected second order rate law [Bonnet L., Rayez J.-C. Int. J. Quantum Chem. 2010, 110, 2355]. An alternative derivation was proposed which allows to overcome this paradox. This derivation allows to get at the same time the good rate law and Eyring equation for the rate constant. The purpose of this paper is to provide rigorous and convincing theoretical argume...

  18. 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.

  19. Overcoming Inter-Subject Variability in BCI Using EEG-Based Identification

    OpenAIRE

    Stastny, J.; P. Sovka; Kostilek, M.

    2014-01-01

    The high dependency of the Brain Computer Interface (BCI) system performance on the BCI user is a well-known issue of many BCI devices. This contribution presents a new way to overcome this problem using a synergy between a BCI device and an EEG-based biometric algorithm. Using the biometric algorithm, the BCI device automatically identifies its current user and adapts parameters of the classification process and of the BCI protocol to maximize the BCI performance. In addition to this we pres...

  20. Overcoming toxicity-challenges in chemoradiation for non-small cell lung cancer

    Science.gov (United States)

    2016-01-01

    Concurrent chemoradiation (CCRT) is the treatment of choice for locally advanced non-small cell lung cancer (NSCLC) with a modest survival benefit over sequential chemoradiation or radiotherapy (SCRT) alone. However, this benefit is at the cost of increasing acute toxicity such as esophagitis. Previous analysis revealed several predictive parameters in dose-volume and patient characteristics which helped us to identify those patients at risk for severe esophagus toxicity. As a result, supportive care interventions including individualized patient information, dietary guidance, adequate medication, hydration and tubefeeding could be initiated. This paper discusses the challenges in overcoming chemoradiation induced acute esophageal toxicity (AET).

  1. Eyring equation and the second order rate law: Overcoming a paradox

    CERN Document Server

    Laurent, Bonnet

    2016-01-01

    The standard transition state theory (TST) of bimolecular reactions was recently shown to lead to a rate law in disagreement with the expected second order rate law [Bonnet L., Rayez J.-C. Int. J. Quantum Chem. 2010, 110, 2355]. An alternative derivation was proposed which allows to overcome this paradox. This derivation allows to get at the same time the good rate law and Eyring equation for the rate constant. The purpose of this paper is to provide rigorous and convincing theoretical arguments in order to strengthen these developments and improve their visibility.

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

    DEFF Research Database (Denmark)

    Vilmann, Peter; Seicean, Andrada; Săftoiu, Adrian

    2014-01-01

    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 to......The diagnostic yield of EUS-FNA depends on several factors, such as the experience of the endosonographer, the characteristics of the lesion, the clinical status of the patient, the size and type of needles, the methods of specimen preparation, as well as cytopathologist expertise. The...

  3. Very rare Q-slope none overcome by electropolishing and baking

    International Nuclear Information System (INIS)

    We discovered the very rare Q-slope none overcome by electropolishing and baking at 120degC for 48 hours. The Q-slope is not related to 'Hydrogen disease'. The Q-slope is not improved by the wiping and steam so that we recognize that the Q-slope is not caused by some cohesion things of the cavity's surface. The rare Q-slope is categorized a low, medium and high rare Q-slope. In this paper, we report the Rare Q-slope and the categorized rare Q-slope. (author)

  4. Overcoming Bifurcation Instability in High-Repetition-Rate Ho:YLF Regenerative Amplifiers

    OpenAIRE

    Kroetz, Peter; Ruehl, Axel; Chatterjee, Gourab; Calendron, Anne-Laure; Murari, Krishna; Cankaya, Huseyin; LI Peng; Kaertner, Franz X.; Hartl, Ingmar; Miller, R. J. Dwayne

    2015-01-01

    We demonstrate a Ho:YLF regenerative amplifier (RA) overcoming bifurcation instability and consequently achieving high extraction energies of 6.9 mJ at a repetition rate of 1 kHz with pulse-to-pulse fluctuations of 1.1%. Measurements of the output pulse energy, corroborated by numerical simulations, identify an operation point that allows high-energy pulse extraction at a minimum noise level. Complete suppression of the onset of bifurcation was achieved by gain saturation after each pumping c...

  5. Bromodomains: Structure, function and pharmacology of inhibition.

    Science.gov (United States)

    Ferri, Elena; Petosa, Carlo; McKenna, Charles E

    2016-04-15

    Bromodomains are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation. The human proteome comprises 46 bromodomain-containing proteins with a total of 61 bromodomains, which, despite highly conserved structural features, recognize a wide array of natural peptide ligands. Over the past five years, bromodomains have attracted great interest as promising new epigenetic targets for diverse human diseases, including inflammation, cancer, and cardiovascular disease. The demonstration in 2010 that two small molecule compounds, JQ1 and I-BET762, potently inhibit proteins of the bromodomain and extra-terminal (BET) family with translational potential for cancer and inflammatory disease sparked intense efforts in academia and pharmaceutical industry to develop novel bromodomain antagonists for therapeutic applications. Several BET inhibitors are already in clinical trials for hematological malignancies, solid tumors and cardiovascular disease. Currently, the field faces the challenge of single-target selectivity, especially within the BET family, and of overcoming problems related to the development of drug resistance. At the same time, new trends in bromodomain inhibitor research are emerging, including an increased interest in non-BET bromodomains and a focus on drug synergy with established antitumor agents to improve chemotherapeutic efficacy. This review presents an updated view of the structure and function of bromodomains, traces the development of bromodomain inhibitors and their potential therapeutic applications, and surveys the current challenges and future directions of this vibrant new field in drug discovery. PMID:26707800

  6. The Anticancer Agent Di-2-pyridylketone 4,4-Dimethyl-3-thiosemicarbazone (Dp44mT) Overcomes Prosurvival Autophagy by Two Mechanisms

    Science.gov (United States)

    Gutierrez, Elaine; Richardson, Des R.; Jansson, Patric J.

    2014-01-01

    Autophagy functions as a survival mechanism during cellular stress and contributes to resistance against anticancer agents. The selective antitumor and antimetastatic chelator di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) causes lysosomal membrane permeabilization and cell death. Considering the integral role of lysosomes in autophagy and cell death, it was important to assess the effect of Dp44mT on autophagy to further understand its mechanism of action. Notably, Dp44mT affected autophagy by two mechanisms. First, concurrent with its antiproliferative activity, Dp44mT increased the expression of the classical autophagic marker LC3-II as a result of induced autophagosome synthesis. Second, this effect was supplemented by a reduction in autophagosome degradation as shown by the accumulation of the autophagic substrate and receptor p62. Conversely, the classical iron chelator desferrioxamine induced autophagosome accumulation only by inhibiting autophagosome degradation. The formation of redox-active iron or copper Dp44mT complexes was critical for its dual effect on autophagy. The cytoprotective antioxidant N-acetylcysteine inhibited Dp44mT-induced autophagosome synthesis and p62 accumulation. Importantly, Dp44mT inhibited autophagosome degradation via lysosomal disruption. This effect prevented the fusion of lysosomes with autophagosomes to form autolysosomes, which is crucial for the completion of the autophagic process. The antiproliferative activity of Dp44mT was suppressed by Beclin1 and ATG5 silencing, indicating the role of persistent autophagosome synthesis in Dp44mT-induced cell death. These studies demonstrate that Dp44mT can overcome the prosurvival activity of autophagy in cancer cells by utilizing this process to potentiate cell death. PMID:25301941

  7. 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.

  8. Counter-stereotypical pictures as a strategy for overcoming spontaneous gender stereotypes.

    Science.gov (United States)

    Finnegan, Eimear; Oakhill, Jane; Garnham, Alan

    2015-01-01

    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 judgment 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 two blocks of such judgment 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 four questions on each one relating to the character's leisure activities, earnings, job satisfaction, and personal life. Accuracy of judgments 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. PMID:26379606

  9. 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.

  10. Overcoming dormancy and determining optimal temperature for slender serradella seed germination

    Directory of Open Access Journals (Sweden)

    Rodrigo Ramos Lopes

    2015-12-01

    Full Text Available ABSTRACT The objective of this study was to identify the most efficient method for overcoming coat-imposed dormancy and determine the optimal germination temperature for Ornithopus pinnatus seeds. Treatments to overcome dormancy were: intact seeds; immersion in hot water at 60 ºC, followed by soaking in the same water (unheated/24 h; immersion in hot water at 90 ºC, followed by soaking in the same water (unheated/24 h; mechanical scarification; chemical scarification, H2SO4/5 min; and chemical scarification, H2SO4/10 min. Percentages were calculated for germinated, abnormal, dormant, and dead seeds. Optimal germination temperatures were calculated using eight constant temperatures (0, 5, 10, 15, 20, 25, 30, and 35 °C, with 8 h of light and 16 h of darkness. Germination rate, frequency, and synchronization index of germination were used as parameters to establish optimum temperature for germination. A completely randomized experimental design was used, with twelve repetitions of 100 seeds per treatment. Data obtained were subjected to analysis of variance and Tukey's test at a 5% significance level. O. pinnatus seeds exhibit dormancy caused by the seed coat's impermeability to water. Mechanical scarification was efficient in promoting seed germination. The species is stenothermal, meaning it cannot tolerate significant temperature variations. The germination rate of seeds was linearly dependent on temperature. Synchronization of the germination process is greater in the optimum temperature range, established between 15 and 20 °C.

  11. Economic damage and state policy on the overcoming of the Chernobyl NPP catastrophe consequences. Chapter 2

    International Nuclear Information System (INIS)

    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

  12. 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.

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

    International Nuclear Information System (INIS)

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Fernandes, Joao; Bjorkli, Knut; Clavo, David Martin; Baron, Thomas, E-mail: Joao.Fernandes@cern.c [CERN IT-UDS-AVC, 1211 Geneva 23 (Switzerland)

    2010-04-01

    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.

  15. English Communication on Migration and Measures to Overcome the Negative Culture

    Institute of Scientific and Technical Information of China (English)

    陈婉媛

    2016-01-01

    Since the reform and opening up, China has more opportunities and European countries, exchanges and cooperation. However, in the process of communication, we may inadvertently ignore each other's culture and customs, the lack of cross-cul-tural communication awareness in local culture to measure the culture of other countries, such behavior is called negative trans-fer culture. Negative Transfer of Culture will have cultural misunderstandings and conflicts between nations and hinder the smooth progress of cross-cultural communication. In order to avoid unnecessary misunderstanding, strengthen the friendship be-tween different countries, we should understand, learn and overcome cultural negative transfer. This will combine theoretical knowledge and examples to explain the culture, language and culture negative relationship between migration and elaborate cul-tural negative transfer of two levels:Negative Transfer negative transfer surface culture and deep culture (including values mi-gration and ethnic psychological aspects), and its negative impact on the English cross-cultural communication. In addition, this paper will propose some strategies and corresponding to the principle of helping people overcome the negative transfer in cross-cultural communication, enhance cross-cultural communication ability, up from psychological acceptance, adaptation, and toler-ance of different cultures.

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

    International Nuclear Information System (INIS)

    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.

  17. Harnessing atomistic simulations to predict the rate at which dislocations overcome obstacles

    Science.gov (United States)

    Saroukhani, S.; Nguyen, L. D.; Leung, K. W. K.; Singh, C. V.; Warner, D. H.

    2016-05-01

    Predicting the rate at which dislocations overcome obstacles is key to understanding the microscopic features that govern the plastic flow of modern alloys. In this spirit, the current manuscript examines the rate at which an edge dislocation overcomes an obstacle in aluminum. Predictions were made using different popular variants of Harmonic Transition State Theory (HTST) and compared to those of direct Molecular Dynamics (MD) simulations. The HTST predictions were found to be grossly inaccurate due to the large entropy barrier associated with the dislocation-obstacle interaction. Considering the importance of finite temperature effects, the utility of the Finite Temperature String (FTS) method was then explored. While this approach was found capable of identifying a prominent reaction tube, it was not capable of computing the free energy profile along the tube. Lastly, the utility of the Transition Interface Sampling (TIS) approach was explored, which does not need a free energy profile and is known to be less reliant on the choice of reaction coordinate. The TIS approach was found capable of accurately predicting the rate, relative to direct MD simulations. This finding was utilized to examine the temperature and load dependence of the dislocation-obstacle interaction in a simple periodic cell configuration. An attractive rate prediction approach combining TST and simple continuum models is identified, and the strain rate sensitivity of individual dislocation obstacle interactions is predicted.

  18. 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.

  19. 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). PMID:25590742

  20. The Role of Carrier Geometry in Overcoming Biological Barriers to Drug Delivery.

    Science.gov (United States)

    Jordan, Carolyn; Shuvaev, Vladimir V; Bailey, Mark; Muzykantov, Vladimir R; Dziubla, Thomas D

    2016-01-01

    For a variety of diseases, effective therapy is severely limited or rendered impossible due to an inability to deliver medications to the intended sites of action. Multiple barriers exist through the body, which have evolved over time to limit the migration of foreign compounds from entering the tissues. Turning toward biology as inspiration, it has been the general goal of drug delivery to create carrier strategies that mimic, in part, features of bacteria/ viruses that allow them overcome these barriers. By packaging drugs into nano and micron scale vehicles, it should be possible to completely change the biodistribution and residence times of pharmaceutically active compounds. Recently, due to advances in formulation technologies, it has become possible to control not just the material selection, surface chemistry, and/or size, but also the overall geometry and plasticity of the drug carriers. These approaches aid in the formulation of nonspherical particles such as, discs, rods, and even unique structures such as cubes and nanodiamonds. The adjustment of size and shape can be used for the aid or prevention in cellular uptake and also to overcome the vascular and mucosal barrier. In this review, we present a summary of some approaches used to control carrier shape and the impact these geometries have upon drug transport across biological barriers. PMID:26675218

  1. 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.

  2. Checkpoint inhibition in meningiomas.

    Science.gov (United States)

    Bi, Wenya Linda; Wu, Winona W; Santagata, Sandro; Reardon, David A; Dunn, Ian F

    2016-06-01

    Meningiomas are increasingly appreciated to share similar features with other intra-axial central nervous system neoplasms as well as systemic cancers. Immune checkpoint inhibition has emerged as a promising therapy in a number of cancers, with durable responses of years in a subset of patients. Several lines of evidence support a role for immune-based therapeutic strategies in the management of meningiomas, especially high-grade subtypes. Meningiomas frequently originate juxtaposed to venous sinuses, where an anatomic conduit for lymphatic drainage resides. Multiple populations of immune cells have been observed in meningiomas. PD-1/PD-L1 mediated immunosuppression has been implicated in high-grade meningiomas, with association between PD-L1 expression with negative prognostic outcome. These data point to the promise of future combinatorial therapeutic strategies in meningioma. PMID:27197540

  3. Backward semantic inhibition in toddlers

    OpenAIRE

    Chow, J.; Aimola Davies, AM; Fuentes, LJ; Plunkett, KR

    2016-01-01

    Attention-switching is a crucial ability required in our everyday life, from toddlerhood to adulthood. In adults, shifting attention from one word (e.g., dog) to another (e.g., sea) results in backward semantic inhibition, i.e., the inhibition of the initial word (dog). This study examines whether attention-switching is accompanied by backward semantic inhibition in toddlers using the preferential looking paradigm. The findings demonstrate that a backward inhibitory mechanism operates during ...

  4. 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

  5. TYPICAL BANKING CRISES INTERNATIONAL BUSINESS ENVIRONMENT AND WAYS TO OVERCOME THEM

    Directory of Open Access Journals (Sweden)

    Ion Gr. IONESCU

    2014-06-01

    Full Text Available International financial environment is characterized as consisting of free trade and especially from the free movement of the capital on the financial markets, so very favourable, which also led to the rapid development of global financial markets. We lack the ability to keep the peace (silence for to counter the excesses of the financial markets. Without this ability, the global economy is exposed to the collapse. Financial capital enjoys a privileged position. He is more mobile than other factors of production and even more mobile than direct investment. Yet crises must be overcome. To support the arguments of this paper, we use a flexible methodology, starting from simple to complex, from theoretical to practical, from principle, to particularly, adding, specialty practice examples, from the international sphere, convinced that work-international banking must be healthy, able to generate profitable and dynamic business environments, safe for entrepreneurs and bankers, but also ordinary people.

  6. 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......The noti®cation of new chemicals in the European Union requires a risk assessment. A Technical Guidance Document (TGD) was prepared for assistance. The TGD proposes QSARs, regressions and models from various sources. Each method has its own range of applicability and its own restrictions....... Regressions used in the assessment of indirect human exposure have a common regression range from log KOW 3.0±4.6. Most models are compartment models, which do not consider a spatial distribution of the chemical, and were originally developed for non-dissociating, lipophilic persistent chemicals with...

  7. Overcoming the sign problem in 1-dimensional QCD by new integration rules with polynomial exactness

    CERN Document Server

    Ammon, A; Jansen, K; Leövey, H; Volmer, J

    2016-01-01

    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 $N\\le 3$. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Cole, Pamala C.; Halverson, Mark A.

    2013-09-01

    The U.S. Department of Energy’s (DOE) Building America program implemented a new Codes and Standards Innovation (CSI) Team in 2013. The Team’s mission is to assist Building America (BA) research teams and partners in identifying and resolving conflicts between Building America innovations and the various codes and standards that govern the construction of residences. A CSI Roadmap was completed in September, 2013. This guidance document was prepared using the information in the CSI Roadmap to provide BA research teams and partners with specific information and approaches to identifying and overcoming potential barriers to Building America (BA) innovations arising in and/or stemming from codes, standards, and rating methods. For more information on the BA CSI team, please email: CSITeam@pnnl.gov

  9. Targeting oncoprotein stability overcomes drug resistance caused by FLT3 kinase domain mutations.

    Directory of Open Access Journals (Sweden)

    Chuanjiang Yu

    Full Text Available FLT3 is the most frequently mutated kinase in acute myeloid leukemia (AML. Internal tandem duplications (ITDs in the juxta-membrane region constitute the majority of activating FLT3 mutations. Several FLT3 kinase inhibitors were developed and tested in the clinic with significant success. However, recent studies have reported the development of secondary drug resistance in patients treated with FLT3 inhibitors. Since FLT3-ITD is an HSP90 client kinase, we here explored if targeting the stability of drug-resistant FLT3 mutant protein could be a potential therapeutic option. We observed that HSP90 inhibitor treatment resulted in the degradation of inhibitor-resistant FLT3-ITD mutants and selectively induced toxicity in cells expressing FLT3-ITD mutants. Thus, HSP90 inhibitors provide a potential therapeutic choice to overcome secondary drug resistance following TKI treatment in FLT3-ITD positive AML.

  10. Decentralizing decision making in modularization strategies: Overcoming barriers from dysfunctional accounting systems

    DEFF Research Database (Denmark)

    Israelsen, Poul; Jørgensen, Brian

    2011-01-01

    Research on product modularity is dominated by an operations management (OM) perspective, through which numerous models to predict optimal modularization strategies have been developed. However, we argue that implementation of these predictions is hampered by prevailing project accounting systems...... which distorts the economic effects of modularization at the level of the individual product. This has the implication that decisions on modularization can only be made by top management if decision authority and relevant information are to be aligned. To overcome this problem, we suggest a solution...... that aligns the descriptions of the economic consequences of modularization at the project and portfolio level which makes it possible to decentralize decision making while making sure that local goals are congruent with the global ones in order to avoid suboptimal behaviour....

  11. Overcoming the Pigou-Downs Paradox Using Advanced Traffic Signal Control

    Science.gov (United States)

    Fowdur, S. C.; Rughooputh, S. D. D. V.

    2013-06-01

    Expansion of a road network has often been observed to cause more congestion and has led researchers to the formulation of traffic paradoxes such as the Pigou-Downs and the Braess paradoxes. In this paper, we present an application of advanced traffic signal control (ATSC) to overcome the Pigou-Downs paradox. Port Louis, the capital city of Mauritius is used to investigate the effect of using a harbor bridge to by-pass the city center. Using traffic cellular automata (TCA) simulations it has been shown how, if traffic is only gradually deviated along the by-pass, an overall longer travel time and decreased flux would result. By making use of ATSC, which involves traffic lights that sense the number of vehicles accumulated in the queue, better travel times and fluxes are achieved.

  12. Overcoming the social crisis in Russia: Systemic modernization as an alternative for its further development

    Directory of Open Access Journals (Sweden)

    Sorokina Lilia G.

    2010-01-01

    Full Text Available The author tackles the ways of further development of Russia and its perspectives in the global world. The main directions in national scientific thought are analyzed - the theories of Westernization, Isolationism, and Eurasianism. Special attention is paid to the theory of modernization as an effective way of overcoming the crisis in contemporary Russian society, which proposes innovative methods of rebuilding Russia's political and economic systems, taking into account the effects of the global financial crisis. The article also highlights the problem of deep spiritual crisis in modern Russian society and suggests a solution for that problem. It supposes an upgrade in the spiritual sphere, the formation of a new mentality, innovative ideology, in which the factors of human creativity, energy and initiative will occupy the leading position.

  13. Evaluation of methods to overcome dormancy in the germination of Ormosia arborea (Vell. Harms

    Directory of Open Access Journals (Sweden)

    Walquíria Fernanda Teixeira

    2011-12-01

    Full Text Available The work aimed to evaluate the effect of different methods to overcome dormancy in the germination of Ormosia arborea. The following treatments were used: 72h of water immersion; chemical scarification with 100% sulfuric acid; mechanical scarification + 24h of imbibing and group control, each treatment being carried out with 12h and 0h photoperiods. The seeds undertook luminosity treatments within the period of germination testing in two germination chambers, BOD model. A completely randomized design was used, with four replications. Greater germination percentages were observed in treatments with chemical scarification. There were no germination percentage differences between the 0h and 12h photoperiods in the species under study. One concludes Ormosia arborea seeds present greater germination percentages when undertaking chemical scarification, and luminosity has no influence over the germination of this species.

  14. Toward overcoming cisplatin resistance via sterically hindered platinum(II) complexes.

    Science.gov (United States)

    Yu, Haiyan; Gou, Shaohua; Wang, Zhimei; Chen, Feihong; Fang, Lei

    2016-05-23

    A number of platinum(II) complexes with steric hindrance derived from (1R,2R)-N(1)-benzylcyclohexane-1,2-diamine derivatives were designed and prepared. Biological assay indicated that most complexes showed antitumor activity against the tested cancer cell lines, especially those with chloride anions as leaving groups had compatible or superior activity to cisplatin and oxaliplatin. Complex 2a, as the most potent agent, is also sensitive to cisplatin resistant SGC7901/CDDP cancer cell line, which has been subsequently studied by cellular uptake, flow cytometry, gel electrophoresis and western blot assays. The steric hindrance resulting from a pending 2-fluorobenzyl moiety of the ligand might be the key factor for its ability to overcome cisplatin resistant cancer cells. PMID:26974381

  15. Graphene as a flexible electronic material: mechanical limitations by defect formation and efforts to overcome

    Directory of Open Access Journals (Sweden)

    Seung-Mo Lee

    2015-07-01

    Full Text Available Defects in chemical vapor deposition (CVD graphene seriously weaken its mechanical properties, and are harmful to other impressive physical properties. In particular, the poor mechanical properties of CVD graphene with defects are one of the most significant obstacles for graphene-based flexible electronics. In this mini-review, the types of defects in CVD graphene generated during the growth and handling stages are first briefly discussed. Then, the fracture behaviors of graphene with such defects are described. In addition, several effective methods for the direct or indirect early detection of those defects present in graphene are summarized. Lastly, recent studies to overcome these mechanical limitations induced by defects are introduced.

  16. Potent Inhibitors of Acetyltransferase Eis Overcome Kanamycin Resistance in Mycobacterium tuberculosis.

    Science.gov (United States)

    Willby, Melisa J; Green, Keith D; Gajadeera, Chathurada S; Hou, Caixia; Tsodikov, Oleg V; Posey, James E; Garneau-Tsodikova, Sylvie

    2016-06-17

    A major cause of tuberculosis (TB) resistance to the aminoglycoside kanamycin (KAN) is the Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. Upregulation of this enzyme is responsible for inactivation of KAN through acetylation of its amino groups. A 123 000-compound high-throughput screen (HTS) yielded several small-molecule Eis inhibitors that share an isothiazole S,S-dioxide heterocyclic core. These were investigated for their structure-activity relationships. Crystal structures of Eis in complex with two potent inhibitors show that these molecules are bound in the conformationally adaptable aminoglycoside binding site of the enzyme, thereby obstructing binding of KAN for acetylation. Importantly, we demonstrate that several Eis inhibitors, when used in combination with KAN against resistant Mtb, efficiently overcome KAN resistance. This approach paves the way toward development of novel combination therapies against aminoglycoside-resistant TB. PMID:27010218

  17. Conceptual preconditions of overcoming of relativistic intentions in modern philosophy of science

    CERN Document Server

    Kulikov, Sergey

    2014-01-01

    The paper defends the thesis that it's possible to maintain some conceptual preconditions of overcoming of relativistic intentions in modern philosophy of science ("there are no any general foundations in philosophy of science"). We found two general foundations in philosophy of science as a minimum. From the first side it's realistic to reveal on the base of special understanding of time the value of time not only in natural thought (especially in theory of gravity) but also in humanitarian knowledge. That's why philosophy of science has independent position in epistemology and ontology corresponding to interpretation of time as a general category of scientific thinking. The nature of time has internally inconsistent (paradoxical) character. Time is phenomenon which existing and not existing at the same time. This phenomenon is identified with imaginary movement and also ideal (formal) process of formation of the nature. The general understanding of time is connected with its "mathematical" meaning as calcul...

  18. Overcoming the solubility limit with solubility-enhancement tags: successful applications in biomolecular NMR studies

    International Nuclear Information System (INIS)

    Although the rapid progress of NMR technology has significantly expanded the range of NMR-trackable systems, preparation of NMR-suitable samples that are highly soluble and stable remains a bottleneck for studies of many biological systems. The application of solubility-enhancement tags (SETs) has been highly effective in overcoming solubility and sample stability issues and has enabled structural studies of important biological systems previously deemed unapproachable by solution NMR techniques. In this review, we provide a brief survey of the development and successful applications of the SET strategy in biomolecular NMR. We also comment on the criteria for choosing optimal SETs, such as for differently charged target proteins, and recent new developments on NMR-invisible SETs.

  19. ALLStars: Overcoming Multi-Survey Selection Bias using Crowd-Sourced Active Learning

    Science.gov (United States)

    Starr, D. L.; Richards, J. W.; Brink, H.; Miller, A. A.; Bloom, J. S.; Butler, N. R.; James, J. B.; Long, J. P.

    2012-09-01

    Developing a multi-survey time-series classifier presents several challenges. One problem is overcoming the sample selection bias which arises when the instruments or observing cadences differ between the training and testing datasets. In this case, the probabilistic distributions characterizing the sources in the training survey dataset differ from the source distributions in the other survey, resulting in poor results when a classifier is naively applied. To resolve this, we have developed the ALLStars active learning framework which allows us to bootstrap a classifier onto a new survey using a small set of optimally chosen sources which are then presented to users for manual classification. Several iterations of this crowd-sourcing process results in a significantly improved classifier. Using this procedure, we have built a variable star light-curve classifier using OGLE, Hipparcos, and ASAS survey data.

  20. Virtuality and Efficiency - Overcoming Past Antinomy in the Remote Collaboration Experience

    CERN Document Server

    Fernandes, J; Martin Clavo, D; Baron, T; CERN. Geneva. IT Department

    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 ...

  1. Leveraging Billions of Faces to Overcome Performance Barriers in Unconstrained Face Recognition

    CERN Document Server

    Taigman, Yaniv

    2011-01-01

    We employ the face recognition technology developed in house at face.com to a well accepted benchmark and show that without any tuning we are able to considerably surpass state of the art results. Much of the improvement is concentrated in the high-valued performance point of zero false positive matches, where the obtained recall rate almost doubles the best reported result to date. We discuss the various components and innovations of our system that enable this significant performance gap. These components include extensive utilization of an accurate 3D reconstructed shape model dealing with challenges arising from pose and illumination. In addition, discriminative models based on billions of faces are used in order to overcome aging and facial expression as well as low light and overexposure. Finally, we identify a challenging set of identification queries that might provide useful focus for future research.

  2. Using animal models to overcome temporal, spatial and combinatorial challenges in HIV persistence research

    DEFF Research Database (Denmark)

    Denton, Paul W.; Søgaard, Ole Schmeltz; Tolstrup, Martin

    2016-01-01

    Research challenges associated with understanding HIV persistence during antiretroviral therapy can be categorized as temporal, spatial and combinatorial. Temporal research challenges relate to the timing of events during establishment and maintenance of HIV persistence. Spatial research challeng...... directly addressing these research challenges. The aim of this manuscript is to provide a comprehensive review of these recent translational advances made in animal models of HIV persistence.......Research challenges associated with understanding HIV persistence during antiretroviral therapy can be categorized as temporal, spatial and combinatorial. Temporal research challenges relate to the timing of events during establishment and maintenance of HIV persistence. Spatial research challenges...... regard the anatomical locations and cell subsets that harbor persistent HIV. Combinatorial research challenges pertain to the order of administration, timing of administration and specific combinations of compounds to be administered during HIV eradication therapy. Overcoming these challenges will...

  3. Widowhood, loneliness and sexuality in old age: mechanisms of coping and overcoming

    Directory of Open Access Journals (Sweden)

    Verónica Montes de Oca Zavala

    2013-12-01

    Full Text Available A long widowhood is associated with negative aspects in the life of the people, especially if they are in the stage of Old Age. However depending on the moment they experience this event in the course of life is possible to activate mechanisms to face life and reorder. This article shows from a exploratory perspective, qualitative and analytical, three case studies in the state of Mexico showing the perceived widowhood, which means in old age, their impacts economic and social, and how discourses and counter-discourses that have been generated subjects analyzed to overcome loneliness, isolation, the need for affection and love beyond providing family and children. Sexuality is seen from a critical and is an element highlighted in the narratives of these three cases and drew attention to the traditional way of analyzing Old Age and widowhood. The article consists of a literature review, objectives and methodology, as well as a section of results and final thoughts.

  4. Neuroscience, mental health and the immune system: overcoming the brain-mind-body trichotomy.

    Science.gov (United States)

    Pariante, C M

    2016-04-01

    Psychiatry is having a great time. Over the last few years, we have seen an exceptional explosion in neuroscience knowledge, and especially in our understanding of the molecular mechanisms through which environmental and genetic factors affect the brain and regulate behaviour, while at the same interacting with peripheral ('body') functions. While this explosion, and its translational implications, can be seen across a variety of fields, this editorial will focus on one particular area where these developments have been more noticeable: the interaction between neuroscience, mental health and the immune system. This editorial will focus on the broader impact of this discipline as an example of successful translational neuroscience overcoming the brain-mind-body trichotomy. PMID:26503420

  5. Density-functional theory cannot be constrained to completely overcome self-interaction error

    CERN Document Server

    Moynihan, Glenn; O'Regan, David D

    2016-01-01

    In approximate density functional theory (DFT), the self-interaction error is a pervasive electron delocalization associated with underestimated insulating gaps. It exhibits a predominantly quadratic energy-density curve that is amenable to correction using computationally efficient, constraint-resembling methods such as DFT + Hubbard U (DFT+U). Constrained DFT (cDFT) exactly enforces conditions on DFT by means of self-consistently optimized Lagrange multipliers, and its use to automate DFT+U type corrections is a compelling possibility. We show that constraints beyond linear order are incompatible with cDFT. For DFT+U, we overcome this by separating its Hubbard U parameters into linear and quadratic terms. For a one-electron system, the resulting generalized DFT+U method can recover the exact subspace occupancy and free-energy, but neither the exact total-energy nor the exact ionization potential, for reasonable parameters. Approximate functionals thus cannot be systematically corrected by constraining their...

  6. Overcoming expression and purification problems of RhoGDI using a family of "parallel" expression vectors.

    Science.gov (United States)

    Sheffield, P; Garrard, S; Derewenda, Z

    1999-02-01

    We describe the construction of expression vectors based on three of the most frequently used gene fusion affinity tags [glutathione S-transferase (GST), maltose binding protein (MBP), and the His6 peptide]. The polylinkers of pGEX4T1, pMal-c2, and a pET vector were replaced with the polylinker isolated from the baculovirus expression plasmid pFastBac. Once appropriate restriction sites have been introduced into a gene, it can be fused to all three affinity tags with little effort, allowing expression-screening experiments to be performed efficiently. We discuss the development and use of these vectors with respect to overcoming purification problems encountered for the RhoA GDP/GTP nucleotide dissociation inhibitor (RhoGDI) and their advantages over commercially available expression vectors. PMID:10024467

  7. Overcoming the solubility limit with solubility-enhancement tags: successful applications in biomolecular NMR studies.

    Science.gov (United States)

    Zhou, Pei; Wagner, Gerhard

    2010-01-01

    Although the rapid progress of NMR technology has significantly expanded the range of NMR-trackable systems, preparation of NMR-suitable samples that are highly soluble and stable remains a bottleneck for studies of many biological systems. The application of solubility-enhancement tags (SETs) has been highly effective in overcoming solubility and sample stability issues and has enabled structural studies of important biological systems previously deemed unapproachable by solution NMR techniques. In this review, we provide a brief survey of the development and successful applications of the SET strategy in biomolecular NMR.We also comment on the criteria for choosing optimal SETs, such as for differently charged target proteins, and recent new developments on NMR-invisible SETs. PMID:19731047

  8. Change in CNE boiler control level and stepback to overcome strong grid transients

    International Nuclear Information System (INIS)

    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

  9. Human health and nutrition: How isotopes are helping to overcome ''hidden hunger''

    International Nuclear Information System (INIS)

    In a number of ways, the work of the IAEA is contributing to efforts directed at overcoming hidden hunger and other nutrition problems. The rationale for the IAEA's involvement is twofold. First, adequate nutrition is an essential component of any strategy for improving health, and the IAEA's Statute specifically identifies ''enlarging the contribution of atomic energy to peace, health and prosperity'' as the major objective of programmes. Second, isotope techniques have a wide variety of applications -some of them unique - for targeted research in human nutrition, for assessing nutritional status, and for monitoring the effectiveness of nutritional intervention programmes. This article provides a brief overview of these techniques and their main applications in areas of human nutrition

  10. Stakeholder cooperation to overcome challenges in orphan medicine development: the example of Duchenne muscular dystrophy.

    Science.gov (United States)

    Straub, Volker; Balabanov, Pavel; Bushby, Kate; Ensini, Monica; Goemans, Nathalie; De Luca, Annamaria; Pereda, Alejandra; Hemmings, Robert; Campion, Giles; Kaye, Edward; Arechavala-Gomeza, Virginia; Goyenvalle, Aurelie; Niks, Erik; Veldhuizen, Olav; Furlong, Pat; Stoyanova-Beninska, Violeta; Wood, Matthew J; Johnson, Alex; Mercuri, Eugenio; Muntoni, Francesco; Sepodes, Bruno; Haas, Manuel; Vroom, Elizabeth; Aartsma-Rus, Annemieke

    2016-07-01

    Duchenne muscular dystrophy is a rare, progressive, muscle-wasting disease leading to severe disability and premature death. Treatment is currently symptomatic, but several experimental therapies are in development. Implemented care standards, validated outcome measures correlating with clinical benefit, and comprehensive information about the natural history of the disease are essential for regulatory approval of any treatment. However, for Duchenne muscular dystrophy and other rare diseases, these requirements are not always in place when potential therapies enter the clinical trial phase. A cooperative effort of stakeholders in Duchenne muscular dystrophy-including representatives from patients' groups, academia, industry, and regulatory agencies-is aimed at addressing this shortfall by identifying strategies to overcome challenges, developing the tools needed, and collecting relevant data. An open and constructive dialogue among European stakeholders has positively affected development of treatments for Duchenne muscular dystrophy; this approach could serve as a paradigm for development of treatments for rare diseases in general. PMID:27302365

  11. Overcoming terminology barrier using Web resources for cross-language medical information retrieval.

    Science.gov (United States)

    Lu, Wen-Hsiang; Lin, Ray Shih-Jui; Chan, Yi-Che; Chen, Kuan-Hsi

    2006-01-01

    A number of authoritative medical websites, such as PubMed and MedlinePlus, provide consumers with the most up-to-date health information. However, non-English speakers often encounter not only language barriers (from other languages to English) but also terminology barriers (from laypersons inverted exclamation mark| terms to professional medical terms) when retrieving information from these websites. Our previous work address language barriers by developing a multilingual medical thesaurus, Chinese-English MeSH, while this study presents an approach to overcome terminology barriers based on Web resources. Two techniques were utilized in our approach: monolingual concept mapping using approximate string matching and crosslingual concept mapping using Web resources. The evaluation shows that our approach can significantly improve the performance on MeSH concept mapping and cross-language medical information retrieval. PMID:17238395

  12. Overcoming bifurcation instability in high-repetition-rate Ho:YLF regenerative amplifiers.

    Science.gov (United States)

    Kroetz, Peter; Ruehl, Axel; Chatterjee, Gourab; Calendron, Anne-Laure; Murari, Krishna; Cankaya, Huseyin; Li, Peng; Kärtner, Franz X; Hartl, Ingmar; Miller, R J Dwayne

    2015-12-01

    We demonstrate a Ho:YLF regenerative amplifier (RA) overcoming bifurcation instability and consequently achieving high extraction energies of 6.9 mJ at a repetition rate of 1 kHz with pulse-to-pulse fluctuations of 1.1%. Measurements of the output pulse energy, corroborated by numerical simulations, identify an operation point (OP) that allows high-energy pulse extraction at a minimum noise level. Complete suppression of the onset of bifurcation was achieved by gain saturation after each pumping cycle in the Ho:YLF crystal via lowering the repetition rate and cooling the crystal. Even for moderate cooling, a significant temperature dependence of the Ho:YLF RA performance was observed. PMID:26625017

  13. Overcoming Bifurcation Instability in High-Repetition-Rate Ho:YLF Regenerative Amplifiers

    CERN Document Server

    Kroetz, Peter; Chatterjee, Gourab; Calendron, Anne-Laure; Murari, Krishna; Cankaya, Huseyin; Li, Peng; Kaertner, Franz X; Hartl, Ingmar; Miller, R J Dwayne

    2015-01-01

    We demonstrate a Ho:YLF regenerative amplifier (RA) overcoming bifurcation instability and consequently achieving high extraction energies of 6.9 mJ at a repetition rate of 1 kHz with pulse-to-pulse fluctuations of 1.1%. Measurements of the output pulse energy, corroborated by numerical simulations, identify an operation point that allows high-energy pulse extraction at a minimum noise level. Complete suppression of the onset of bifurcation was achieved by gain saturation after each pumping cycle in the Ho:YLF crystal via lowering the repetition rate and cooling the crystal. Even for moderate cooling, a significant temperature dependence of the Ho:YLF RA performance was observed.

  14. ["Mobilize the masses to urgently go into action and overcome the drought"].

    Science.gov (United States)

    1981-08-14

    At present, the drought is serious. Urgently taking action and doing everything possible to overcome the drought and strive for a bumper autumn harvest is an extremely urgent combat task facing the people of our province. Since mid-June, it has rained in our province several times but it has not rained very evenly. It has not rained in many places during the past 1/2 year and more. By the end of July, autumn crops on 37.35 million mu of land have been affected by the drought, accounting for more than 1/3 of the total area of the autumn crops. The drought has greatly harmed the growth of autumn crops. If we do not act now the drought will seriously affect the autumn harvest. Mobilizing the masses to urgently go into action to overcome the drought and strive for a bumper autumn harvest is a major task which has a bearing on the livelihood of both the urban and rural people of our province and on the further development of the excellent situation. Therefore, party committees at all levels must pay attention to this, concentrate the forces to grasp it firmly and well, and not lower their guard. The party members, cadres, and masses must carry forward the spirit of fighting continuously and struggling hard, make full use of all water conservancy projects and antidrought machinery and tools, try their best to find new water resources, and use water reasonably and sparingly. All walks of life and trades must do everything possible to vigorously support the struggle against the drought and do well in supplying the oil and electricity needed for agricultural machinery and help to repair machinery and tools. We all must contribute toward the effort to achieve a bumper autumn harvest. PMID:12338066

  15. Right supramarginal gyrus is crucial to overcome emotional egocentricity bias in social judgments.

    Science.gov (United States)

    Silani, Giorgia; Lamm, Claus; Ruff, Christian C; Singer, Tania

    2013-09-25

    Humans tend to use the self as a reference point to perceive the world and gain information about other people's mental states. However, applying such a self-referential projection mechanism in situations where it is inappropriate can result in egocentrically biased judgments. To assess egocentricity bias in the emotional domain (EEB), we developed a novel visuo-tactile paradigm assessing the degree to which empathic judgments are biased by one's own emotions if they are incongruent to those of the person we empathize with. A first behavioral experiment confirmed the existence of such EEB, and two independent fMRI experiments revealed that overcoming biased empathic judgments is associated with increased activation in the right supramarginal gyrus (rSMG), in a location distinct from activations in right temporoparietal junction reported in previous social cognition studies. Using temporary disruption of rSMG with repetitive transcranial magnetic stimulation resulted in a substantial increase of EEB, and so did reducing visuo-tactile stimulation time as shown in an additional behavioral experiment. Our findings provide converging evidence from multiple methods and experiments that rSMG is crucial for overcoming emotional egocentricity. Effective connectivity analyses suggest that this may be achieved by early perceptual regulation processes disambiguating proprioceptive first-person information (touch) from exteroceptive third-person information (vision) during incongruency between self- and other-related affective states. Our study extends previous models of social cognition. It shows that although shared neural networks may underlie emotional understanding in some situations, an additional mechanism subserved by rSMG is needed to avoid biased social judgments in other situations. PMID:24068815

  16. Nanocomplexes for gene therapy of respiratory diseases: Targeting and overcoming the mucus barrier.

    Science.gov (United States)

    Di Gioia, Sante; Trapani, Adriana; Castellani, Stefano; Carbone, Annalucia; Belgiovine, Giuliana; Craparo, Emanuela Fabiola; Puglisi, Giovanni; Cavallaro, Gennara; Trapani, Giuseppe; Conese, Massimo

    2015-10-01

    Gene therapy, i.e. the delivery and expression of therapeutic genes, holds great promise for congenital and acquired respiratory diseases. Non-viral vectors are less toxic and immunogenic than viral vectors, although they are characterized by lower efficiency. However, they have to overcome many barriers, including inflammatory and immune mediators and cells. The respiratory and airway epithelial cells, the main target of these vectors, are coated with a layer of mucus, which hampers the effective reaching of gene therapy vectors carrying either plasmid DNA or small interfering RNA. This barrier is thicker in many lung diseases, such as cystic fibrosis. This review summarizes the most important advancements in the field of non-viral vectors that have been achieved with the use of nanoparticulate (NP) systems, composed either of polymers or lipids, in the lung gene delivery. In particular, different strategies of targeting of respiratory and airway lung cells will be described. Then, we will focus on the two approaches that attempt to overcome the mucus barrier: coating of the nanoparticulate system with poly(ethylene glycol) and treatment with mucolytics. Our conclusions are: 1) Ligand and physical targeting can direct therapeutic gene expression in specific cell types in the respiratory tract; 2) Mucopenetrating NPs are endowed with promising features to be useful in treating respiratory diseases and should be now advanced in pre-clinical trials. Finally, we discuss the development of such polymer- and lipid-based NPs in the context of in vitro and in vivo disease models, such as lung cancer, as well as in clinical trials. PMID:26192479

  17. Overcoming Barriers: Adolescents’ Experiences Using a Mobile Phone Dietary Assessment App

    Science.gov (United States)

    Svensson, Åsa; Magnusson, Maria

    2016-01-01

    Background The use of new technology has the potential to increase participation rates in dietary studies and improve the validity of collected dietary data. However, to evaluate the usability of developed dietary methods, qualitative studies of participants’ experiences and perceptions are needed. Objective To explore adolescents’ experiences using a newly developed mobile phone dietary assessment app, with a focus on factors that could affect their recording of dietary intake. Methods Focus group interviews were conducted with 75 participants who had used a newly developed mobile phone dietary assessment app in a quantitative evaluation study. The interviews were analyzed using qualitative content analysis and the theoretical framework of Self Determination Theory was applied. Results The adolescents’ use of the mobile phone dietary assessment app was characterized by their struggle to overcome several perceived barriers. Facilitators that helped adolescents complete the method were also identified. Motivation was found to be an important facilitator, and intrinsically motivated participants completed the method because they found it fun to use. The autonomous extrinsically motivated participants completed the method for the greater good, in order to contribute to the study. The controlled extrinsically motivated participants completed the method to get a reward or avoid punishment. Amotivated participants did not complete the method. More motivated participants were assumed to be more able to overcome barriers and needed less facilitators. Conclusions Future studies that examine the recording of food intake should include systematic efforts that aim to minimize identified barriers and promote identified facilitators. Further research should specifically aim at studying methods for (and effects of) increasing intrinsic motivation by supporting autonomy, competence, and relatedness among adolescents asked to participate in dietary studies. PMID:27473462

  18. Can Arousal Modulate Response Inhibition?

    Science.gov (United States)

    Weinbach, Noam; Kalanthroff, Eyal; Avnit, Amir; Henik, Avishai

    2015-01-01

    The goal of the present study was to examine if and how arousal can modulate response inhibition. Two competing hypotheses can be drawn from previous literature. One holds that alerting cues that elevate arousal should result in an impulsive response and therefore impair response inhibition. The other suggests that alerting enhances processing of…

  19. Forcing contact inhibition of locomotion

    OpenAIRE

    Roycroft, A.; Mayor, R.

    2015-01-01

    Contact inhibition of locomotion drives a variety of biological phenomenon, from cell dispersion to collective cell migration and cancer invasion. New imaging techniques have allowed contact inhibition of locomotion to be visualised in vivo for the first time, helping to elucidate some of the molecules and forces involved in this phenomenon.

  20. Inhibition of Ampicillin-resistance in Bacteria by Modified DNAzymes

    Institute of Scientific and Technical Information of China (English)

    CHEN Fei; LI Zhe; YANG Shuo; WANG Rui-jian; LIU Bin; SONG Yu-ming; SUN Yan-hong; HAO Dong-yun; NG Xlao-ping

    2008-01-01

    To overcome ampicillin-resistance of bacteria which is believed to attribute their endogenous β-lactamase,we designed three 10-23 DNAzymes(DZ1,Dz2,Dz3) targeting the coding region of β-lactamase mRNA and examined their inhibitory capabilities of the ampicillin-resistance of TEM-1 and TEM-3 bacteria,Dz1 was a traditional 10-23 DNAzyme,Dz2 was the mutant of Dz1 by addition of the protected nucleotide to each arm of the enzyme,and Dz3 was a mutant of DZ1 at antisense arms of which phosphorothioate modifications were made,Kinetic analysis,bacterial growth,and β-lactamase activity measurement showed that all the three DNAzymes worked efficiently in vitro and in vivo,A 9 hours bacterial growth inhibition test showed that the inhibition rates of TEM-1 bacteria by Dz1,Dz2,and Dz3 were 27%,50%,and 29%,respectively,In addition,the inhibition rates of TEM-3 bacteria by those three DNAzymes were found to be 49%,58%,and 45%,respectively,The current findings suggest that DNAzymes may become potential candidates of alternative inhibitors for bacteria drug-resistance.

  1. Balanced feedforward inhibition and dominant recurrent inhibition in olfactory cortex.

    Science.gov (United States)

    Large, Adam M; Vogler, Nathan W; Mielo, Samantha; Oswald, Anne-Marie M

    2016-02-23

    Throughout the brain, the recruitment of feedforward and recurrent inhibition shapes neural responses. However, disentangling the relative contributions of these often-overlapping cortical circuits is challenging. The piriform cortex provides an ideal system to address this issue because the interneurons responsible for feedforward and recurrent inhibition are anatomically segregated in layer (L) 1 and L2/3 respectively. Here we use a combination of optical and electrical activation of interneurons to profile the inhibitory input received by three classes of principal excitatory neuron in the anterior piriform cortex. In all classes, we find that L1 interneurons provide weaker inhibition than L2/3 interneurons. Nonetheless, feedforward inhibitory strength covaries with the amount of afferent excitation received by each class of principal neuron. In contrast, intracortical stimulation of L2/3 evokes strong inhibition that dominates recurrent excitation in all classes. Finally, we find that the relative contributions of feedforward and recurrent pathways differ between principal neuron classes. Specifically, L2 neurons receive more reliable afferent drive and less overall inhibition than L3 neurons. Alternatively, L3 neurons receive substantially more intracortical inhibition. These three features--balanced afferent drive, dominant recurrent inhibition, and differential recruitment by afferent vs. intracortical circuits, dependent on cell class--suggest mechanisms for olfactory processing that may extend to other sensory cortices. PMID:26858458

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

    International Nuclear Information System (INIS)

    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

  3. 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.

  4. Increasing the Oxidative Stress Response Allows Escherichia coli To Overcome Inhibitory Effects of Condensed Tannins

    OpenAIRE

    Smith, Alexandra H.; Imlay, James A.; Mackie, Roderick I.

    2003-01-01

    Tannins are plant-derived polyphenols with antimicrobial effects. The mechanism of tannin toxicity towards Escherichia coli was determined by using an extract from Acacia mearnsii (Black wattle) as a source of condensed tannins (proanthocyanidins). E. coli growth was inhibited by tannins only when tannins were exposed to oxygen. Tannins auto-oxidize, and substantial hydrogen peroxide was generated when they were added to aerobic media. The addition of exogenous catalase permitted growth in ta...

  5. Treatment of isolated pistils with protease inhibitors overcomes the self-incompatibility response in buckwheat

    Directory of Open Access Journals (Sweden)

    Miljuš-Đukić Jovanka D.

    2007-01-01

    Full Text Available Isolated pistils of distylous buckwheat (Fagopyrum esculentum Moench were treated with protease inhibitors (PMSF, pepstatin A, and antipain. Pistils were cross- or self- pollinated, and growth of pollen tubes was observed under a fluorescence microscope. Treatments with all inhibitors suppressed inhibition of self-pollen tube growth, suggesting that activity of proteases is involved in rejection of self-pollen during the SI response.

  6. EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer.

    Science.gov (United States)

    Amato, Katherine R; Wang, Shan; Tan, Li; Hastings, Andrew K; Song, Wenqiang; Lovly, Christine M; Meador, Catherine B; Ye, Fei; Lu, Pengcheng; Balko, Justin M; Colvin, Daniel C; Cates, Justin M; Pao, William; Gray, Nathanael S; Chen, Jin

    2016-01-15

    Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFR(T790M) mutations in vitro and inhibited tumor growth and progression in an inducible EGFR(L858R+T790M)-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors. PMID:26744526

  7. Checkpoint inhibition for colorectal cancer: progress and possibilities.

    Science.gov (United States)

    Paul, Barry; O'Neil, Bert H; McRee, Autumn J

    2016-06-01

    Colorectal cancer (CRC) remains the third most common cause of cancer death in the USA. Despite an increase in the repertoire of treatment options available for CRC, median overall survival has plateaued at approximately 2.5 years. Strategies that engage the patient's native immune system to overcome checkpoint inhibition have proven to be promising in subsets of CRCs, specifically those with mismatch repair deficiency. Further studies are required to determine combinations of standard therapies with immunotherapy drugs and to discover the best biomarkers to predict response. This review provides insight into the progress made in treating patients with advanced CRC with immunotherapeutics and the areas that demand further research to make these drugs more effective in this patient population. PMID:27197538

  8. 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

    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......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...

  9. Social Inhibition of Maturation in Natural Populations of Xiphophorus variatus (Pisces: Poeciliidae).

    Science.gov (United States)

    Borowsky, R

    1978-09-01

    According to analyses of field samples, social inhibition of maturation is at work in natural populations of the variable platyfish, Xiphophorus variatus. In the laboratory, adult males inhibit the maturation of juveniles; the inhibition is overcome as the juveniles increase in size. The proportion of maturing males in any field collection is related to the number of adult males present and the size of the juveniles. The more adults, the fewer maturing males are present; the larger the average juvenile, the greater the number of males maturing. The evolution of this system is best understood in terms of individual selection, but consequences of the system buffer the population against the effects of predation. PMID:17729573

  10. Cluster-forming factors and tools to overcome negative conditions of regionalhousing policy implementation

    Directory of Open Access Journals (Sweden)

    Zhul'kova Yuliya Nikolaevna

    2014-01-01

    Full Text Available The society in its development periodically faces the problem of insufficiently intense social and economic development, stagnation in industrial production and changes of consumer demand for various goods and services including the construction products. Current conditions dictate the need for the development and use of mechanisms enhancing the socio-economic well-being of the population growth in some regions and the Russian society as a whole.On choosing ways of development special attention should be paid to providing synergy of the combination of economic sectors resources, significantly determining the socio-economic well-being of the population. The comparative analysis of the socio-economic development is a tool of identifying and restraining the negative and constraint factors for subsequent adjustments and development of measures to reduce their role or liquidate them in order to solve the housing problem, the most severe for vulnerable groups, as well as members of the middle class.In this regard, a new approach to the implementation of housing policies basing on the principle of cluster was proposed. Clustering provides joining of efforts of main economic sectors (public, real, social and financial to overcome the negative conditions of the housing policy and combines technological connection of the development of residential real estate with the finance and credit support for cluster initiatives.This is a systematic approach to overcome the negative factors and the creation of qualitative and quantitative acceleration of processes of housing construction, which determines the methodological suitability of using cluster mechanism to implement housing policy, which at the moment doesn’t show significant achievements in providing citizens with affordable housing.Using this concept of interaction of economic sectors will allow determining the direction of cluster initiatives development in the subjects of federal districts on the

  11. Evidence for Health II: Overcoming barriers to using evidence in policy and practice.

    Science.gov (United States)

    Andermann, Anne; Pang, Tikki; Newton, John N; Davis, Adrian; Panisset, Ulysses

    2016-01-01

    Even the highest quality evidence will have little impact unless it is incorporated into decision-making for health. It is therefore critical to overcome the many barriers to using evidence in decision-making, including (1) missing the window of opportunity, (2) knowledge gaps and uncertainty, (3) controversy, irrelevant and conflicting evidence, as well as (4) vested interests and conflicts of interest. While this is certainly not a comprehensive list, it covers a number of main themes discussed in the knowledge translation literature on this topic, and better understanding these barriers can help readers of the evidence to be more savvy knowledge users and help researchers overcome challenges to getting their evidence into practice. Thus, the first step in being able to use research evidence for improving population health is ensuring that the evidence is available at the right time and in the right format and language so that knowledge users can take the evidence into consideration alongside a multitude of other factors that also influence decision-making. The sheer volume of scientific publications makes it difficult to find the evidence that can actually help inform decisions for health. Policymakers, especially in low- and middle-income countries, require context-specific evidence to ensure local relevance. Knowledge synthesis and dissemination of policy-relevant local evidence is important, but it is still not enough. There are times when the interpretation of the evidence leads to various controversies and disagreements, which act as barriers to the uptake of evidence. Research evidence can also be influenced and misused for various aims and agendas. It is therefore important to ensure that any new evidence comes from reliable sources and is interpreted in light of the overall body of scientific literature. It is not enough to simply produce evidence, nor even to synthesize and package evidence into a more user-friendly format. Particularly at the policy

  12. Overcoming multidrug resistance via photodestruction of ABCG2-rich extracellular vesicles sequestering photosensitive chemotherapeutics.

    Directory of Open Access Journals (Sweden)

    Vicky Goler-Baron

    Full Text Available Multidrug resistance (MDR remains a dominant impediment to curative cancer chemotherapy. Efflux transporters of the ATP-binding cassette (ABC superfamily including ABCG2, ABCB1 and ABCC1 mediate MDR to multiple structurally and functionally distinct antitumor agents. Recently we identified a novel mechanism of MDR in which ABCG2-rich extracellular vesicles (EVs form in between attached neighbor breast cancer cells and highly concentrate various chemotherapeutics in an ABCG2-dependent manner, thereby sequestering them away from their intracellular targets. Hence, development of novel strategies to overcome MDR modalities is a major goal of cancer research. Towards this end, we here developed a novel approach to selectively target and kill MDR cancer cells. We show that illumination of EVs that accumulated photosensitive cytotoxic drugs including imidazoacridinones (IAs and topotecan resulted in intravesicular formation of reactive oxygen species (ROS and severe damage to the EVs membrane that is shared by EVs-forming cells, thereby leading to tumor cell lysis and the overcoming of MDR. Furthermore, consistent with the weak base nature of IAs, MDR cells that are devoid of EVs but contained an increased number of lysosomes, highly accumulated IAs in lysosomes and upon photosensitization were efficiently killed via ROS-dependent lysosomal rupture. Combining targeted lysis of IAs-loaded EVs and lysosomes elicited a synergistic cytotoxic effect resulting in MDR reversal. In contrast, topotecan, a bona fide transport substrate of ABCG2, accumulated exclusively in EVs of MDR cells but was neither detected in lysosomes of normal breast epithelial cells nor in non-MDR breast cancer cells. This exclusive accumulation in EVs enhanced the selectivity of the cytotoxic effect exerted by photodynamic therapy to MDR cells without harming normal cells. Moreover, lysosomal alkalinization with bafilomycin A1 abrogated lysosomal accumulation of IAs, consequently

  13. Animals In Synchrotrons: Overcoming Challenges For High-Resolution, Live, Small-Animal Imaging

    Science.gov (United States)

    Donnelley, Martin; Parsons, David; Morgan, Kaye; Siu, Karen

    2010-07-01

    Physiological studies in small animals can be complicated, but the complexity is increased dramatically when performing live-animal synchrotron X-ray imaging studies. Our group has extensive experience in high-resolution live-animal imaging at the Japanese SPring-8 synchrotron, primarily examining airways in two-dimensions. These experiments normally image an area of 1.8 mm×1.2 mm at a pixel resolution of 0.45 μm and are performed with live, intact, anaesthetized mice. There are unique challenges in this experimental setting. Importantly, experiments must be performed in an isolated imaging hutch not specifically designed for small-animal imaging. This requires equipment adapted to remotely monitor animals, maintain their anesthesia, and deliver test substances while collecting images. The horizontal synchrotron X-ray beam has a fixed location and orientation that limits experimental flexibility. The extremely high resolution makes locating anatomical regions-of-interest slow and can result in a high radiation dose, and at this level of magnification small animal movements produce motion-artifacts that can render acquired images unusable. Here we describe our experimental techniques and how we have overcome several challenges involved in performing live mouse synchrotron imaging. Experiments have tested different mouse strains, with hairless strains minimizing overlying skin and hair artifacts. Different anesthetics have also be trialed due to the limited choices available at SPring-8. Tracheal-intubation methods have been refined and controlled-ventilation is now possible using a specialized small-animal ventilator. With appropriate animal restraint and respiratory-gating, motion-artifacts have been minimized. The animal orientation (supine vs. head-high) also appears to affect animal physiology, and can alter image quality. Our techniques and image quality at SPring-8 have dramatically improved and in the near future we plan to translate this experience to the

  14. Animals In Synchrotrons: Overcoming Challenges For High-Resolution, Live, Small-Animal Imaging

    International Nuclear Information System (INIS)

    Physiological studies in small animals can be complicated, but the complexity is increased dramatically when performing live-animal synchrotron X-ray imaging studies. Our group has extensive experience in high-resolution live-animal imaging at the Japanese SPring-8 synchrotron, primarily examining airways in two-dimensions. These experiments normally image an area of 1.8 mmx1.2 mm at a pixel resolution of 0.45 μm and are performed with live, intact, anaesthetized mice.There are unique challenges in this experimental setting. Importantly, experiments must be performed in an isolated imaging hutch not specifically designed for small-animal imaging. This requires equipment adapted to remotely monitor animals, maintain their anesthesia, and deliver test substances while collecting images. The horizontal synchrotron X-ray beam has a fixed location and orientation that limits experimental flexibility. The extremely high resolution makes locating anatomical regions-of-interest slow and can result in a high radiation dose, and at this level of magnification small animal movements produce motion-artifacts that can render acquired images unusable. Here we describe our experimental techniques and how we have overcome several challenges involved in performing live mouse synchrotron imaging.Experiments have tested different mouse strains, with hairless strains minimizing overlying skin and hair artifacts. Different anesthetics have also be trialed due to the limited choices available at SPring-8. Tracheal-intubation methods have been refined and controlled-ventilation is now possible using a specialized small-animal ventilator. With appropriate animal restraint and respiratory-gating, motion-artifacts have been minimized. The animal orientation (supine vs. head-high) also appears to affect animal physiology, and can alter image quality. Our techniques and image quality at SPring-8 have dramatically improved and in the near future we plan to translate this experience to the

  15. Combined Targeting of JAK2 and Bcl-2/Bcl-xL to Cure Mutant JAK2-Driven Malignancies and Overcome Acquired Resistance to JAK2 Inhibitors

    Directory of Open Access Journals (Sweden)

    Michaela Waibel

    2013-11-01

    Full Text Available To design rational therapies for JAK2-driven hematological malignancies, we functionally dissected the key survival pathways downstream of hyperactive JAK2. In tumors driven by mutant JAK2, Stat1, Stat3, Stat5, and the Pi3k and Mek/Erk pathways were constitutively active, and gene expression profiling of TEL-JAK2 T-ALL cells revealed the upregulation of prosurvival Bcl-2 family genes. Combining the Bcl-2/Bcl-xL inhibitor ABT-737 with JAK2 inhibitors mediated prolonged disease regressions and cures in mice bearing primary human and mouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was able to circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment. Thus, inhibiting the oncogenic JAK2 signaling network at two nodal points, at the initiating stage (JAK2 and the effector stage (Bcl-2/Bcl-xL, is highly effective and provides a clearly superior therapeutic benefit than targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2.

  16. High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells.

    Science.gov (United States)

    Oppermann, Sina; Ylanko, Jarkko; Shi, Yonghong; Hariharan, Santosh; Oakes, Christopher C; Brauer, Patrick M; Zúñiga-Pflücker, Juan C; Leber, Brian; Spaner, David E; Andrews, David W

    2016-08-18

    Novel agents such as the Bcl-2 inhibitor venetoclax (ABT-199) are changing treatment paradigms for chronic lymphocytic leukemia (CLL) but important problems remain. Although some patients exhibit deep and durable responses to venetoclax as a single agent, other patients harbor subpopulations of resistant leukemia cells that mediate disease recurrence. One hypothesis for the origin of resistance to venetoclax is by kinase-mediated survival signals encountered in proliferation centers that may be unique for individual patients. An in vitro microenvironment model was developed with primary CLL cells that could be incorporated into an automated high-content microscopy-based screen of kinase inhibitors (KIs) to identify agents that may improve venetoclax therapy in a personalized manner. Marked interpatient variability was noted for which KIs were effective; nevertheless, sunitinib was identified as the most common clinically available KI effective in overcoming venetoclax resistance. Examination of the underlying mechanisms indicated that venetoclax resistance may be induced by microenvironmental signals that upregulate antiapoptotic Bcl-xl, Mcl-1, and A1, which can be counteracted more efficiently by sunitinib than by ibrutinib or idelalisib. Although patient-specific drug responses are common, for many patients, combination therapy with sunitinib may significantly improve the therapeutic efficacy of venetoclax. PMID:27297795

  17. Pre-systemic metabolism of orally administered drugs and strategies to overcome it.

    Science.gov (United States)

    Pereira de Sousa, Irene; Bernkop-Schnürch, Andreas

    2014-10-28

    The oral bioavailability of numerous drugs is not only limited by poor solubility and/or poor membrane permeability as addressed by the biopharmaceutical classification system (BCS) but also by a pre-systemic metabolism taking place to a high extent in the intestine. Enzymes responsible for metabolic reactions in the intestine include cytochromes P450 (CYP450), transferases, peptidases and proteases. Furthermore, in the gut nucleases, lipases as well as glycosidases influence the metabolic pathway of drugs and nutrients. A crucial role is also played by the intestinal microflora able to metabolize a wide broad of pharmaceutical compounds. Strategies to provide a protective effect towards an intestinal pre-systemic metabolism are based on the co-administration of enzyme inhibitor being optimally immobilized on unabsorbable and undegradable polymeric excipients in order to keep them concentrated there where an inhibitory effect is needed. Furthermore, certain polymeric excipients such as polyacrylates exhibit per se enzyme inhibitory properties. In addition, by incorporating drugs in cyclodextrines, in self-emulsifying drug delivery systems (SEDDS) or liposomes a protective effect towards an intestinal enzymatic attack can be achieved. Being aware of the important role of this pre-systemic metabolism by integrating it in the BCS as third dimension and keeping strategies to overcome this enzymatic barrier in mind, the therapeutic efficacy of many orally given drugs can certainly be substantially improved. PMID:25128718

  18. To be a midwife: overcoming the obstacles in Canada (part 2).

    Science.gov (United States)

    Jordan, Nané

    2015-09-01

    This two-part article introduces my working background in grassroots Canadian midwifery, and my subsequent shift into 'thinking birth' through what I call the 'philosopher-midwife' I broach the idea that midwifery is a site of not only holistic birth care, but of woman-centred birth studies and enquiry. Part 1 conveyed a storied account of my working background in midwifery care, situated in the re-emergence of North American midwifery. I discussed how midwifery is a relational, woman-centred method of knowing and enquiry. I have come to understand midwifery as a metaphor for attending to the gift of life, a woman-centred way of healing, and an ongoing practice of overcoming oppositional circumstances. Part 2 introduces ideas on how birth, in concept and experience, has not been adequately addressed in social philosophy and understanding. I suggest this be remedied through attention to midwives' and women's birth experiences. In this attention, I muse on how the 'philosopher-midwife' may further guide new birth-based enquiries. PMID:26547998

  19. Overcoming the difficulties of inquiry-based teaching through the use of coaching

    Science.gov (United States)

    Kraus, Rudolf

    This research examines the use of coaching as a professional development approach to enhance the introduction of inquiry-based teaching methods. Previous professional development efforts are well documented in the science education literature, and implementation rates are generally low, despite a wide-spread belief that inquiry-based teaching methods are beneficial to student learning. Difficulties that are often found include a lack of time, tension from high-stakes testing, a lack of content knowledge, a lack of inquiry knowledge, a scarcity of inquiry resources, and a conflict between the teacher's learning style and the inherent style of inquiry. These barriers lead to slow, poorly understood progress in adopting inquiry methods, and a shortage of concrete suggestions on how best to proceed. To examine how teacher-coach pairs overcome these difficulties, a multiple-case study was planned that uncovered specific steps taken by creating a richly detailed narrative of how this science curriculum is implemented. This narrative was closely affiliated with a certain specific context of underperforming high schools in a major American city, but the results may generalize to other similar contexts as well. Additionally, the findings from these case studies may serve to validate other analogous findings from the literature.

  20. Sustainable fuel, food, fertilizer and ecosystems through a global artificial photosynthetic system: overcoming anticompetitive barriers.

    Science.gov (United States)

    Bruce, Alex; Faunce, Thomas

    2015-06-01

    This article discusses challenges that artificial photosynthetic (AP) systems will face when entering and competing in a global market characterized by established fossil fuel technology. It provides a perspective on the neoliberal principles underpinning much policy entrenching such environmentally destructive technology and outlines how competition law could aid overcoming these hurdles for AP development. In particular, it critiques the potential for competition law to promote a global AP initiative with greater emphasis on atmospheric carbon dioxide and nitrogen fixation (as well as solar-driven water splitting) to produce an equitable, globally distributed source of human food, fertilizer and biosphere sustainability, as well as hydrogen-based fuel. Some relevant strategies of competition law evaluated in this context include greater citizen-consumer involvement in shaping market values, legal requirements to factor services from the natural environment (i.e. provision of clean air, water, soil pollution degradation) into corporate costs, reform of corporate taxation and requirements to balance maximization of shareholder profit with contribution to a nominated public good, a global financial transactions tax, as well as prohibiting horizontal cartels, vertical agreements and unilateral misuse of market power. PMID:26052427

  1. Making Games Not Work: Paradoxes Embedded in Game-Based Training and Concepts for Overcoming Them

    Science.gov (United States)

    Jones, Phillip N.; Cuper, Taryn

    2010-01-01

    An interest in game-based training solutions is natural. All one has to do is watch someone fully engaged in a modern game to see the potential of harnessing that attention for training. However, the reality of game-based training has not fully satisfied these expectations. This paper explains two paradoxes that must be overcome for games to support training. These paradoxes are a result of the realities of the basic human condition clashing with the requirements of learning theory. 80th paradoxes arise from the concept of "engagement" that is central to games. The first comes from a more robust definition of engagement, which is the condition of Flow or Optimal Experience. Flow is the state game developers want to see in users. One aspect of Flow is loss of sense of self as the individual becomes immersed in the experience. The paradox arises because this loss of self directly contradicts the learning requirement of self-reflection. The second paradox comes from theories of play, which state in part that play requires a level of individual freedom. The contradiction arises when game-based play must be harnessed to an organizational training program or regimen. The paper will discuss these paradoxes in the context of an effort to design a game-based training modality to train combat medics and will close with a review of compensating strategies identified by the designers. The paper will provide information important to anyone interested in conceptualizing and designing game-based training.

  2. Energetic heavy ions overcome tumor radioresistance caused by overexpression of Bcl-2

    International Nuclear Information System (INIS)

    Background and purpose: Overexpression of Bcl-2 is frequent in human cancers and has been associated with radioresistance. Here we investigated the potential impact of heavy ions on Bcl-2 overexpressing tumors. Materials and methods: Bcl-2 cells (Bcl-2 overexpressing HeLa cells) and Neo cells (neomycin resistant gene-expressing HeLa cells) exposed to γ-rays or heavy ions were assessed for the clonogenic survival, apoptosis and cell cycle distribution. Results: Whereas Bcl-2 cells were more resistant to γ-rays (0.2 keV/μm) and helium ions (16.2 keV/μm) than Neo cells, heavy ions (76.3-1610 keV/μm) yielded similar survival regardless of Bcl-2 overexpression. Carbon ions (108 keV/μm) decreased the difference in the apoptotic incidence between Bcl-2 and Neo cells, and prolonged G2/M arrest that occurred more extensively in Bcl-2 cells than in Neo cells. Conclusions: High-LET heavy ions overcome tumor radioresistance caused by Bcl-2 overexpression, which may be explained at least in part by the enhanced apoptotic response and prolonged G2/M arrest. Thus, heavy-ion therapy may be a promising modality for Bcl-2 overexpressing radioresistant tumors

  3. Overcoming Codes and Standards Barriers to Innovations in Building Energy Efficiency

    Energy Technology Data Exchange (ETDEWEB)

    Cole, Pamala C.; Gilbride, Theresa L.

    2015-02-15

    In this journal article, the authors discuss approaches to overcoming building code barriers to energy-efficiency innovations in home construction. Building codes have been a highly motivational force for increasing the energy efficiency of new homes in the United States in recent years. But as quickly as the codes seem to be changing, new products are coming to the market at an even more rapid pace, sometimes offering approaches and construction techniques unthought of when the current code was first proposed, which might have been several years before its adoption by various jurisdictions. Due to this delay, the codes themselves can become barriers to innovations that might otherwise be helping to further increase the efficiency, comfort, health or durability of new homes. . The U.S. Department of Energy’s Building America, a program dedicated to improving the energy efficiency of America’s housing stock through research and education, is working with the U.S. housing industry through its research teams to help builders identify and remove code barriers to innovation in the home construction industry. The article addresses several approaches that builders use to achieve approval for innovative building techniques when code barriers appear to exist.

  4. A Novel Approach for Microencapsulation of Nanoemulsions to Overcome the Oxidation of Bioactives in Aqueous Phase

    Directory of Open Access Journals (Sweden)

    Haroon Jamshaid Qazi

    2015-02-01

    Full Text Available Microencapsulation is a promising technique to retain the physical attributes of nanoemulsions and to overcome the oxidation of bioactives that become more available to aqueous phase during emulsification. Purity Gum Ultra (PGU and Hi-CAP 100 (HiCap emulsified nanoemulsions of Clove Oil (CO co-encapsulated with Canola oil (CA and Medium Chain Triglyceride (MCT (5:5% v/v CO:CA and CO:MCT were prepared through high pressure homogenization. Microencapsulation of nanoemulsions was performed using Whey Protein Isolates (WPI under vacuum using freeze drying, which is considered as appropriate method for heat sensitive compounds. The reconstituted emulsions of microencapsulated powder had similar particle sizes as that of fresh nanoemulsions while uncoated showed a big increase (<400 nm. Oxidation of bioactives with and without CO, before and after freeze drying was investigated at different intervals during 60 days of storage at 4 and 25°C by Thiobarbituric Acid Reactive Substances (TBARS assay. Microencapsulated PGU-CO:CA showed minimum TBARS values compared to other emulsions. Gas chromatography analysis of microcapsules also showed higher retention of CO and lower content on the interphase for aqueous interaction. Conclusively, this study proposes a novel strategy using a freeze drying process to microencapsulate nanoemulsion.

  5. Overcoming power broadening of the quantum dot emission in a pure wurtzite nanowire

    Science.gov (United States)

    Reimer, M. E.; Bulgarini, G.; Fognini, A.; Heeres, R. W.; Witek, B. J.; Versteegh, M. A. M.; Rubino, A.; Braun, T.; Kamp, M.; Höfling, S.; Dalacu, D.; Lapointe, J.; Poole, P. J.; Zwiller, V.

    2016-05-01

    One of the key challenges in developing quantum networks is to generate single photons with high brightness, purity, and long temporal coherence. Semiconductor quantum dots potentially satisfy these requirements; however, due to imperfections in the surrounding material, the coherence generally degrades with increasing excitation power yielding a broader emission spectrum. Here we overcome this power-broadening regime and demonstrate an enhanced coherence at exciton saturation where the detected count rates are highest. We detect single-photon count rates of 460 000 counts per second under pulsed laser excitation while maintaining a single-photon purity greater than 99%. Importantly, the enhanced coherence is attained with quantum dots in ultraclean wurtzite InP nanowires, where the surrounding charge traps are filled by exciting above the wurtzite InP nanowire band gap. By raising the excitation intensity, the number of possible charge configurations in the quantum dot environment is reduced, resulting in a narrower emission spectrum. Via Monte Carlo simulations we explain the observed narrowing of the emission spectrum with increasing power. Cooling down the sample to 300 mK, we further enhance the single-photon coherence twofold as compared to operation at 4.5 K, resulting in a homogeneous coherence time, T2, of 1.2 ns, and two-photon interference visibility as high as 83% under strong temporal postselection (˜5 % without temporal postselection).

  6. The Production of Turkish Relative Clauses in Second Language Acquisition: Overcoming Student Difficulties

    Directory of Open Access Journals (Sweden)

    Anjel Toczu

    2010-01-01

    Full Text Available This study focuses on teaching relative clauses (R.Cs in Turkish, a left-branching language, and discusses the relative difficulty of producing RCs in Turkish by English-speaking learners by investigating whether the production of subject relative clauses in Turkish is easier than that of the object relative clauses. It also offers suggestions as to how to help learners overcome these difficulties. Turkish and English belong to two different language families, Altaic and Inda-European respectively. This study lends further insight that Turkish does not have RCs similar to those found in Inda-European languages. Instead, in Turkish RCs comprise nominalized verbs and participles. The characteristics of Turkish are also explained such as its word order, agglutinating morphology, vowel and consonant harmony rules as well as case markers indicating grammatical relations between sentence constituents, which shed light to our understanding of RCs in Turkish. Data was collected through written and oral tasks from students enrolled in a military intensive Turkish language training program in the United States. Moreover, their performance was studied through classroom observations and one-on-one speaking activities.

  7. Identifying the determinants of premature mortality in Russia: overcoming a methodological challenge

    Directory of Open Access Journals (Sweden)

    Leon David A

    2007-11-01

    Full Text Available Abstract Background It is thought that excessive alcohol consumption is related to the high mortality among working age men in Russia. Moreover it has been suggested that alcohol is a key proximate driver of the very sharp fluctuations in mortality seen in this group since the mid-1980s. Designing an individual-level study suitable to address the potential acute effects of alcohol consumption on mortality in Russia has posed a challenge to epidemiologists, especially because of the need to identify factors that could underlie the rapid changes up and down in mortality rates that have been such a distinctive feature of the Russian mortality crisis. In order to address this study question which focuses on exposures acting shortly before sudden death, a cohort would be unfeasibly large and would suffer from recruitment bias. Methods Although the situation in Russia is unusual, with a very high death rate characterised by many sudden and apparently unexpected deaths in young men, the methodological problem is common to research on any cause of death where many deaths are sudden. Results We describe the development of an innovative approach that has overcome some of these challenges: a case-control study employing proxy informants and external data sources to collect information about proximate determinants of mortality. Conclusion This offers a set of principles that can be adopted by epidemiologists studying sudden and unexpected deaths in other settings.

  8. 2012 in review - part II: overcoming the obstacles in the pharma/biotech industry.

    Science.gov (United States)

    Rabasseda, X; Dulsat, C; Navarro, D; Cruces, E; Graul, A I; Jago, C; Tracy, M

    2013-02-01

    As highlighted in the first part of this review published last month, the year 2012 saw the approval of a remarkable number of new drugs, and among the new drugs reaching the market, a significant proportion were orphan drugs developed for treating less prevalent diseases. These drugs are certainly not expected to become blockbusters, but are of high interest because of their efficacy in a narrow spectrum of patients. This trend aligns with the general tendency of staying away from fit-for-all blockbusters into personalized medicine as one of the strategies for overcoming the patent cliff that resulted in a long list of drugs going off patent and being approved as generics also during last year. The emerging scenario resulting from new developments in the form of new drugs and biosimilars and newly available generic medications paralleled by strategic movements within the pharmaceutical industry to reinforce their position in the market, as reflected by merger and acquisition deals accompanied by significant efforts into prioritization resulting in spin-off and split transactions, is reviewed in this second part. This paper includes a significant amount of data in tables for quick review and to profile the new strategic movements in drug pipelines. Further information, including details on mechanisms of action, current status, itemized pharmacology, pharmacokinetic and clinical trial research findings and updated information can be found in the proprietary databases Thomson Reuters Integrity(SM) and Thomson Reuters Cortellis™. PMID:23462626

  9. Overcoming obstacles in risk factor management in type 2 diabetes mellitus.

    Science.gov (United States)

    Handelsman, Yehuda; Jellinger, Paul S

    2011-08-01

    Type 2 diabetes mellitus (T2DM) is characterized by progressively worsening hyperglycemia that leads to microvascular and macrovascular complications. Optimal management of T2DM aims to simultaneously control hyperglycemia, hypertension, and dyslipidemia to reduce the overall risk. However, a large proportion of patients in clinical practice do not reach treatment targets. Some of the obstacles to achieving treatment targets include high medication costs, costs associated with health insurance, poor patient adherence to medication, patient fear of potential adverse effects, improper patient education, and failure by health care providers to appropriately initiate or intensify therapy (clinical inertia). Possible causes of clinical inertia include the influence exerted on physicians by reluctant patients and the influence of media-driven attention and the negative spin of clinical trial results on physicians' prescribing behavior and on patients' attitudes towards treatment. This negative publicity can be disproportionate to the overall body of scientific evidence and may, therefore, prove to be unfounded in the long-term. There is clear evidence of the benefits of the effective management of T2DM to achieve goals. Overcoming the obstacles to achieving treatment targets may include use of strategies such as early intensive treatment and combination therapy with drugs with complementary mechanisms of action. PMID:21806772

  10. Doxorubicin loaded Polymeric Nanoparticulate Delivery System to overcome drug resistance in osteosarcoma

    Directory of Open Access Journals (Sweden)

    Ryu Keinosuke

    2009-11-01

    Full Text Available Abstract Background Drug resistance is a primary hindrance for the efficiency of chemotherapy against osteosarcoma. Although chemotherapy has improved the prognosis of osteosarcoma patients dramatically after introduction of neo-adjuvant therapy in the early 1980's, the outcome has since reached plateau at approximately 70% for 5 year survival. The remaining 30% of the patients eventually develop resistance to multiple types of chemotherapy. In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR tumor cells, we explored the possibility of loading doxorubicin onto biocompatible, lipid-modified dextran-based polymeric nanoparticles and evaluated the efficacy. Methods Doxorubicin was loaded onto a lipid-modified dextran based polymeric nano-system. The effect of various concentrations of doxorubicin alone or nanoparticle loaded doxorubicin on KHOS, KHOSR2, U-2OS, and U-2OSR2 cells was analyzed. Effects on drug retention, immunofluorescence, Pgp expression, and induction of apoptosis were also analyzed. Results Dextran nanoparticles loaded with doxorubicin had a curative effect on multidrug resistant osteosarcoma cell lines by increasing the amount of drug accumulation in the nucleus via Pgp independent pathway. Nanoparticles loaded with doxorubicin also showed increased apoptosis in osteosarcoma cells as compared with doxorubicin alone. Conclusion Lipid-modified dextran nanoparticles loaded with doxorubicin showed pronounced anti-proliferative effects against osteosarcoma cell lines. These findings may lead to new treatment options for MDR osteosarcoma.

  11. Doxorubicin loaded Polymeric Nanoparticulate Delivery System to overcome drug resistance in osteosarcoma

    International Nuclear Information System (INIS)

    Drug resistance is a primary hindrance for the efficiency of chemotherapy against osteosarcoma. Although chemotherapy has improved the prognosis of osteosarcoma patients dramatically after introduction of neo-adjuvant therapy in the early 1980's, the outcome has since reached plateau at approximately 70% for 5 year survival. The remaining 30% of the patients eventually develop resistance to multiple types of chemotherapy. In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) tumor cells, we explored the possibility of loading doxorubicin onto biocompatible, lipid-modified dextran-based polymeric nanoparticles and evaluated the efficacy. Doxorubicin was loaded onto a lipid-modified dextran based polymeric nano-system. The effect of various concentrations of doxorubicin alone or nanoparticle loaded doxorubicin on KHOS, KHOSR2, U-2OS, and U-2OSR2 cells was analyzed. Effects on drug retention, immunofluorescence, Pgp expression, and induction of apoptosis were also analyzed. Dextran nanoparticles loaded with doxorubicin had a curative effect on multidrug resistant osteosarcoma cell lines by increasing the amount of drug accumulation in the nucleus via Pgp independent pathway. Nanoparticles loaded with doxorubicin also showed increased apoptosis in osteosarcoma cells as compared with doxorubicin alone. Lipid-modified dextran nanoparticles loaded with doxorubicin showed pronounced anti-proliferative effects against osteosarcoma cell lines. These findings may lead to new treatment options for MDR osteosarcoma

  12. Nano-carrier systems: Strategies to overcome the mucus gel barrier.

    Science.gov (United States)

    Dünnhaupt, S; Kammona, O; Waldner, C; Kiparissides, C; Bernkop-Schnürch, A

    2015-10-01

    The present review provides an overview of nanotechnology-based strategies to overcome various mucus gel barriers including the intestinal, nasal, ocular, vaginal, buccal and pulmonary mucus layer without destroying them. It focuses on the one hand on strategies to improve the mucus permeation behavior of particles and on the other hand on systems avoiding the back-diffusion of particles out of the mucus gel layer. Nanocarriers with improved mucus permeation behavior either exhibit a high density of positive and negative charges, bearing mucolytic enzymes such as papain and bromelain on their surface or display a slippery surface due to PEG-ylation. Furthermore, self-nanoemulsifying-drug-delivery-systems (SNEDDS) turned out to exhibit comparatively high mucus permeating properties. Strategies in order to avoid back-diffusion are based on thiolated polymers reacting to a higher extent with cysteine subunits of the mucus at pH 7 in deeper mucus regions than at pH 5 being prevalent in luminal mucus regions of the intestinal and vaginal mucosa. Furthermore, particles changing their zeta potential from negative to positive once they have reached the epithelium seem to be promising carriers. The summarized knowledge should provide a good starting point for further developments in this field. PMID:25712487

  13. Overcoming challenges to initiating cell therapy clinical trials in rapidly developing countries: India as a model.

    Science.gov (United States)

    Viswanathan, Sowmya; Rao, Mahendra; Keating, Armand; Srivastava, Alok

    2013-08-01

    Increasingly, a number of rapidly developing countries, including India, China, Brazil, and others, are becoming global hot spots for the development of regenerative medicine applications, including stem cell-based therapies. Identifying and overcoming regulatory and translational research challenges and promoting scientific and ethical clinical trials with cells will help curb the growth of stem cell tourism for unproven therapies. It will also enable academic investigators, local regulators, and national and international biotechnology and biopharmaceutical companies to accelerate stem cell-based clinical research that could lead to effective innovative treatments in these regions. Using India as a model system and obtaining input from regulators, clinicians, academics, and industry representatives across the stem cell field in India, we reviewed the role of key agencies and processes involved in this field. We have identified areas that need attention and here provide solutions from other established and functioning models in the world to streamline and unify the regulatory and ethics approval processes for cell-based therapies. We also make recommendations to check the growth and functioning of clinics offering unproven treatments. Addressing these issues will remove considerable hurdles to both local and international investigators, accelerate the pace of research and development, and create a quality environment for reliable products to emerge. By doing so, these countries would have taken one important step to move to the forefront of stem cell-based therapeutics. PMID:23836804

  14. Lung gene therapy with highly compacted DNA nanoparticles that overcome the mucus barrier.

    Science.gov (United States)

    Suk, Jung Soo; Kim, Anthony J; Trehan, Kanika; Schneider, Craig S; Cebotaru, Liudmila; Woodward, Owen M; Boylan, Nicholas J; Boyle, Michael P; Lai, Samuel K; Guggino, William B; Hanes, Justin

    2014-03-28

    Inhaled gene carriers must penetrate the highly viscoelastic and adhesive mucus barrier in the airway in order to overcome rapid mucociliary clearance and reach the underlying epithelium; however, even the most widely used viral gene carriers are unable to efficiently do so. We developed two polymeric gene carriers that compact plasmid DNA into small and highly stable nanoparticles with dense polyethylene glycol (PEG) surface coatings. These highly compacted, densely PEG-coated DNA nanoparticles rapidly penetrate human cystic fibrosis (CF) mucus ex vivo and mouse airway mucus ex situ. Intranasal administration of the mucus penetrating DNA nanoparticles greatly enhanced particle distribution, retention and gene transfer in the mouse lung airways compared to conventional gene carriers. Successful delivery of a full-length plasmid encoding the cystic fibrosis transmembrane conductance regulator protein was achieved in the mouse lungs and airway cells, including a primary culture of mucus-covered human airway epithelium grown at air-liquid interface, without causing acute inflammation or toxicity. Highly compacted mucus penetrating DNA nanoparticles hold promise for lung gene therapy. PMID:24440664

  15. Multimodal biometrics approach using face and ear recognition to overcome adverse effects of pose changes

    Science.gov (United States)

    Wang, Yu; He, Dejian; Yu, Chongchong; Jiang, Tongqiang; Liu, Zaiwen

    2012-10-01

    A personal identification method is proposed which uses face and ear together to overcome mass information loss resulting from pose changes. Several aspects are mainly considered: First, ears are at both sides of the face. Their physiological position is approximately orthogonal and their information is complementary to each other when the head pose changes. Therefore, fusing the face and ear is reasonable. Second, the texture feature is extracted using a uniform local binary pattern (ULBP) descriptor which is more compact. Third, Haar wavelet transform, blocked-based, and multiscale ideas are taken into account to further strengthen the extracted texture information. Finally, texture features of face and ear are fused using serial strategy, parallel strategy, and kernel canonical correlation analysis to further increase the recognition rate. Experimental results show that it is both fast and robust to use ULBP to extract texture features. Haar wavelet transform, block-based, and multiscale methods can effectively enhance texture information of the face or ear ULBP descriptor. Multimodal biometrics fusion about face and ear is feasible and effective. The recognition rates of the proposed approach outperform remarkably those of the classic principal component analysis (PCA), kernel PCA, or Gabor texture feature extraction method especially when sharp pose change happens.

  16. Barriers to the Uptake of Human-based Test Methods, and How to Overcome Them.

    Science.gov (United States)

    Archibald, Kathy; Drake, Tamara; Coleman, Robert

    2015-11-01

    Although there is growing concern as to the questionable value of animal-based methods for determining the safety and efficacy of new medicines, which has in turn led to many groups developing innovative human-based methods, there are many barriers to their adoption for regulatory submissions. The reasons for this are various, and include a lack of confidence that the available human-based methods, be they in vivo, in silico or in vitro, can be sufficiently predictive of clinical outcomes. However, this is not the only problem: the issue of validation presents a serious impediment to progress, a particularly frustrating situation, in view of the fact that the existing animal-based methods have never themselves been formally validated. Superimposed upon this is the issue of regulatory requirements, where, although regulators may be willing to accept non-animal approaches in place of particular animal tests, nowhere is this explicitly stated in their guidelines. Such problems are far from trivial, and represent major hurdles to be overcome. In addition, there are a range of other barriers, real or self-imposed, that are hindering a more-predictive approach to establishing a new drug's clinical safety and efficacy profiles. Some of these barriers are identified, and ways forward are suggested. PMID:26551287

  17. Widowhood, solitude and sexuality in old age: confronting and overcoming mechanisms

    Directory of Open Access Journals (Sweden)

    Verónica Montes de Oca Zavala

    2012-06-01

    Full Text Available Widowhood is usually associated to negative aspects of life mainly when the people involved are in old age. However, depending on the moment this phase of life is faced, it is possible to activate certain mechanisms allowing confrontation and reorganization of life. This article presents, from an exploratory, qualitative and analytical perspective, three case studies in the state of Mexico showing how widowhood is seen, whatit means in old age, its social and economic impacts, as well as its discourses and antidiscoursesgenerated from the subjects analyzed so as to overcome solitude, isolation, the need for afection and love that go beyond what family and children provide for. Sexuality is seen from a critical perspective and it is an element that stands out both in the narrative of such three cases and when compared to the traditional view that analyses widowhood and old age. This article is composed of a bibliographic review, objectives, methodology and a section of final results and reflections.

  18. ANALYSIS OF THE FORCE DURING OVERCOMING THE ROADBLOCK – THE PRELIMINARY EXPERIMENTAL TESTS

    Directory of Open Access Journals (Sweden)

    Jakub POLASIK

    2016-03-01

    Full Text Available The paper applies to the issue of preservation of passenger vehicles during overcoming the roadblocks on a dry asphalt surface with the constant speed. The study aimed to estimate the forces which are affecting the suspension of the vehicle during the contact between a tyre and roadblock. Using the video recording it is possible to calculate the values of the tyre deflection and forces acting in the system. The obtained deflections of the tyres were compared to earlier laboratory test results and load-deflection characteristics of the tyres with the same size. The roadblock with the defined geometry causes a dynamic deflection of the tyre. During the study a significant change in the geometry of the suspension has not occurred. The paper presents the characteristics of the vehicles research with a particular regard to model and type of tyres. The determination of the exact dimensions of the roadblocks and application of the ADIS 16385 system for acquisition and archiving the features of the kinematic motion of the vehicle allowed to determine the speed at the moment of collision with the roadblock.

  19. Topological robustness analysis of protein interaction networks reveals key targets for overcoming chemotherapy resistance in glioma

    Science.gov (United States)

    Azevedo, Hátylas; Moreira-Filho, Carlos Alberto

    2015-11-01

    Biological networks display high robustness against random failures but are vulnerable to targeted attacks on central nodes. Thus, network topology analysis represents a powerful tool for investigating network susceptibility against targeted node removal. Here, we built protein interaction networks associated with chemoresistance to temozolomide, an alkylating agent used in glioma therapy, and analyzed their modular structure and robustness against intentional attack. These networks showed functional modules related to DNA repair, immunity, apoptosis, cell stress, proliferation and migration. Subsequently, network vulnerability was assessed by means of centrality-based attacks based on the removal of node fractions in descending orders of degree, betweenness, or the product of degree and betweenness. This analysis revealed that removing nodes with high degree and high betweenness was more effective in altering networks’ robustness parameters, suggesting that their corresponding proteins may be particularly relevant to target temozolomide resistance. In silico data was used for validation and confirmed that central nodes are more relevant for altering proliferation rates in temozolomide-resistant glioma cell lines and for predicting survival in glioma patients. Altogether, these results demonstrate how the analysis of network vulnerability to topological attack facilitates target prioritization for overcoming cancer chemoresistance.

  20. Strategies for Overcoming Barriers to Improving Safety in Small Construction Organisations

    Directory of Open Access Journals (Sweden)

    Sunindijo R.Y.

    2015-12-01

    Full Text Available The majority of organisations in the construction industry are small organisations, how ever their safety performance is still far behind their larger counterparts. Therefore, it is important to focus on improving safety performance of small organisations so that the overall industry performance may be improved. Using a questionnaire survey, this research collected data from construction organisations based in New South Wales, Australia. Data analysis results have identified key barriers faced by small organisations when implementing safety. These barriers include the use of lowest bid price to evaluate tender submissions, lack of safety commitment from construction clients, and fierce competition. The analysis results have also revealed potential strategies for overcoming the barriers, such as including safety as an indicator in tender evaluation, more effective safety regulation enforcement by inspection and linking safety performance with insurance premium and licencing system, and subsidising safety training for small organisations. Improving safety performance in this sector cannot be done in isolation. The government, clients, and large organisations have important roles to play to change the norms and culture in the industry so that small organisations are supported in their effort to improve their safety performance.

  1. Overcoming low yields of plant-made antibodies by a protein engineering approach.

    Science.gov (United States)

    Zischewski, Julia; Sack, Markus; Fischer, Rainer

    2016-01-01

    The commercial development of plant-based antibody production platforms is often limited by low and variable yields, but little is known about the factors that affect antibody accumulation during and after translation. Here, we present a strategy to identify yield-limiting regions in the transcript and protein. We exchanged variable heavy chain (VH) domain sequences between two human antibodies at structurally conserved positions, thus creating ten chimeric VH domains containing sequences from M12 (∼1000 μg/g leaf fresh weight [FW]) and 4E10 (∼100 μg/g FW). After transient expression in Nicotiana benthamiana leaves, we measured mRNA and protein levels by quantitative real-time PCR and surface plasmon resonance spectroscopy, respectively. Transcript levels were similar for all constructs, but antibody levels ranged from ∼250 μg/g to over 2000 μg/g FW. Analysis of the expression levels showed that: i) 4E10 yields were only marginally increased by suppression of post-transcriptional gene silencing; ii) the CDR3 of 4E10 contains a protease site; and iii) a bipartite, yield-limiting region exists in the CDR2/CDR3. Our findings highlight the strong impact of cotranslational and posttranslational events on antibody yields and show that protein engineering is a powerful tool that can be used to overcome the remaining limitations affecting antibody production in plants. PMID:26632507

  2. Overcoming technophobia in poorly-educated elderly – the HELPS-seniors service learning program

    Directory of Open Access Journals (Sweden)

    Chwen-Chi Wang

    2015-09-01

    Full Text Available Aging populations, increased incidence of chronic disease, technological advances, health-care consumerism, and rapidly escalating health care costs are driving health care into the home. Advances in the miniaturization and portability of diagnostic technologies, information technologies, remote monitoring, and long-distance care have increased the viability of home-based care. The ability of older adults to use e-health tools is a critical issue, because such tools could effectively enhance medical care for this population. However, fear of technology is more prevalent among older generations who did not grow up with computers, complicated acronyms or digital games. This paper introduces the Health Education Learning Program with Science for seniors (HELPS-seniors program, which encourages subjects to use new self-management tools for technophobic elderly people. We then explain how to integrate HELPS-senior into a health professional service learning program, and how to train students to become empathetic and smart health promoters. The present findings support the development of service-learning projects within medical education to overcome the technophobia among the elderly.

  3. Strategies used by nurses, academics and students to overcome intercultural communication challenges.

    Science.gov (United States)

    Henderson, Saras; Barker, Michelle; Mak, Anita

    2016-01-01

    Nurse clinicians and academics need to understand intercultural communication challenges to improve their communication skills and better support students' learning. Gaps exist in the literature regarding intercultural communication resources for students, academics and clinicians. The aim of this study was to explore the experiences of clinical nurses, nurse academics, and student nurses regarding intercultural communication challenges. Data were collected using focus group interviews with nineteen clinical facilitators (nurses who supervise nursing students in clinical practice), five clinical nurses, and ten nursing students. Seven nurse academics were interviewed via telephone. The purposive sample was drawn from a tertiary hospital and a university in Australia. Participants were invited to discuss challenging intercultural scenarios they had experienced including strategies they used to overcome such challenges. Using qualitative content analysis data were analysed resulting in four categories which were: 1) prejudice based on cultural diversity; 2) unfamiliarity with cultural boundaries; 3) stereotyping cultural behaviours; and 4) difficulty understanding English. Strategies participants used to mitigate challenges included resorting to cultural validation through alliance building, proactively seeking clarification, and acquiring cultural awareness knowledge. This study highlights intercultural challenges students, clinicians and academics face and signpost the way forward with useful strategies to better inform nurse education. PMID:26365507

  4. Operational intervention levels (OILs): a tool to overcome differences in intervention levels?

    International Nuclear Information System (INIS)

    The intervention levels for evacuation, sheltering and iodine blockade still differ in many countries, although international organisation like IAEA, NEA or ICRP aspire to harmonise them on an international level. Even if the dose values of the limits are in agreement, they are not necessarily comparable because the type of dose (projected dose, averted dose), the respected exposure pathways (external dose, inhalation, ingestion) or the integration time might differ significantly. The question is raised, how can harmonisation being achieved? International organisations recommend 'operational intervention levels' (OILs) for promptly assessing the results of environmental monitoring and to decide on protective actions. OILs are measurable values derived from dose limits. Best examples are the derived intervention levels for food and feed in the codex alimentarius or by the EC, which limit the ingestion dose to about 5 mSv/a. This paper discusses the properties and potential use of OILs, identifies and derives useful OILs and addresses their benefit in practise both for early and later countermeasures. Furthermore it is discussed whether OILs might be a useful tool to overcome national differences in intervention levels because an OIL value covers a relative wide range of the projected dose due to the uncertainty of the parameters needed for derivation. (author)

  5. Parametrically excited MEMS vibration energy harvesters with design approaches to overcome the initiation threshold amplitude

    International Nuclear Information System (INIS)

    Resonant-based vibration harvesters have conventionally relied upon accessing the fundamental mode of directly excited resonance to maximize the conversion efficiency of mechanical-to-electrical power transduction. This paper explores the use of parametric resonance, which unlike the former, the resonant-induced amplitude growth, is not limited by linear damping and wherein can potentially offer higher and broader nonlinear peaks. A numerical model has been constructed to demonstrate the potential improvements over the convention. Despite the promising potential, a damping-dependent initiation threshold amplitude has to be attained prior to accessing this alternative resonant phenomenon. Design approaches have been explored to passively reduce this initiation threshold. Furthermore, three representative MEMS designs were fabricated with both 25 and 10 μm thick device silicon. The devices include electrostatic cantilever-based harvesters, with and without the additional design modification to overcome initiation threshold amplitude. The optimum performance was recorded for the 25 μm thick threshold-aided MEMS prototype with device volume ∼0.147 mm3. When driven at 4.2 ms−2, this prototype demonstrated a peak power output of 10.7 nW at the fundamental mode of resonance and 156 nW at the principal parametric resonance, as well as a 23-fold decrease in initiation threshold over the purely parametric prototype. An approximate doubling of the half-power bandwidth was also observed for the parametrically excited scenario. (paper)

  6. Future Regulatory Science through a Global Product Development Strategy to Overcome the Device Lag.

    Science.gov (United States)

    Tsuchii, Isao

    2016-01-01

    Environment that created "medical device lag (MDL)" has changed dramatically, and currently that term is not heard often. This was mainly achieved through the leadership of three groups: government, which determined to overcome MDL and took steps to do so; medical societies, which exhibited accountability in trial participation; and MD companies, which underwent a change in mindset that allowed comprehensive tripartite cooperation to reach the current stage. In particular, the global product development strategy (GPDS) of companies in a changing social environment has taken a new-turn with international harmonization trends, like Global Harmonization Task Force and International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. As a result, this evolution has created opportunities for treatment with cutting-edge MDs in Japanese society. Simultaneously, it has had a major impact on the planning process of GPDS of companies. At the same time, the interest of global companies has shifted to emerging economies for future potential profit since Japan no longer faces MDL issue. This economic trend makes MDLs a greater problem for manufacturers. From the regulatory science viewpoint, this new environment has not made it easy to plan a global strategy that will be adaptable to local societies. Without taking hasty action, flexible thinking from the global point of view is necessary to enable the adjustment of local strategies to fit the situation on the ground so that the innovative Japanese medical technology can be exported to a broad range of societies. PMID:27040334

  7. Overcoming Insulin Insufficiency by Forced Follistatin Expression in β-cells of db/db Mice.

    Science.gov (United States)

    Zhao, Chunxia; Qiao, Chunping; Tang, Ru-Hang; Jiang, Jiangang; Li, Jianbin; Martin, Carrie Bette; Bulaklak, Karen; Li, Juan; Wang, Dao Wen; Xiao, Xiao

    2015-05-01

    Diabetes poses a substantial burden to society as it can lead to serious complications and premature death. The number of cases continues to increase worldwide. Two major causes of diabetes are insulin resistance and insulin insufficiency. Currently, there are few antidiabetic drugs available that can preserve or protect β-cell function to overcome insulin insufficiency in diabetes. We describe a therapeutic strategy to preserve β-cell function by overexpression of follistatin (FST) using an AAV vector (AAV8-Ins-FST) in diabetic mouse model. Overexpression of FST in the pancreas of db/db mouse increased β-cell islet mass, decreased fasting glucose level, alleviated diabetic symptoms, and essentially doubled lifespan of the treated mice. The observed islet enlargement was attributed to β-cell proliferation as a result of bioneutralization of myostatin and activin by FST. Overall, our study indicates overexpression of FST in the diabetic pancreas preserves β-cell function by promoting β-cell proliferation, opening up a new therapeutic avenue for the treatment of diabetes. PMID:25676679

  8. Operational Intervention Levels (OILs) - A tool to overcome differences in intervention levels?

    International Nuclear Information System (INIS)

    The intervention levels for evacuation, sheltering and iodine blockade still differ in many countries, although international organisation like IAEA, NEA or ICRP aspire to harmonise them on an international level. Even if the dose values of the limits are in agreement, they are not necessarily comparable because the type of dose (projected dose, averted dose), the respected exposure pathways (external dose, inhalation, ingestion) or the integration time might differ significantly. The question is raised, how can harmonisation being achieved? International organisations recommend 'operational intervention levels' (OILs) for promptly assessing the results of environmental monitoring and to decide on protective actions. OILs are measurable values derived from dose limits. Best examples are the derived intervention levels for food and feed in the codex alimentarius or by the EC, which limit the ingestion dose to about 5 mSv/a. This paper discusses the properties and potential use of OILs, identifies and derives useful OILs and addresses their benefit in practise both for early and later countermeasures. Furthermore it is discussed whether OILs might be a useful tool to overcome national differences in intervention levels because an OIL value covers a relative wide range of the projected dose due to the uncertainty of the parameters needed for derivation. (author)

  9. Creating sustainable local health information exchanges: can barriers to stakeholder participation be overcome?

    Science.gov (United States)

    Grossman, Joy M; Kushner, Kathryn L; November, Elizabeth A

    2008-02-01

    Local health information exchanges (HIEs) hold the promise of collecting patient clinical data across sites of care to provide more complete and timely information for treatment, as well as supporting quality improvement and reporting, public health activities, and clinical research. Findings from a study of stakeholder perspectives on participation in four HIEs by the Center for Studying Health System Change (HSC) and the National Institute for Health Care Management (NIHCM) Foundation suggest, however, that barriers to achieving data exchange remain high. Concerns about loss of competitive advantage and data misuse impede provider and health plan willingness to contribute patient data. Additionally, uncertainty about who benefits from HIEs is affecting stakeholder willingness to fund the exchanges. The more mature exchanges--Cincinnati-based HealthBridge and the Indiana Health Information Exchange (IHIE)--have achieved some viability by meeting a specific business need--more efficient delivery of hospital test results to physicians. The newer exchanges--CareSpark, serving northeast Tennessee and southwest Virginia, and the Tampa Bay Regional Health Information Organization (RHIO)--have struggled to identify and finance initial services without a similar critical mass of hospital participation. While narrow data exchange efforts that improve transaction efficiency may be a pragmatic first step to overcome barriers to stakeholder participation, expanding HIEs to achieve the broad-based data exchange necessary for quality reporting and pay-for-performance (P4P) activities raises more challenges. PMID:18496926

  10. A technique of enhanced sensitivity and overcome radioactive contamination in thermal ionization mass spectrometry

    International Nuclear Information System (INIS)

    In order to overcome the radioactive contamination and enhance the sensitivity of thermal ionization mass spectrometry, some quantities of uranium of plutonium are electroplated on the single rhenium filament, then a thin layer of platinum is overlaid on the filament. The sample atoms thermally diffuse through a platinum layer before they can evaporate as neutral atoms or as ions. Since thermal diffusion is generally a much slower process than direct evaporation and a platinum layer limits the prompt escape of neutral atoms, the filament can be operated at higher temperature, yielding higher ionization efficiency without rapid loss of the sample. The samples of uranium and plutonium are prepared for electrode position by adding 1.0 mol·L-1 HCl to dilute the uranium and plutonium concentrations to 0.1 g/L and 0.01 g/L, respectively. Three kinds of sample plating solutions are the mixtures of the ammonium chloride and chlorhydric acid; the ammonium chloride, chlorhydric acid and oxalic acid; the nitric acid, ammonia and oxalic acid, respectively. Two kinds of platinum solutions in the electrolyte are the chloroplatinic acid, chlorhydric acid and oxalic acid; the platinic sodium hydroxide, sodium hydroxide and oxalic acid, respectively. The ion currents observed for the 100 ng uranium or 50 ng plutonium are 2 x 10-14 A during 40∼60 min

  11. Mechanical insights into ribosomal progression overcoming RNA G-quadruplex from periodical translation suppression in cells

    Science.gov (United States)

    Endoh, Tamaki; Sugimoto, Naoki

    2016-03-01

    G-quadruplexes formed on DNA and RNA can be roadblocks to movement of polymerases and ribosome on template nucleotides. Although folding and unfolding processes of the G-quadruplexes are deliberately studied in vitro, how the mechanical and physical properties of the G-quadruplexes affect intracellular biological systems is still unclear. In this study, mRNAs with G-quadruplex forming sequences located either in the 5‧ untranslated region (UTR) or in the open reading frame (ORF) were constructed to evaluate positional effects of the G-quadruplex on translation suppression in cells. Periodic fluctuation of translation suppression was observed at every three nucleotides within the ORF but not within the 5‧ UTR. The results suggested that difference in motion of ribosome at the 5‧ UTR and the ORF determined the ability of the G-quadruplex structure to act as a roadblock to translation in cells and provided mechanical insights into ribosomal progression to overcome the roadblock.

  12. Sustainable fuel, food, fertilizer and ecosystems through a global artificial photosynthetic system: overcoming anticompetitive barriers

    Science.gov (United States)

    Bruce, Alex; Faunce, Thomas

    2015-01-01

    This article discusses challenges that artificial photosynthetic (AP) systems will face when entering and competing in a global market characterized by established fossil fuel technology. It provides a perspective on the neoliberal principles underpinning much policy entrenching such environmentally destructive technology and outlines how competition law could aid overcoming these hurdles for AP development. In particular, it critiques the potential for competition law to promote a global AP initiative with greater emphasis on atmospheric carbon dioxide and nitrogen fixation (as well as solar-driven water splitting) to produce an equitable, globally distributed source of human food, fertilizer and biosphere sustainability, as well as hydrogen-based fuel. Some relevant strategies of competition law evaluated in this context include greater citizen–consumer involvement in shaping market values, legal requirements to factor services from the natural environment (i.e. provision of clean air, water, soil pollution degradation) into corporate costs, reform of corporate taxation and requirements to balance maximization of shareholder profit with contribution to a nominated public good, a global financial transactions tax, as well as prohibiting horizontal cartels, vertical agreements and unilateral misuse of market power. PMID:26052427

  13. Memory inhibition across the lifespan

    OpenAIRE

    Teale, Julia C.

    2015-01-01

    Age can affect memory performance. This statement is so often heard that it has become almost a truism. When research surrounding memory inhibition – the ability to ignore irrelevant material to aid in the retrieval of a target memory – is examined specifically, a more mixed picture of findings emerges. Whilst some previous work has found evidence of an age-related deficit, other research has rather found intact memory inhibition in older adults. Less often discussed, too, are the effects of ...

  14. Homo Economicus Belief Inhibits Trust

    OpenAIRE

    Ziqiang Xin; Guofang Liu

    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 t...

  15. Valpromide inhibits human epoxide hydrolase.

    OpenAIRE

    Pacifici, G. M.; Franchi, M; Bencini, C; Rane, A

    1986-01-01

    The effect of antipileptic drug valpromide (VPM) on the activity of epoxide hydrolase was studied in human adult and foetal liver, kidneys, lungs, intestine and in placenta. The activity of the epoxide hydrolase was measured with both styrene oxide and benzo(a)pyrene-4,5-oxide as substrates. VPM inhibited the epoxide hydrolase obtained from all organs studied. The degree of inhibition was independent of the substrate used. A lowering of the epoxide hydrolase activity by 50% was observed when ...

  16. 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

  17. PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma.

    Directory of Open Access Journals (Sweden)

    Georg Karpel-Massler

    Full Text Available 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.

  18. The fighter, the punk and the clown – how to overcome the position of victim of bullying?

    DEFF Research Database (Denmark)

    Viala, Eva Silberschmidt

    2015-01-01

    Despite extensive research on the causes of bullying and how it can be stopped, little is known about how or why some children overcome or transgress their position as victim of bullying. Based on analyses of three “extreme cases” in which peer victimization have been stopped or prevented, the...... paper attempts to describe how and why some children succeed in overcoming their position of victim of bullying. The analyses indicate that it is possible to exceed or avert the victim position, but the strategies applied are different and the issue of dignity emerges as important in the victims...

  19. Overcoming Hypoxic-Resistance of Tumor Cells to TRAIL-Induced Apoptosis through Melatonin

    Directory of Open Access Journals (Sweden)

    You-Jin Lee

    2014-07-01

    Full Text Available A solid tumor is often exposed to hypoxic or anoxic conditions; thus, tumor cell responses to hypoxia are important for tumor progression as well as tumor therapy. Our previous studies indicated that tumor cells are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL-induced cell apoptosis under hypoxic conditions. Melatonin inhibits cell proliferation in many cancer types and induces apoptosis in some particular cancer types. Here, we examined the effects of melatonin on hypoxic resistant cells against TRAIL-induced apoptosis and the possible mechanisms of melatonin in the hypoxic response. Melatonin treatment increased TRAIL-induced A549 cell death under hypoxic conditions, although hypoxia inhibited TRAIL-mediated cell apoptosis. In a mechanistic study, hypoxia inducible factor-1α and prolyl-hydroxylase 2 proteins, which increase following exposure to hypoxia, were dose-dependently down-regulated by melatonin treatment. Melatonin also blocked the hypoxic responses that reduced pro-apoptotic proteins and increased anti-apoptotic proteins including Bcl-2 and Bcl-xL. Furthermore, melatonin treatment reduced TRAIL resistance by regulating the mitochondrial transmembrane potential and Bax translocation. Our results first demonstrated that melatonin treatment induces apoptosis in TRAIL-resistant hypoxic tumor cells by diminishing the anti-apoptotic signals mediated by hypoxia and also suggest that melatonin could be a tumor therapeutic tool by combining with other apoptotic ligands including TRAIL, particularly in solid tumor cells exposed to hypoxia.

  20. Structures of HIV Protease Guide Inhibitor Design to Overcome Drug Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Weber, Irene T.; Kovalevsky, Andrey Y.; Harrison, Robert W. (GSU)

    2008-06-03

    The HIV/AIDS infection continues to be a major epidemic worldwide despite the initial promise of antiviral drugs. Current therapy includes a combination of drugs that inhibit two of the virally-encoded enzymes, the reverse transcriptase and the protease. The first generation of HIV protease inhibitors that have been in clinical use for treatment of AIDS since 1995 was developed with the aid of structural analysis of protease-inhibitor complexes. These drugs were successful in improving the life span of HIV-infected people. Subsequently, the rapid emergence of drug resistance has necessitated the design of new inhibitors that target mutant proteases. This second generation of antiviral protease inhibitors has been developed with the aid of data from medicinal chemistry, kinetics, and X-ray crystallographic analysis. Traditional computational methods such as molecular mechanics and dynamics can be supplemented with intelligent data mining approaches. One approach, based on similarities to the protease interactions with substrates, is to incorporate additional interactions with main chain atoms that cannot easily be eliminated by mutations. Our structural and inhibition data for darunavir have helped to understand its antiviral activity and effectiveness on drug resistant HIV and demonstrate the success of this approach.

  1. Overcoming resistance to innovation: Suggestions for encouraging change in language teaching

    Directory of Open Access Journals (Sweden)

    Albert Weideman

    2011-08-01

    Full Text Available As in many other countries, communicative language teaching (CLT became the orthodoxy in second language teaching in many sub-Saharan African education systems in the last two decades of the previous century. There is enough evidence, however, to indicate that it has not been adopted by a critical mass of language teachers in their day-to-day classroom practice, as distinct from their professed adherence to its main tenets. There may be many reasons for this resistance. Markee’s (1993 discussion of these indeed picks up a number of points that may be worth following up. This paper looks at three instructional tools that may assist teachers in overcoming resistance and adopting a communicative approach. The first is an instrument developed by Shaalukeni (2000 for use in her own work as an advisory teacher in northern Namibia. The paper discusses the employment of this instrument in her action research study into stimulating the use of pair work tasks in English second language classes. The second and third instruments help teachers to articulate their beliefs about language learning, as well as to examine whether these beliefs are in harmony with what we know about language learning, and aligned with what the teachers themselves profess. Such strategies are not sufficient to bring about change, but they may be the beginning of overcoming resistance to what is new.   Gedurende die laaste twee dekades van die twintigste eeu het kommunikatiewe taalonderrig, soos elders ook die geval is, tweedetaalonderrig in talle onderwyssisteme van Afrika-lande suid van die Sahara oorheers. Daar is egter meer as genoeg bewyse dat ’n kritieke massa onderwysers hierdie aanpak nog nie in hul daaglikse onderwyspraktyk geïmplimenteer het nie, alhoewel hierdie onderwysers tog te kenne gee dat hulle die aanpak oor die algemeen professioneel aanvaarbaar vind. Daar kan seker vele redes aangevoer word vir hierdie weerstand. Markee (1993 se uiteensetting van moontlike

  2. Overcoming potential energy distortions in constrained internal coordinate molecular dynamics simulations

    Science.gov (United States)

    Kandel, Saugat; Salomon-Ferrer, Romelia; Larsen, Adrien B.; Jain, Abhinandan; Vaidehi, Nagarajan

    2016-01-01

    The Internal Coordinate Molecular Dynamics (ICMD) method is an attractive molecular dynamics (MD) method for studying the dynamics of bonded systems such as proteins and polymers. It offers a simple venue for coarsening the dynamics model of a system at multiple hierarchical levels. For example, large scale protein dynamics can be studied using torsional dynamics, where large domains or helical structures can be treated as rigid bodies and the loops connecting them as flexible torsions. ICMD with such a dynamic model of the protein, combined with enhanced conformational sampling method such as temperature replica exchange, allows the sampling of large scale domain motion involving high energy barrier transitions. Once these large scale conformational transitions are sampled, all-torsion, or even all-atom, MD simulations can be carried out for the low energy conformations sampled via coarse grained ICMD to calculate the energetics of distinct conformations. Such hierarchical MD simulations can be carried out with standard all-atom forcefields without the need for compromising on the accuracy of the forces. Using constraints to treat bond lengths and bond angles as rigid can, however, distort the potential energy landscape of the system and reduce the number of dihedral transitions as well as conformational sampling. We present here a two-part solution to overcome such distortions of the potential energy landscape with ICMD models. To alleviate the intrinsic distortion that stems from the reduced phase space in torsional MD, we use the Fixman compensating potential. To additionally alleviate the extrinsic distortion that arises from the coupling between the dihedral angles and bond angles within a force field, we propose a hybrid ICMD method that allows the selective relaxing of bond angles. This hybrid ICMD method bridges the gap between all-atom MD and torsional MD. We demonstrate with examples that these methods together offer a solution to eliminate the potential

  3. Systemic administration of RANKL overcomes the bottleneck of oral vaccine delivery through microfold cells in ileum.

    Science.gov (United States)

    Maharjan, Sushila; Singh, Bijay; Jiang, Tao; Yoon, So-Yeon; Li, Hui-Shan; Kim, Girak; Gu, Min Jeong; Kim, Soo Ji; Park, Ok-Jin; Han, Seung Hyun; Kang, Sang-Kee; Yun, Cheol-Heui; Choi, Yun-Jaie; Cho, Chong-Su

    2016-04-01

    A successful delivery of antigen through oral route requires to overcome several barriers, such as enzymatic barrier of gastrointestinal tract and epithelial barrier that constitutes of microfold cells (M cells) for antigen uptake. Although each barrier represents a critical step in determining the final efficiency of antigen delivery, the transcytosis of antigen by M cells in the follicle-associated epithelium (FAE) to Peyer's patches appears to be a major bottleneck. Considering the systemic administration of receptor activator of nuclear factor (NF)-ĸB ligand (RANKL) induces differentiation of receptor activator of nuclear factor (NF)-ĸB (RANK)-expressing enterocytes into M cells, here, we illustrated a promising approach of antigen delivery using full length transmembrane RANKL (mRANKL). The results showed that the intraperitoneal injection of mRANKL increased the population of dendritic cells and macrophages in mesenteric lymph nodes and spleen. Subsequently, systemic administration of mRANKL resulted in significantly higher number of functional GP2(+) M cells leading higher transcytosis of fluorescent beads through them. To corroborate the effect of mRANKL in antigen delivery through M cells, we orally delivered microparticulate antigen to mice treated with mRANKL. Oral immunization induced strong protective IgA and systemic IgG antibody responses against orally delivered antigen in mRANKL-treated mice. The higher antibody responses are attributed to the higher transcytosis of antigens through M cells. Ultimately, the higher memory B cells and effector memory CD4 T cells after oral immunization in RANKL-treated mice confirmed potency of RANKL-mediated antigen delivery. To the best of our knowledge, this is the first study to demonstrate significant induction of mucosal and humoral immune responses to M cell targeted oral vaccines after the systemic administration of RANKL. PMID:26851393

  4. Nanoparticulated docetaxel exerts enhanced anticancer efficacy and overcomes existing limitations of traditional drugs

    Science.gov (United States)

    Choi, Jinhyang; Ko, Eunjung; Chung, Hye-Kyung; Lee, Jae Hee; Ju, Eun Jin; Lim, Hyun Kyung; Park, Intae; Kim, Kab-Sig; Lee, Joo-Hwan; Son, Woo-Chan; Lee, Jung Shin; Jung, Joohee; Jeong, Seong-Yun; Song, Si Yeol; Choi, Eun Kyung

    2015-01-01

    Nanoparticulation of insoluble drugs improves dissolution rate, resulting in increased bioavailability that leads to increased stability, better efficacy, and reduced toxicity of drugs. Docetaxel (DTX), under the trade name Taxotere™, is one of the representative anticancer chemotherapeutic agents of this era. However, this highly lipophilic and insoluble drug has many adverse effects. Our novel and widely applicable nanoparticulation using fat and supercritical fluid (NUFS™) technology enabled successful nanoscale particulation of DTX (Nufs-DTX). Nufs-DTX showed enhanced dissolution rate and increased aqueous stability in water. After confirming the preserved mechanism of action of DTX, which targets microtubules, we showed that Nufs-DTX exhibited similar effects in proliferation and clonogenic assays using A549 cells. Interestingly, we observed that Nufs-DTX had a greater in vivo tumor growth delay effect on an A549 xenograft model than Taxotere™, which was in agreement with the improved drug accumulation in tumors according to the biodistribution result, and was caused by the enhanced permeability and retention (EPR) effect. Although both Nufs-DTX and Taxotere™ showed negative results for our administration dose in the hematologic toxicity test, Nufs-DTX showed much less toxicity than Taxotere™ in edema, paralysis, and paw-withdrawal latency on a hot plate analysis that are regarded as indicators of fluid retention, peripheral neuropathy, and thermal threshold, respectively, for toxicological tests. In summary, compared with Taxotere™, Nufs-DTX, which was generated by our new platform technology using lipid, supercritical fluid, and carbon dioxide (CO2), maintained its biochemical properties as a cytotoxic agent and had better tumor targeting ability, better in vivo therapeutic effect, and less toxicity, thereby overcoming the current hurdles of traditional drugs. PMID:26457052

  5. Training bottlenose dolphins to overcome avoidance of environmental enrichment objects in order to stimulate play activities.

    Science.gov (United States)

    Neto, Márcia P; Silveira, Miguel; Dos Santos, Manuel E

    2016-05-01

    Enrichment programs may contribute to the quality of life and stress reduction in bottlenose dolphins (Tursiops truncatus) kept in zoos and aquaria. The results of these programs are generally positive in terms of welfare, but the magnitude of their effects may vary greatly between individuals of the same species, especially when the enrichment plans are based on the introduction of manipulative objects. Some animals will interact spontaneously with novel objects, even without food rewards and in the absence of the trainers, while others show no interest or even aversion toward the objects. To determine if formal training can improve these conditions, we measured the effects of an operant conditioning program in the manipulation of objects by dolphins that initially avoided them. This program took place between April and October 2013 at Zoomarine Portugal. Subjects were two female and two male bottlenose dolphins (adults with ages from 17 to 35 years) that after a preliminary analysis showed avoidance or low interest in the manipulation of various toys. The level of interaction with introduced enrichment objects was observed before and after formal training to explore the toys (sixteen 20-min observation sessions per animal "before" and "after training"). In all subjects, an index of interest in object manipulation, in the absence of trainers, increased significantly after the application of the training techniques. The results show that an initial reinforcement program focused on the manipulation of toys may overcome resistance, improving the effects of environmental enrichment plans, and it is a potentially useful strategy to increase the welfare of some captive animals. Zoo Biol. 35:210-215, 2016. © 2016 Wiley Periodicals, Inc. PMID:26969822

  6. Melatonin overcomes resistance to clofarabine in two leukemic cell lines by increased expression of deoxycytidine kinase.

    Science.gov (United States)

    Yamanishi, Miho; Narazaki, Hidehiko; Asano, Takeshi

    2015-03-01

    Drug resistance remains a serious problem in leukemia therapy. Among newly developed nucleoside antimetabolites, clofarabine has broad cytotoxic activity showing therapeutic promise and is currently approved for relapsed acute lymphoblastic leukemia. To investigate the mechanisms responsible for clofarabine resistance, we established two clofarabine-resistant lymphoblastic leukemia cell lines from parental lines. To elucidate the mechanisms against clofarabine resistance in two newly established clofarabine-resistant cell lines, we measured the expression of export pumps multidrug resistance protein 1, multidrug resistance-associated protein 1, and ATP-binding cassette subfamily G member 2. There were no differences in the expression between clofarabine-sensitive and -resistant cell lines. Next, we determined expression of deoxycytidine kinase (dCK), which phosphorylates clofarabine to exert cytotoxicity, in clofarabine-sensitive and -resistant cells. Clofarabine-resistant cells showed significantly decreased expression of dCK RNA when compared with sensitive cells. To elucidate the mechanisms of decreased dCK expression in clofarabine-resistant cells, we analyzed the methylation status of CpG islands of the dCK promoter and found no differences in methylation status between clofarabine-sensitive and -resistant cells. Next, we measured the acetylation status of histone and found that total histone acetylation, and histone H3 and H4 acetylation on chromatin immunoprecipitation assay were significantly decreased in resistant cells. Melatonin is an indolamine that functions in the regulation of chronobiological rhythms to exert cytotoxic effects. We examined the effects of melatonin in clofarabine-resistant cells and found that melatonin treatment led to significantly increased cytotoxicity with clofarabine in resistant cells via increased acetylation. Melatonin may be a useful candidate for overcoming clofarabine resistance in two newly established clofarabine

  7. Strategies to overcome clinical, regulatory, and financial challenges in the implementation of personalized medicine.

    Science.gov (United States)

    Tsimberidou, Apostolia M; Ringborg, Ulrik; Schilsky, Richard L

    2013-01-01

    This article highlights major developments over the last decade in personalized medicine in cancer. Emerging data from clinical studies demonstrate that the use of targeted agents in patients with targetable molecular aberrations improves clinical outcomes. Despite a surge of studies, however, significant gaps in knowledge remain, especially in identifying driver molecular aberrations in patients with multiple aberrations, understanding molecular networks that control carcinogenesis and metastasis, and most importantly, discovering effective targeted agents. Implementation of personalized medicine requires continued scientific and technological breakthroughs; standardization of tumor tissue acquisition and molecular testing; changes in oncology practice and regulatory standards for drug and device access and approval; modification of reimbursement policies by health care payers; and innovative ways to collect and analyze electronic patient information that are linked to prospective clinical registries and rapid learning systems. Informatics systems that integrate clinical, laboratory, radiologic, molecular, and economic data will improve clinical care and will provide infrastructure to enable clinical research. The initiative of the EurocanPlatform aims to overcome the challenges of implementing personalized medicine in Europe by sharing patients, biologic materials, and technological resources across borders. The EurocanPlatform establishes a complete translational cancer research program covering the drug development process and strengthening collaborations among academic centers, pharmaceutical companies, regulatory authorities, health technology assessment organizations, and health care systems. The CancerLinQ rapid learning system being developed by ASCO has the potential to revolutionize how all stakeholders in the cancer community assemble and use information obtained from patients treated in real-world settings to guide clinical practice, regulatory

  8. Overcoming barriers to trust in agricultural biotechnology projects: a case study of Bt cowpea in Nigeria

    Directory of Open Access Journals (Sweden)

    Ezezika Obidimma C

    2012-11-01

    Full Text Available Abstract Background Nigeria, Africa’s most populous country, has been the world’s largest cowpea importer since 2004. The country is currently in the early phases of confined field trials for two genetically modified crops: Bacillus thuringiensis (Bt cowpea and nutritionally enhanced cassava (“BioCassava Plus”. Using the bio-safety guidelines process as a backdrop, we evaluate the role of trust in the operation of the Cowpea Productivity Improvement Project, which is an international agricultural biotechnology public-private partnership (PPP aimed at providing pest-resistant cowpea varieties to Nigerian farmers. Methods We reviewed the published literature and collected data through direct observations and semi-structured, face-to-face interviews. Data were analyzed based on emergent themes to create a comprehensive narrative on how trust is understood and built among the partners and with the community. Results Our findings highlight the importance of respecting mandates and eliminating conflicts of interest; holding community engagement initiatives early on; having on-going internal discussion and planning; and serving a locally-defined need. These four lessons could prove helpful to other agricultural biotechnology initiatives in which partners may face similar trust-related challenges. Conclusions Overcoming challenges to building trust requires concerted effort throughout all stages of project implementation. Currently, plans are being made to backcross the cowpea strain into a local variety in Nigeria. The development and adoption of the Bt cowpea seed hinges on the adoption of a National Biosafety Law in Nigeria. For countries that have decided to adopt biotech crops, the Nigerian cowpea experiment can be used as a model for other West African nations, and is actually applied as such in Ghana and Burkina Faso, interested in developing a Bt cowpea.

  9. Overcoming potential energy distortions in constrained internal coordinate molecular dynamics simulations

    International Nuclear Information System (INIS)

    The Internal Coordinate Molecular Dynamics (ICMD) method is an attractive molecular dynamics (MD) method for studying the dynamics of bonded systems such as proteins and polymers. It offers a simple venue for coarsening the dynamics model of a system at multiple hierarchical levels. For example, large scale protein dynamics can be studied using torsional dynamics, where large domains or helical structures can be treated as rigid bodies and the loops connecting them as flexible torsions. ICMD with such a dynamic model of the protein, combined with enhanced conformational sampling method such as temperature replica exchange, allows the sampling of large scale domain motion involving high energy barrier transitions. Once these large scale conformational transitions are sampled, all-torsion, or even all-atom, MD simulations can be carried out for the low energy conformations sampled via coarse grained ICMD to calculate the energetics of distinct conformations. Such hierarchical MD simulations can be carried out with standard all-atom forcefields without the need for compromising on the accuracy of the forces. Using constraints to treat bond lengths and bond angles as rigid can, however, distort the potential energy landscape of the system and reduce the number of dihedral transitions as well as conformational sampling. We present here a two-part solution to overcome such distortions of the potential energy landscape with ICMD models. To alleviate the intrinsic distortion that stems from the reduced phase space in torsional MD, we use the Fixman compensating potential. To additionally alleviate the extrinsic distortion that arises from the coupling between the dihedral angles and bond angles within a force field, we propose a hybrid ICMD method that allows the selective relaxing of bond angles. This hybrid ICMD method bridges the gap between all-atom MD and torsional MD. We demonstrate with examples that these methods together offer a solution to eliminate the potential

  10. Nanoparticles decorated with proteolytic enzymes, a promising strategy to overcome the mucus barrier.

    Science.gov (United States)

    Pereira de Sousa, Irene; Cattoz, Beatrice; Wilcox, Matthew D; Griffiths, Peter C; Dalgliesh, Robert; Rogers, Sarah; Bernkop-Schnürch, Andreas

    2015-11-01

    The intestinal mucus gel layer represents a stumbling block for drug adsorption. This study is aimed to formulate a nanoparticulate system able to overcome this barrier by cleaving locally the glycoprotein substructures of the mucus. Mucolytic enzymes such as papain (PAP) and bromelain (BRO) were covalently conjugated to poly(acrylic acid) (PAA). Nanoparticles (NPs) were then formulated via ionic gelation method and characterized by particle size, zeta potential, enzyme content and enzymatic activity. The NPs permeation quantified by rotating tube studies was correlated with changes in the mucus gel layer structure determined by pulsed-gradient-spin-echo NMR (PGSE-NMR), small-angle neutron scattering (SANS) and spin-echo SANS (SESANS). PAP and BRO functionalized NPs had an average size in the range of 250 and 285 nm and a zeta potential that ranged between -6 and -5 mV. The enzyme content was 242 μg enzyme/mg for PAP modified NPs and 253 μg enzyme/mg for BRO modified NPs. The maintained enzymatic activity was 43% for PAP decorated NPs and 76% for BRO decorated NPs. The rotating tube technique revealed a better performance of BRO decorated NPs compared to PAA decorated NPs, with a 4.8-fold higher concentration of NPs in the inner slice of mucus. Addition of 0.5 wt% of enzyme functionalized NPs to 5 wt% intestinal mucin led to c.a. 2-fold increase in the mobility of the mucin as measured by PGSE-NMR indicative of a significant break-up of the structure of the mucin. SANS and SESANS measurements further revealed a change in structure of the intestinal mucus induced by the incorporation of the functionalized NPs mostly occurring at a length scale longer than 0.5 μm. Accordingly, BRO decorated NPs show higher potential than PAP functionalized NPs as mucus permeating drug delivery systems. PMID:25661320

  11. Characteristics of the ion beam exposure for overcoming the cross incompatibility

    International Nuclear Information System (INIS)

    In wild species, there are valuable genes controlling resistance to disease, insect and environmental stress. The introduction of such genes from wild species to cultivar is extremely useful in plant breeding. However, it is very difficult or impossible to obtain an interspecific hybrid in a wide cross, because of the strong cross-incompatibility. We have been searching for an effective procedure of interspecific hybridization in Nicotiana. Because N. gossei Domin (wild species) has been reported to be resistant to more disease and insects than other Nicotiana species, many attempts to hybridize it with N. tabacum L. (cultivar) have been made. In N. gossei x N. tabacum, it is easy to get hybrid seeds with conventional cross, but hybrid plants can not survive, On the other hand, in N. tabacum x N. gossei, few seeds with viability can be obtained. In this species combination, we had obtained the viable hybrid plant by means of the cross with the gamma-rays-irradiated pollen at the rate of 3.7 x 10-5. Ion beams have higher LET (Linear Energy Transfer), in comparison with that of gamma-rays, and can be controlled the range in the target material. Accordingly, a lot of energy can be deposited on the focused point of material exposed to ion beams. The cross (N. gossei x N. tabacum) with pollen exposed to ion beams, e. g., he, C and Ne ions, produced the viable hybrid plants at the rate 1 x 10-2, which was much higher than that of gamma-rays. Morphological characters in some of hybrid plants were intermediate between parents and uniform, suggesting that they had no mutation induced by the ion beam exposure. Conclusively, it is said that ion beams are more effective for overcoming the cross incompatibility than radiations with low LET. (author)

  12. Complex DNA repair pathways as possible therapeutic targets to overcome temozolomide resistance in glioblastoma

    Directory of Open Access Journals (Sweden)

    Koji eYoshimoto

    2012-12-01

    Full Text Available Many conventional chemotherapeutic drugs exert their cytotoxic function by inducing DNA damage in the tumor cell. Therefore, a cell-inherent DNA repair pathway, which reverses the DNA-damaging effect of the cytotoxic drugs, can mediate therapeutic resistance to chemotherapy. The monofunctional DNA-alkylating agent temozolomide (TMZ is a commonly used chemotherapeutic drug and the gold standard treatment for glioblastoma. Although the activity of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT has been described as the main modulator to determine the sensitivity of glioblastoma to TMZ, a subset of glioblastoma does not respond despite MGMT inactivation, suggesting that another DNA repair mechanism may also modulate the tolerance to TMZ. Considerable interest has focused on MGMT, mismatch repair (MMR, and the base-excision repair (BER pathway in the mechanism of mediating TMZ resistance, but emerging roles for the DNA strand-break repair pathway have been demonstrated. In the first part of this review article, we briefly review the significant role of MGMT, MMR, and the BER pathway in the tolerance to TMZ; in the last part, we review the recent publications that demonstrate possible roles of DNA strand-break repair pathways, such as single-strand break (SSB repair and double-strand break (DSB repair, as well as the Fanconi anemia pathway in the repair process after alkylating agent-based therapy. It is possible that all of these repair pathways have a potential to modulate the sensitivity to TMZ and aid in overcoming the therapeutic resistance in the clinic.

  13. Genome network medicine: innovation to overcome huge challenges in cancer therapy.

    Science.gov (United States)

    Roukos, Dimitrios H

    2014-01-01

    The post-ENCODE era shapes now a new biomedical research direction for understanding transcriptional and signaling networks driving gene expression and core cellular processes such as cell fate, survival, and apoptosis. Over the past half century, the Francis Crick 'central dogma' of single n gene/protein-phenotype (trait/disease) has defined biology, human physiology, disease, diagnostics, and drugs discovery. However, the ENCODE project and several other genomic studies using high-throughput sequencing technologies, computational strategies, and imaging techniques to visualize regulatory networks, provide evidence that transcriptional process and gene expression are regulated by highly complex dynamic molecular and signaling networks. This Focus article describes the linear experimentation-based limitations of diagnostics and therapeutics to cure advanced cancer and the need to move on from reductionist to network-based approaches. With evident a wide genomic heterogeneity, the power and challenges of next-generation sequencing (NGS) technologies to identify a patient's personal mutational landscape for tailoring the best target drugs in the individual patient are discussed. However, the available drugs are not capable of targeting aberrant signaling networks and research on functional transcriptional heterogeneity and functional genome organization is poorly understood. Therefore, the future clinical genome network medicine aiming at overcoming multiple problems in the new fields of regulatory DNA mapping, noncoding RNA, enhancer RNAs, and dynamic complexity of transcriptional circuitry are also discussed expecting in new innovation technology and strong appreciation of clinical data and evidence-based medicine. The problematic and potential solutions in the discovery of next-generation, molecular, and signaling circuitry-based biomarkers and drugs are explored. PMID:24318985

  14. Overcoming potential energy distortions in constrained internal coordinate molecular dynamics simulations

    Energy Technology Data Exchange (ETDEWEB)

    Kandel, Saugat; Salomon-Ferrer, Romelia; Larsen, Adrien B.; Vaidehi, Nagarajan, E-mail: nvaidehi@coh.org [Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California 91010 (United States); Jain, Abhinandan, E-mail: Abhi.Jain@jpl.nasa.gov [Jet Propulsion Laboratory, California Institute of Technology, 4800 Oak Grove Drive, Pasadena, California 91109 (United States)

    2016-01-28

    The Internal Coordinate Molecular Dynamics (ICMD) method is an attractive molecular dynamics (MD) method for studying the dynamics of bonded systems such as proteins and polymers. It offers a simple venue for coarsening the dynamics model of a system at multiple hierarchical levels. For example, large scale protein dynamics can be studied using torsional dynamics, where large domains or helical structures can be treated as rigid bodies and the loops connecting them as flexible torsions. ICMD with such a dynamic model of the protein, combined with enhanced conformational sampling method such as temperature replica exchange, allows the sampling of large scale domain motion involving high energy barrier transitions. Once these large scale conformational transitions are sampled, all-torsion, or even all-atom, MD simulations can be carried out for the low energy conformations sampled via coarse grained ICMD to calculate the energetics of distinct conformations. Such hierarchical MD simulations can be carried out with standard all-atom forcefields without the need for compromising on the accuracy of the forces. Using constraints to treat bond lengths and bond angles as rigid can, however, distort the potential energy landscape of the system and reduce the number of dihedral transitions as well as conformational sampling. We present here a two-part solution to overcome such distortions of the potential energy landscape with ICMD models. To alleviate the intrinsic distortion that stems from the reduced phase space in torsional MD, we use the Fixman compensating potential. To additionally alleviate the extrinsic distortion that arises from the coupling between the dihedral angles and bond angles within a force field, we propose a hybrid ICMD method that allows the selective relaxing of bond angles. This hybrid ICMD method bridges the gap between all-atom MD and torsional MD. We demonstrate with examples that these methods together offer a solution to eliminate the potential

  15. Overcoming energy efficiency barriers through systems approach—A conceptual framework

    International Nuclear Information System (INIS)

    In this paper we propose a framework which categorizes energy efficiency barriers based on the stage at which the barriers exist. Barriers to energy efficiency have been widely studied but to our knowledge, except for a few studies, we found inadequate consideration for barrier–barrier interactions when proposing policy measures for improving energy efficiency. Leveraging systems thinking's power as a problem solver which identifies underlying structure that explains (similar) patterns of behavior in a variety of different situations, we attempted to identify patterns of barriers to adoption of energy efficiency measures in industrial companies. Inspired by systems thinking, the proposed framework has four stages, namely, Motivation, Capability, Implementation and Results, as well as a feedback loop. Using a case study, we show that following the four stages will lead to positive feedback for future energy efficiency implementations. The framework highlights the interconnected nature of the barriers and a need for policymakers to address these barriers in a holistic manner. We argue that the overall effectiveness of energy efficiency policies is only as strong as the weakest link in the four-stage framework. This differs from most prior research that addressed barriers in isolation, where a solution is proposed for each of the barriers without considering the relationship between the barriers. Our framework also offers a way to understand the roles and responsibilities of major stakeholders such as governments and energy service companies (ESCOs) in driving energy efficiency. This allows the assessment and identification of weak links in energy efficiency policies. - Highlights: ► We propose a systems approach to overcome energy efficiency barriers. ► Barriers are grouped into Motivation, Capability, Implementation and Results. ► Case study shows that there is a feedback loop from Results to Motivation. ► Current Results will affect future Motivation.

  16. Brazilian Strategies to Overcome Molybdenum Crisis: Present and Future Perspectives of the Multipurpose Research Reactor

    International Nuclear Information System (INIS)

    Nuclear Medicine applications in Brazil have been widely growing in the past few decades, following the world trends. Procedures in oncology and cardiology can be highlighted among its major contributions. Nowadays more than 80% of diagnosis procedures are performed with 99mTc, readily available from the elution of 99Mo-99mTc generators. The Brazilian demand, attended solely by IPEN-CNEN/SP, reaches out more than 320 generators per week with a total activity of about 16.7 TBq (450 Ci), which corresponds to 4% of the overall 99Mo global demand at an importation cost of US$20 million/year, most of it from Canada. The recent 99Mo supply crisis deeply affected the distribution of generators in Brazil. A short term solution was achieved with the purchase of 99Mo from Argentine and more recently from South Africa and also the distribution of generators produced by IBA and Israel. Mid term and long term projects are under way aiming the nationalization of the production of 99Mo. Both solutions will use the recently approved new Brazilian Multipurpose Reactor (BMR) that will be built near Sao Paulo city and will have a 30 MW power. The mid term project consists on the production of (n,γ) 99Mo and distribution of 99mTc and monodoses of radiopharmaceuticals labelled with 99mTc to hospitals near Sao Paulo. The long term project deals with the production of 99Mo through the fission of 235U using LEU targets. This work describes the efforts taken by IPEN-CNEN/SP to overcome the recent 99Mo supply crisis and an up-to-date on the projects aiming the nationalization of the 99Mo production. (author)

  17. The Main Directions to Overcome the Challenges of the 21st Century in Agriculture

    Directory of Open Access Journals (Sweden)

    Fanus Nagimovich Garipov

    2016-03-01

    Full Text Available In the article, on the basis of the world and national approaches to the solution of the food problem, the main vectors of the agricultural development aimed at overcoming the challenges of the XXI century and eventually attain the food independence of Russia are proved. The reasons for the decline per capita food production in the world are revealed; the increasing influence, in addition to the population growth, of the equalization of level and quality of food on its dynamics is noted. The dominant current public incentives form the growth rate of demand in advance the production. It is proposed to correct the strategy of agrarian development, while maintaining the principles of multiculturalism in the economy, focusing on the leading role of the large, vertically integrated business entities, and on the import substitution of the basic foodstuffs through the involvement of regional internal resources, including the development of cooperation principles, historically attended the emergence of commodity-money relations in the village. The growth of productivity of production factors is grounded as the main vector that may rectify the situation. It is recommended to diversify a set of cultivated plants and breeds of animals, as well as to develop a new commodity structure of production. The need for food imports is stressed in view of the fact that for the imported products, which are manufactured using primarily the renewable resources, Russia has to pay the price of the potential non-renewable natural resources, making it strategically disadvantageous. In order to achieve the sustainability of the basic parameters and enhance the results of the agricultural activity, it is recommended to use the tools of economic and mathematical modeling of the distribution of economic resources. The findings will be reflected in the justification of the strategy for the regional agricultural development

  18. Overcoming Barriers to Eye Care: Patient Response to a Medical Social Worker in a Glaucoma Service.

    Science.gov (United States)

    Fudemberg, Scott J; Amarasekera, Dilru C; Silverstein, Marlee H; Linder, Kathryn M; Heffner, Paul; Hark, Lisa A; Waisbourd, Michael

    2016-08-01

    This paper investigates the patient response to a medical social worker in a glaucoma clinic. The literature suggests that medical social workers are effective in a variety of health care settings, yet the efficacy of a medical social worker in an adult ophthalmic setting has not been studied. We present the results of a retrospective chart review of 50 patients with glaucoma referred to a medical social worker between January 5, 2015 and June 31, 2015 in an outpatient clinic of an urban eye hospital. Clinical and demographic data, as well as the data from a quality of care questionnaire, were collected for each patient. Patients rated their interaction with the medical social worker as highly positive (mean = 4.75, 5-point Likert scale), and nearly 90 % of patients expressed interest in future contact with the social worker. Additionally, most patients reported that the social worker resolved the issues they were facing (61.1 %), supported them in seeing their ophthalmologist (70.6 %), and helped them to manage their glaucoma (69.7 %). Reported barriers to glaucoma care were emotional distress; cost of office visits and medications; lack of medical insurance; transportation; poor medication adherence; impairment of daily activities; follow-up adherence; and language. As vision loss from glaucoma is irreversible, it is important to detect and treat patients at early stages of the disease. Therefore, it is imperative for patients to regularly visit their eye care providers and adhere to treatment and follow-up recommendations. This study suggests that a medical social worker could play a pivotal role in helping patients with glaucoma overcome barriers to treatment and facilitate disease management. PMID:26860278

  19. Overcoming of the Diffraction Limit for the Discrete Case in Time Reversed Acoustics

    Science.gov (United States)

    Velázquez-Arcos, J. M.; Vargas, C. A.; Fernández-Chapou, L.; Granados-Samaniego, J.

    2008-04-01

    The time reversal phenomenon in sound waves for the discrete case is revisited. Our purpose is to improve a previous explanation of this problem in which there was a more limited scope. We develop a formulation which includes sink terms in the time reversed process, which allow going beyond the diffraction limit. By employing a reversed signal it is possible to reach a definition of a fourteenth of the wavelength. In the present work we discuss a matrix formulation for the discrete case in terms of the Fourier transforms of the input and output signals and the Green function. With this function it is possible to characterize the propagation of signals emitted by an array of devices. We are able to express the time reversed signal and precisely select the destination site, among other useful objectives. Finally we show an experimental arrangement using a Michelson interferometer in order to observe this phenomenon. Time Reversal originates from the second order time derivative in the wave equation. This is different from the case of nonlinear behavior in media known as acoustic or electromagnetic inverse scattering. Some of the fields which Time Reversal opens for investigation are the time reversal of a signal by a sound mirror (Time Reversal Mirror or TRM) or by a Time Reversal Cavity (TRC), and the possibility of sending a message to a precise physical location. Recently a new and powerful application has been reported in the literature, namely the abovementioned overcoming of the diffraction limit in wave physics. Although our experimental proposal is based on reports from others authors, the experimental arrangement used here, the specific way of operation and the image construction are original.

  20. Targeting galectin-1 overcomes breast cancer-associated immunosuppression and prevents metastatic disease.

    Science.gov (United States)

    Dalotto-Moreno, Tomás; Croci, Diego O; Cerliani, Juan P; Martinez-Allo, Verónica C; Dergan-Dylon, Sebastián; Méndez-Huergo, Santiago P; Stupirski, Juan C; Mazal, Daniel; Osinaga, Eduardo; Toscano, Marta A; Sundblad, Victoria; Rabinovich, Gabriel A; Salatino, Mariana

    2013-02-01

    Galectin-1 (Gal1), an evolutionarily conserved glycan-binding protein, contributes to the creation of an immunosuppressed microenvironment at sites of tumor growth. In spite of considerable progress in elucidating its role in tumor-immune escape, the mechanisms underlying the inhibitory functions of Gal1 remain obscure. Here, we investigated the contribution of tumor Gal1 to tumor growth, metastasis, and immunosuppression in breast cancer. We found that the frequency of Gal1(+) cells in human breast cancer biopsies correlated positively with tumor grade, while specimens from patients with benign hyperplasia showed negative or limited Gal1 staining. To examine the pathophysiologic relevance of Gal1 in breast cancer, we used the metastatic mouse mammary tumor 4T1, which expresses and secretes substantial amounts of Gal1. Silencing Gal1 expression in this model induced a marked reduction in both tumor growth and the number of lung metastases. This effect was abrogated when mice were inoculated with wild-type 4T1 tumor cells in their contralateral flank, suggesting involvement of a systemic modulation of the immune response. Gal1 attenuation in 4T1 cells also reduced the frequency of CD4(+)CD25(+) Foxp3(+) regulatory T (T(reg)) cells within the tumor, draining lymph nodes, spleen, and lung metastases. Further, it abrogated the immunosuppressive function of T(reg) cells and selectively lowered the expression of the T-cell regulatory molecule LAT (linker for activation of T cells) on these cells, disarming their suppressive activity. Taken together, our results offer a preclinical proof of concept that therapeutic targeting of Gal1 can overcome breast cancer-associated immunosuppression and can prevent metastatic disease. PMID:23204230

  1. Poured of corporate culture on overcoming conflicts on enterprise as important direction of providing of efficiency manager’s labour

    OpenAIRE

    Galyna, Nagornyak; Vasyl, Muliarchuk

    2010-01-01

    In the article the features of origin and problem of overcoming conflicts on an enterprise are considered, role of corporate culture in providing of efficiency of manager’s labour and the various ways of prevention and removal of heavy consequences of conflicts situations are offered.

  2. The Role of the Teacher in Helping Learners Overcome the Negative Impact of Child Sexual Abuse: A South African Perspective

    Science.gov (United States)

    Phasha, Tlakale Nareadi

    2008-01-01

    Current literature suggesting the negative impact of childhood experiences of sexual abuse on school functioning makes it imperative to consider the role of the teacher in helping survivors overcome the negative impact of such experiences. Schools cannot ignore the reason why some learners cannot learn. This article presents the findings of a…

  3. Families OverComing under Stress (FOCUS) for Early Childhood: Building Resilience for Young Children in High Stress Families

    Science.gov (United States)

    Mogil, Catherine; Paley, Blair; Doud, Tricia; Havens, Linda; Moore-Tyson, Jessica; Beardslee, William R.; Lester, Patricia

    2010-01-01

    Parental distress and trauma affects the entire family, including the youngest children. Families OverComing Under Stress (FOCUS) is a targeted prevention program for high-risk families that aims to enhance family cohesion, support the parent-child relationship, and build emotional regulation, communication, and problem-solving skills across the…

  4. G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia

    OpenAIRE

    Lee, Hee Kyu; Kim, Hong Woo; Lee, In Yong; Lee, Jungmi; Lee, Jaekyoo; Jung, Dong Sik; Lee, Sang Yeop; Park, Sung Ho; Hwang, Haejun; Choi, Jang-Sik; Kim, Jung-Ho; Kim, Se Won; Kim, Jung Keun; Cools, Jan; Koh, Jong Sung

    2014-01-01

    A novel inhibitor G-749 is very potent against FLT3 kinase mutants including D835Y and ITD/F691L that confer resistance to PKC412 and AC220.G-749 shows several desirable characteristics to overcome other drug resistances conferred by patient plasma, FLT3 ligand, and stromal cells.

  5. Translating Research to Practice: Overcoming Barriers to Implementing Effective Off-Campus Party Intervention. Issues in Prevention

    Science.gov (United States)

    Higher Education Center for Alcohol, Drug Abuse, and Violence Prevention, 2012

    2012-01-01

    This issue of "Issues in Prevention" focuses on overcoming barriers in implementing effective off-campus party intervention. This issue contains the following articles: (1) Confronting the Problems Associated With Off-Campus Parties With Evidence-Based Strategies (John D. Clapp); (2) Overview of Research on Effective Off-Campus Party…

  6. Biotechnological strategies to overcome inhibitors in lignocellulose hydrolysates for ethanol production: review.

    Science.gov (United States)

    Parawira, W; Tekere, M

    2011-03-01

    One of the major challenges faced in commercial production of lignocellulosic bioethanol is the inhibitory compounds generated during the thermo-chemical pre-treatment step of biomass. These inhibitory compounds are toxic to fermenting micro-organisms. The ethanol yield and productivity obtained during fermentation of lignocellulosic hydrolysates is decreased due to the presence of inhibiting compounds, such as weak acids, furans and phenolic compounds formed or released during thermo-chemical pre-treatment step such as acid and steam explosion. This review describes the application and/or effect of biological detoxification (removal of inhibitors before fermentation) or use of bioreduction capability of fermenting yeasts on the fermentability of the hydrolysates. Inhibition of yeast fermentation by the inhibitor compounds in the lignocellulosic hydrolysates can be reduced by treatment with enzymes such as the lignolytic enzymes, for example, laccase and micro-organisms such as Trichoderma reesei, Coniochaeta ligniaria NRRL30616, Trametes versicolor, Pseudomonas putida Fu1, Candida guilliermondii, and Ureibacillus thermosphaericus. Microbial and enzymatic detoxifications of lignocellulosic hydrolysate are mild and more specific in their action. The efficiency of enzymatic process is quite comparable to other physical and chemical methods. Adaptation of the fermentation yeasts to the lignocellulosic hydrolysate prior to fermentation is suggested as an alternative approach to detoxification. Increases in fermentation rate and ethanol yield by adapted micro-organisms to acid pre-treated lignocellulosic hydrolysates have been reported in some studies. Another approach to alleviate the inhibition problem is to use genetic engineering to introduce increased tolerance by Saccharomyces cerevisiae, for example, by overexpressing genes encoding enzymes for resistance against specific inhibitors and altering co-factor balance. Cloning of the laccase gene followed by

  7. SOCIAL AND CULTURAL ACTIVITIES WITH PEOPLE OF THE THIRD AGE TO OVERCOME THE SOCIAL EXCLUSION: A REGIONAL PERSPECTIVE

    Directory of Open Access Journals (Sweden)

    Elena V. Kharkovskaya

    2016-06-01

    Full Text Available Introduction: this paper discusses the specifics of socio-cultural activities with people of the third age to overcome the social exclusion, identifies reasons for the decline of alienation level in this category of citizens in conditions of activity of cultural institutions. Materials and Methods: the authors’ findings are based on the philosophical, sociological, cultural, psychological and pedagogical literature and research methodology: observation, survey and content analysis. Results: the most effective methods of social and cultural activities in terms of overcoming the social exclusion of people of the third age were developed and experimentally tested. The main objective of the research was to examine the problems of exclusion among persons of the third age, as well as the possibilities of using social and cultural activities to overcome the social exclusion. In the paper the authors analyse the regional approach to the organisation of social and cultural activities of the elderly in institutions of social and cultural sphere. On the basis of the study the authors propose to extend and modify the variety of forms of leisure and intensify their use in working with people of the third age to overcome the social exclusion of an individual. All work on social and cultural activities with the elderly should be aimed primarily at optimising the social inclusion of elderly in society. Discussion and Conclusions: organisation of social and cultural activities for the elderly is a host of opportunities for the realisation of creative ideas. It is these new approaches to the activities of cultural institution’s collective that help to enhance the interaction between cultural institutions employees and retirees. This study is not exhaustive and does not finalise the research into the role of social and cultural activities as a condition for overcoming the social exclusion of people of the third age. This topic needs further exploration.

  8. Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumours

    International Nuclear Information System (INIS)

    Oxygen deficient hypoxic cells, which are resistant to sparsely ionising radiation, have now been identified in most animal and some human solid tumours and will influence the response of those tumours to radiation treatment. This hypoxia can be either chronic, arising from an oxygen diffusion limitation, or acute, resulting from transient stoppages in microregional blood flow. Extensive experimental studies, especially in the last decade, have shown that nicotinamide and structurally related analogs can effectively sensitize murine tumours to both single and fractionated radiation treatments and that they do so in preference to the effects seen in mouse normal tissues. The earliest studies suggested that this enhancement of radiation damage was the result of an inhibition of the repair mechanisms. However, recent studies in mouse tumours have shown that these drugs prevent transient cessations in blood flow, thus inhibiting the development of acute hypoxia. This novel discovery led to the suggestion that the potential role of these agents as radiosensitizers would be when combined with treatments that overcame chronic hypoxia. The combined nicotinamide with hyperthermia proved that the enhancement of radiation damage by both agents together was greater than that seen with each agent alone. Similar results were later seen for nicotinamide combined with a perfluorochemical emulsion, carbogen breathing, and pentoxifylline, and in all these studies the effects in tumours were always greater than those seen in appropriate normal tissues. Of all the analogs, it is nicotinamide itself which has been the most extensively studied as a radiosensitizer in vivo and the one that shows the greatest effect in animal tumours. It is also an agent that has been well established clinically, with daily doses of up to 6 g, associated with a low incidence of side effects. This human dose is equivalent to 100-200 mg/kg in mice and such doses will maximally sensitize murine tumours to

  9. Tunneling inhibition for subwavelength light

    CERN Document Server

    Huang, Changming; Ye, Fangwei; Kartashov, Yaroslav V; Chen, Xianfeng; Torner, Lluis

    2013-01-01

    We show that light tunneling inhibition may take place in suitable dynamically modulated waveguide arrays for light spots whose features are remarkably smaller than the wavelength of light. We found that tunneling between neighboring waveguides can be suppressed for specific frequencies of the out-of-phase refractive index modulation, affording undistorted propagation of the input subwavelength light spots over hundreds of Rayleigh lengths. Tunneling inhibition turns out to be effective only when the waveguide separation in the array is above a critical threshold. Inclusion of a weak focusing nonlinearity is shown to improve localization. We analyze the phenomenon in purely dielectric structures and also in arrays containing periodically spaced metallic layers.

  10. 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. PMID:24146907

  11. 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.

  12. Nanoparticulated docetaxel exerts enhanced anticancer efficacy and overcomes existing limitations of traditional drugs

    Directory of Open Access Journals (Sweden)

    Choi J

    2015-09-01

    edema, paralysis, and paw-withdrawal latency on a hot plate analysis that are regarded as indicators of fluid retention, peripheral neuropathy, and thermal threshold, respectively, for toxicological tests. In summary, compared with Taxotere™, Nufs-DTX, which was generated by our new platform technology using lipid, supercritical fluid, and carbon dioxide (CO2, maintained its biochemical properties as a cytotoxic agent and had better tumor targeting ability, better in vivo therapeutic effect, and less toxicity, thereby overcoming the current hurdles of traditional drugs. Keywords: Nufs-DTX, docetaxel, anticancer efficacy, toxicity

  13. Quantification of cell-free DNA in normal and complicated pregnancies: overcoming biological and technical issues.

    Directory of Open Access Journals (Sweden)

    Irina Manokhina

    Full Text Available The characterization of cell-free DNA (cfDNA originating from placental trophoblast in maternal plasma provides a powerful tool for non-invasive diagnosis of fetal and obstetrical complications. Due to its placental origin, the specific epigenetic features of this DNA (commonly known as cell-free fetal DNA can be utilized in creating universal 'fetal' markers in maternal plasma, thus overcoming the limitations of gender- or rhesus-specific ones. The goal of this study was to compare the performance of relevant approaches and assays evaluating the amount of cfDNA in maternal plasma throughout gestation (7.2-39.5 weeks. Two fetal- or placental-specific duplex assays (RPP30/SRY and RASSF1A/β-Actin were applied using two technologies, real-time quantitative PCR (qPCR and droplet digital PCR (ddPCR. Both methods revealed similar performance parameters within the studied dynamic range. Data obtained using qPCR and ddPCR for these assays were positively correlated (total cfDNA (RPP30: R = 0.57, p = 0.001/placental cfDNA (SRY: R = 0.85, p<0.0001; placental cfDNA (RASSF1A: R = 0.75, p<0.0001. There was a significant correlation in SRY and RASSF1A results measured with qPCR (R = 0.68, p = 0.013 and ddPCR (R = 0.56, p = 0.039. Different approaches also gave comparable results with regard to the correlation of the placental cfDNA concentration with gestational age and pathological outcome. We conclude that ddPCR is a practical approach, adaptable to existing qPCR assays and well suited for analysis of cell-free DNA in plasma. However, it may need further optimization to surpass the performance of qPCR.

  14. Hurdles overcome in technology transfer for AIET and Positive outcome in Indian patients

    Directory of Open Access Journals (Sweden)

    Dedeepiya V

    2012-01-01

    Full Text Available Introduction Cell based immunotherapies have been in practice in Japan for the past two decades with established clinical trials on its efficacy in both solid tumours and hematological malignancies including gastric cancer, ovarian cancer , lung cancer and liver cancer. [1,2,3,4] In India, NCRM has been providing Autologous Immune Enhancement Therapy (AIET using autologous Natural Killer (NK cells and activated T Lymphocytes for Cancer since 2005 following the established protocols practiced by the Biotherapy Institute of Japan. Significant outcome achieved after AIET in advanced pancreatic cancer, Acute Myeloid leukemia (AML in Indian patients have already been reported. [5, 6] Here we report our experience in few more patients and present the hurdles overcome and lessons learned in translating the technology from Japan to India Case Details: Case 1: A 54 year-old female presented with Stage IV recurrent ovarian malignancy in 2010 with a history of previous surgery and chemotherapy for ovarian malignancy in June 2009. The CA-125 level of 243 U/ml. CT scan revealed lesions in the liver, spleen, along the greater curvature of body of stomach and in the perisplenic region, between the medial aspect of liver and stomach and in the right inguinal region. She was suggested six cycles of chemotherapy with Doxorubicin (50 mg and Carboplatin (450 mg along with AIET. After proper informed consent, the peripheral blood was withdrawn and the in vitro expansion of the NK cells, activated T Lymphocytes from the peripheral blood was performed using the protocol reported earlier. [7] Average cell count after the in vitro expansion was 1.2 X 108 cells. Six transfusions of the in vitro expanded NK cells and activated T lymphocytes were administered following which the CA-125 decreased to 4.7 U/mL. CT scan taken in December 2010 showed a regression of the lesions in the spleen and perisplenic peritoneal deposits, stable hepatic lesions and resolution of

  15. Inhibition of human platelet function in vitro and ex vivo by acetaminophen.

    Science.gov (United States)

    Lages, B; Weiss, H J

    1989-03-15

    The effects of acetaminophen (APAP) in vitro, or ex vivo following APAP ingestion, on human platelet aggregation, 14C-5HT secretion, and thromboxane B2 (TxB2) formation were assessed. APAP added in vitro to citrated platelet-rich plasma (PRP) inhibited aggregation, secretion, and TxB2 formation induced by collagen, epinephrine, arachidonate, and the ionophore A23187, but had no effect on the responses induced by the endoperoxide analog U44069. Arachidonate-induced responses were inhibited by lower concentrations of APAP than were the responses to the other agonists. In PRP obtained 1 hour after ingestion of 650 mg or 1000 mg APAP, arachidonate-induced TxB2 formation was inhibited by 40-99% in five subjects tested, whereas inhibition of collagen- or epinephrine-induced TxB2 formation was less consistent. Aggregation and secretion responses were not altered by APAP ingestion in 4 of the 5 subjects, but were inhibited in the remaining subject, who had the highest plasma APAP levels. In contrast to aspirin and indomethacin, APAP-induced inhibition of collagen-stimulated TxB2 formation could be partially overcome with increasing collagen concentrations. No such partial correction occurred with epinephrine, however. In washed platelet suspensions labeled with 3H-arachidonate, both APAP and aspirin inhibited the formation of labeled PGD2 and PGE2, as well as TxB2. These results suggest that APAP acts in human platelets as a reversible inhibitor of cyclo-oxygenase, as found previously in other tissues, and that recent APAP ingestion can, on occasion, produce inhibition of platelet functional responses measured in vitro. PMID:2499947

  16. Testing of Biologically Inhibiting Surface

    DEFF Research Database (Denmark)

    Bill Madsen, Thomas; Larsen, Erup

    2003-01-01

    The main purpose of this course is to examine a newly developed biologically inhibiting material with regards to galvanic corrosion and electrochemical properties. More in detail, the concern was how the material would react when exposed to cleaning agents, here under CIP cleaning (Cleaning In...

  17. Behavioral Inhibition: Type or Continuum?

    Science.gov (United States)

    Scholmerich, Axel; And Others

    This study investigated whether behavioral inhibition is best conceptualized as a continuous variable or as a distinct typology with two or more subcategories. The following data were gathered on 58 infants at 5, 7, 10, and 13 months of age; physiological functioning (cardiovascular activity and salivary cortisol); emotional expressivity in…

  18. Cadmium inhibits mismatch repair by blocking the ATPase activity of the MSH2-MSH6 complex.

    Science.gov (United States)

    Banerjee, Sreeparna; Flores-Rozas, Hernan

    2005-01-01

    Cadmium (Cd2+) is a known carcinogen that inactivates the DNA mismatch repair (MMR) pathway. In this study, we have tested the effect of Cd2+ exposure on the enzymatic activity of the mismatch binding complex MSH2-MSH6. Our results indicate that Cd2+ is highly inhibitory to the ATP binding and hydrolysis activities of MSH2-MSH6, and less inhibitory to its DNA mismatch binding activity. The inhibition of the ATPase activity appears to be dose and exposure time dependent. However, the inhibition of the ATPase activity by Cd2+ is prevented by cysteine and histidine, suggesting that these residues are essential for the ATPase activity and are targeted by Cd2+. A comparison of the mechanism of inhibition with N-ethyl maleimide, a sulfhydryl group inhibitor, indicates that this inhibition does not occur through direct inactivation of sulfhydryl groups. Zinc (Zn2+) does not overcome the direct inhibitory effect of Cd2+ on the MSH2-MSH6 ATPase activity in vitro. However, the increase in the mutator phenotype of yeast cells exposed to Cd2+ was prevented by excess Zn2+, probably by blocking the entry of Cd2+ into the cell. We conclude that the inhibition of MMR by Cd2+ is through the inactivation of the ATPase activity of the MSH2-MSH6 heterodimer, resulting in a dominant negative effect and causing a mutator phenotype. PMID:15746000

  19. Vitamin E derivative-based multifunctional nanoemulsions for overcoming multidrug resistance in cancer.

    Science.gov (United States)

    Zheng, Nannan; Gao, Yanan; Ji, Hongyu; Wu, Linhua; Qi, Xuejing; Liu, Xiaona; Tang, Jingling

    2016-08-01

    The multidrug resistance (MDR), including intrinsic and acquired multidrug resistance, is a major problem in tumor chemotherapy. Here, we proposed a strategy for modulating intrinsic and/or acquired multidrug resistance by altering the levels of Bax and Bcl-2 expression and inhibiting the transport function of P-gp, increasing the intracellular concentration of its substrate anticancer drugs. Vitamin E derivative-based nanoemulsions containing paclitaxel (MNEs-PTX) were fabricated in this study, and in vitro anticancer efficacy of the nanoemulsion system was evaluated in the paclitaxel-resistant human ovarian carcinoma cell line A2780/Taxol. The MNEs-PTX exhibited a remarkably enhanced antiproliferation effect on A2780/Taxol cells than free paclitaxel (PTX) (p Vitamin E derivative-based multifunctional nanoemulsion (MNEs) obviously increased intracellular accumulation of rhodamine 123 (P-gp substrate). Overexpression of Bcl-2 is generally associated with tumor drug resistance, we found that MNEs could reduce Bcl-2 protein level and increase Bax protein level. Taken together, our findings suggest that anticancer drugs associated with MNEs could play a role in the development of MDR in cancers. PMID:26710274

  20. Overcoming barriers to the implementation of a pharmacy bar code scanning system for medication dispensing: a case study.

    Science.gov (United States)

    Nanji, Karen C; Cina, Jennifer; Patel, Nirali; Churchill, William; Gandhi, Tejal K; Poon, Eric G

    2009-01-01

    Technology has great potential to reduce medication errors in hospitals. This case report describes barriers to, and facilitators of, the implementation of a pharmacy bar code scanning system to reduce medication dispensing errors at a large academic medical center. Ten pharmacy staff were interviewed about their experiences during the implementation. Interview notes were iteratively reviewed to identify common themes. The authors identified three main barriers to pharmacy bar code scanning system implementation: process (training requirements and process flow issues), technology (hardware, software, and the role of vendors), and resistance (communication issues, changing roles, and negative perceptions about technology). The authors also identified strategies to overcome these barriers. Adequate training, continuous improvement, and adaptation of workflow to address one's own needs mitigated process barriers. Ongoing vendor involvement, acknowledgment of technology limitations, and attempts to address them were crucial in overcoming technology barriers. Staff resistance was addressed through clear communication, identifying champions, emphasizing new information provided by the system, and facilitating collaboration. PMID:19567797

  1. Toward the prevention of childhood undernutrition: Diet diversity strategies using locally produced food can overcome gaps in nutrient supply

    DEFF Research Database (Denmark)

    Parlesak, Alexandr; Geelhoed, Diederike; Robertson, Aileen

    2014-01-01

    or liver, dried fish and fresh moringa leaves, before applying linear programming decreased the price by a factor of up to 2.6. As a result, the top three quintiles could afford the FNFB optimized using both diversification strategy and linear programming. CDFPs, when added to the baskets, were...... programming, to investigate whether diet diversification using local foods should be prioritized in order to reduce the prevalence of chronic undernutrition. Methods. Market prices of local foods were collected in Tete City, Mozambique. Linear programming was applied to calculate the cheapest possible fully...... unable to overcome the micronutrient gaps without greatly exceeding recommended energy intakes, due to their high ratio of energy to micronutrient density. Conclusions. Dietary diversification strategies using local, low-cost, nutrient-dense foods can meet all micronutrient recommendations and overcome...

  2. OVERCOMING OBSTACLES TO IMPLEMENTING THE UN DECLARATION ON THE RIGHTS OF INDIGENOUS PEOPLES IN CANADA

    Directory of Open Access Journals (Sweden)

    Brenda L Gunn

    2015-02-01

    Full Text Available The majority vote by the General Assembly, which brought the UN Declaration on the Rights of Indigenous Peoples into existence as an international instrument, was just the first step.  Now the long and difficult road of implementation begins.  Implementation requires the application of international law in a specific national context.  This article explores the potential obstacles to implement the UN Declaration in Canada and suggest avenues to overcome these obstacles.  This article concludes that the main obstacle is not a legal one, but rather a lack of political will.  Given the limited understandings of the UN Declaration as an international instrument and how international law applies in Canada, this article provides an overview of the significance of a Declaration in international law and also explains how international law applies in Canada.  The main recommendation to promote implementation is greater education on the UN Declaration.  However, there are also many actions that Indigenous peoples, lawyers and advocates can take to promote implementation in legal and political domains that are discussed at the end of the article.   Le vote majoritaire de l’Assemblée générale, qui a donné naissance à la Déclaration des Nations unies sur les droits des peuples autochtones comme instrument international, était la toute première étape.  Commence maintenant le long et difficile parcours vers sa mise en œuvre.  Cette mise en œuvre requiert l’application du droit international dans un contexte national particulier.  Le présent article examine les obstacles potentiels à la mise en œuvre de la Déclaration des Nations unies au Canada et propose des avenues pour surmonter ces obstacles. Cet article conclut que le principal obstacle n’est pas de nature juridique, mais réside dans l’absence de volonté politique. Étant donné que la Déclaration des Nations unies en tant qu’instrument international et la fa

  3. Alpha particle emitters in cancer therapy: establishing the rationale and overcoming the difficulties

    International Nuclear Information System (INIS)

    rapidly accessible disease. Alpha particles will be most useful in situations in which targeting is rapid, killing of isolated single-cells is important and access to normal tissue is minimized. The latter may be achieved by intracavitary administration or by labeling an agent that does not reach normal tissues before the radionuclide has decayed below an acceptable level. Although alpha-particle emitters have shown promise in animal models, they have not been examined in patients. The decay of 212Bi is accompanied by emission of high energy (2.6 MeV) photons which are difficult to shield; 211At is cyclotron produced and of limited availability. The initial obstacles to the use of alpha-particle emitters for therapy are availability, handling and radiochemistry. These are being overcome with the introduction of new radionuclides and better radiochemistry. Bismuth-213, for example, is similar to Bi-212 in its alpha particle emissions but does not emit the highly energetic photon seen with Bi-212. Once the initial, logistical obstacles are surmounted, the dosimetry and normal tissue toxicity must be investigated

  4. Pluronic P85-coated poly(butylcyanoacrylate) nanoparticles overcome phenytoin resistance in P-glycoprotein overexpressing rats with lithium-pilocarpine-induced chronic temporal lobe epilepsy.

    Science.gov (United States)

    Fang, Ziyan; Chen, Shuda; Qin, Jiaming; Chen, Bao; Ni, Guanzhong; Chen, Ziyi; Zhou, Jueqian; Li, Ze; Ning, Yuping; Wu, Chuanbin; Zhou, Liemin

    2016-08-01

    P-glycoprotein (Pgp) overexpression in the blood brain barrier (BBB) is hypothesized to lower brain drug concentrations and thus inhibit anticonvulsant effects in drug-resistant epilepsy. Recently, the poly(butylcyanoacrylate) (PBCA) nanoparticle system was shown to overcome the obstacle of the BBB to deliver drugs into the brain. To determine whether pluronic P85-coated phenytoin poly(butylcyanoacrylate) nanoparticles (P85-PHT-PBCA-NPs) target PHT to the brain, PHT-resistant rats overexpressing Pgp in the BBB were screened by response to PHT treatment after chronic temporal lobe epilepsy induced by lithium-pilocarpine, followed by direct verification of PHT transport via measurement of brain PHT concentrations using microdialysis. Thereafter, the PHT-resistant rats were divided into three groups, which were treated with PHT, PHT + tariquidar (TQD), or P85-PHT-PBCA-NPs. PHT + TQD and P85-PHT-PBCA-NPs showed anticonvulsant activity in the PHT-resistant rats and increased the ratio of the area under the curve of the PHT concentrations in the brain/plasma in comparison with that observed in animals subjected to PHT treatment. However, the ratios of the PHT concentrations in the liver/plasma and kidney/plasma following P85-PHT-PBCA-NPs treatment were much lower than those measured following PHT + TQD treatment. Thus, Pgp overexpression decreases therapeutic drug concentrations in the brains of subjects with drug-resistant epilepsy and P85-PHT-PBCA-NPs could increase these drug concentrations. PMID:27162079

  5. PEG-PE-based micelles co-loaded with paclitaxel and cyclosporine A or loaded with paclitaxel and targeted by anticancer antibody overcome drug resistance in cancer cells.

    Science.gov (United States)

    Sarisozen, Can; Vural, Imran; Levchenko, Tatyana; Hincal, A Atilla; Torchilin, Vladimir P

    2012-05-01

    The over-expression of the P-glycoprotein (P-gp) in cancer cells is one of the main reasons of the acquired Multidrug Resistance (MDR). Combined treatment of MDR cancer cells with P-gp inhibitors and chemotherapeutic agents could result in reversal of resistance in P-gp-expressing cells. In this study, paclitaxel (PTX) was co-encapsulated in actively targeted (anticancer mAb 2C5-modified) polymeric lipid-core PEG-PE-based micelles with Cyclosporine A (CycA), which is one of the most effective first generation P-gp inhibitors. Cell culture studies performed using MDCKII (parental and MDR1) cell lines to investigate the potential MDR reversal effect of the formulations. The average size of both empty and loaded PEG₂₀₀₀-PE/Vitamin E mixed micelles was found between 10 and 25 nm. Zeta potentials of the formulations were found between -7 and -35 mV. The percentage of PTX in the micelles was found higher than 3% for both formulations and cumulative PTX release of about 70% was demonstrated. P-gp inhibition with CycA caused an increase in the cytotoxicity of PTX. Dual-loaded micelles demonstrated significantly higher cytotoxicity in the resistant MDCKII-MDR1 cells than micelles loaded with PTX alone. Micelle modification with mAb 2C5 results in the highest cytotoxicity against resistant cells, with or without P-gp modulator, probably because of better internalization bypassing the P-gp mechanism. Our results suggest that micelles delivering a combination of P-gp modulator and anticancer drug or micelles loaded with only PTX, but targeted with mAb 2C5 represent a promising approach to overcome drug resistance in cancer cells. PMID:22506922

  6. Sertraline reduces IL-1β and TNF-α mRNA expression and overcomes their rise induced by seizures in the rat hippocampus.

    Directory of Open Access Journals (Sweden)

    María Sitges

    Full Text Available We recently discovered that the antidepressant sertraline is an effective inhibitor of hippocampus presynaptic Na+ channel permeability in vitro and of tonic-clonic seizures in animals in vivo. Several studies indicate that the pro-inflammatory cytokines in the central nervous system are increased in epilepsy and depression. On the other hand inhibition of Na+ channels has been shown to decrease pro-inflammatory cytokines in microglia. Therefore, the possibility that sertraline could overcome the rise in pro-inflammatory cytokine expression induced by seizures has been investigated. For this purpose, IL-1β and TNF-α mRNA expression was determined by RT-PCR in the hippocampus of rats administered once, or for seven consecutive days with sertraline at a low dose (0.75 mg/kg. The effect of sertraline at doses within the range of 0.75 to 25 mg/kg on the increase in IL-1β and TNF-α mRNA expression accompanying generalized tonic-clonic seizures, and increase in the pro-inflammatory cytokines expression induced by lipopolysaccharide was also investigated. We found that under basal conditions, a single 0.75 mg/kg sertraline dose decreased IL-1β mRNA expression, and also TNF-α expression after repeated doses. The increase in IL-1β and TNF-α expression induced by the convulsive agents and by the inoculation of lipopolysaccharide in the hippocampus was markedly reduced by sertraline also. Present results indicate that a reduction of brain inflammatory processes may contribute to the anti-seizure sertraline action, and that sertraline can be safely and successfully used at low doses to treat depression in epileptic patients.

  7. Identification of retinoic acid in a high content screen for agents that overcome the anti-myogenic effect of TGF-beta-1.

    Directory of Open Access Journals (Sweden)

    Chateen Krueger

    Full Text Available BACKGROUND: Transforming growth factor beta 1 (TGF-β1 is an inhibitor of muscle cell differentiation that is associated with fibrosis, poor regeneration and poor function in some diseases of muscle. When neutralizing antibodies to TGF-β1 or the angiotensin II inhibitor losartan were used to reduce TGF-β1 signaling, muscle morphology and function were restored in mouse models of Marfan Syndrome and muscular dystrophy. The goal of our studies was to identify additional agents that overcome the anti-myogenic effect of TGF-β1. METHODOLOGY/PRINCIPAL FINDINGS: A high-content cell-based assay was developed in a 96-well plate format that detects the expression of myosin heavy chain (MHC in C2C12 cells. The assay was used to quantify the dose-dependent responses of C2C12 cell differentiation to TGF-β1 and to the TGF-β1 Type 1 receptor kinase inhibitor, SB431542. Thirteen agents previously described as promoting C2C12 differentiation in the absence of TGF-β1 were screened in the presence of TGF-β1. Only all-trans retinoic acid and 9-cis retinoic acid allowed a maximal level of C2C12 cell differentiation in the presence of TGF-β1; the angiotensin-converting enzyme inhibitor captopril and 10 nM estrogen provided partial rescue. Vitamin D was a potent inhibitor of retinoic acid-induced myogenesis in the presence of TGF-β1. TGF-β1 inhibits myoblast differentiation through activation of Smad3; however, retinoic acid did not inhibit TGF-β1-induced activation of a Smad3-dependent reporter gene in C2C12 cells. CONCLUSIONS/SIGNIFICANCE: Retinoic acid alleviated the anti-myogenic effect of TGF-β1 by a Smad3-independent mechanism. With regard to the goal of improving muscle regeneration and function in individuals with muscle disease, the identification of retinoic acid is intriguing in that some retinoids are already approved for human therapy. However, retinoids also have well-described adverse effects. The quantitative, high-content assay will be

  8. Detection and screening of small molecule agents for overcoming Sorafenib resistance of hepatocellular carcinoma: a bioinformatics study

    OpenAIRE

    Lv, Jinli; Zhu, Bo; Zhang, Liang; Xie, Qichao; Zhuo, Wenlei

    2015-01-01

    Sorafenib, a novel orally-available multikinase inhibitor blocking several crucial oncogenic signaling pathways, presented survival benefits and became the first-line drug for treatment of patients with Hepatocellular carcinoma (HCC). However, the acquired resistance to Sorafenib resulted in limited benefits. In this study, we aimed to explore possible agents that might overcome Sorafenib resistance by bioinformatics methods. The gene expression profiles of HCC-3sp (acquired Sorafenib-resista...

  9. Water management and water harvesting: how to overcome constraints in community gardening in semi-arid Mali

    OpenAIRE

    Bass, Hans-Heinrich; Freyhold, Klaus von; Weisskoeppel, Cordula

    2013-01-01

    Malnutrition, i.e. the undersupply of micro-nutrients, is a common phenomenon in the villages of West African Mali. Community gardening can help to overcome the gap between supply of and requirements for micro-nutrients. In addition to its effect on nutrition, community gardening supports the pro-poor orientation of economic growth, and has a potentially positive effect on human capital formation, communal coherence, and women’s empowerment. Water supply, however, is a major bottleneck for ga...

  10. The Influence of Creativity Level on Overcoming the Barriers of Teachers’ Professional Development

    OpenAIRE

    2015-01-01

    The paper summarizes the research findings concerning the influence of creativity on overcoming the barriers of teachers’ professional development. The re- search subject includes defining the interrelations between the creativity and profes- sional burn-out. The aim of the studies is to find out the influencing factors of creativ- ity eliminating the destructive trends of professional pedagogic activity. The methodology is based on the E. E. Simanyuk’s concept describing the de- structive te...

  11. If you try, you’ll get by: Chinese private firms’ efficiency gains from overcoming financial constraints

    OpenAIRE

    Galina Hale; Cheryl Long

    2010-01-01

    It appears to be common knowledge that external financing in China is mostly limited to state-owned firms and is hard to obtain for smaller private firms. In this paper we first confirm this pattern for more recent data and then investigate ways in which private firms overcome their financing constraints. We find that private firms reduce their need for external funds through more efficient management of inventory levels and accounts receivable. We further show that the low levels of inventor...

  12. A Novel submicron emulsion system loaded with doxorubicin overcome multi-drug resistance in MCF-7/ADR cells

    OpenAIRE

    Zhou, W. P.; H Y Hua; Sun, P. C.; Y.X. Zhao

    2015-01-01

    The purpose of the present study was to develop the Solutol HS15-based doxorubicin submicron emulsion with good stability and overcoming multi-drug resistance. In this study, we prepared doxorubicin submicron emulsion, and examined the stability after autoclaving, the in vitro cytotoxic activity, the intracellular accumulation and apoptpsis of doxorubicin submicron emulsion in MCF-7/ADR cells. The physicochemical properties of doxorubicin submicron emulsion were not significantly affected aft...

  13. The Application of Lateral Inhibition Model in Image's Contour Enhancement and Design of Its Electro-Model

    Directory of Open Access Journals (Sweden)

    Hongwei Fu

    2009-12-01

    Full Text Available For overcoming the problems such as distortion and shift of object’s edge, easily losing the object detail information of methods in image edge detection, and satisfying higher demand for object detection in the modern war, a new image edge detection method was designed. LOG edge detection as a typical image processing method was introduced and the disadvantage of this model was analyzed firstly. Based on lateral inhibition theory, an acyclic lateral inhibition network model (ALINM based on biology vision information processing mechanism was designed. The feasibility of object detection by lateral inhibition model was analyzed, in order to express the advantage such as rapid calculation easily real time operation of ALINM, the calculation magnitude of circulation difference lateral inhibition model was analyzed. Besides the correctness of ALINM was confirmed with two input cells, its transfer function was deduced. An algorithm of image edge detection based on this model was established finally, lateral inhibition effect also was confirmed by one-dimension and two-dimension circuit model based ALINM. Simulative experiment with different parameters and physics experiment prove that acyclic lateral inhibition network model can be realized easily, it can preserve the farthest detail information of object and has faster calculation speed than LOG operator. ALINM and lateral inhibition theory provide a useful method based on biology vision for object detection under difficult imaging conditions.

  14. Osteogenic Inhibition in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Nasim Kalantari

    2013-01-01

    Full Text Available Objective: Multiple myeloma (MM is a plasma cell malignancy where plasma cells are increased in the bone marrow (BM and usually do not enter peripheral blood, but produce harmful factors creating problems in these patients (e.g. malignant plasma cells over activate osteoclasts and inhibit osteoblasts with factors like RANKL and DKK. These factors are a main cause of bone lesion in MM patients. Recently SOST gene which responsible to encodes the sclerostin protein was identify. This protein specifically inhibits Wnt signaling in osteoblasts (inhibition of osteoblast differentiation and proliferation and decrease bone formation and can also cause bone lesion in MM patients.Materials and Methods: In this experimental study, human myeloma cell lines (U266 b1 were purchased from Pasteur Institute of Iran. Samples consisted of BM aspirates from the iliac crest of MM patients. BM with more than 70% plasma cell were selected for our study (6 patients and one healthy donor. RNA extraction was done with Qiagen kit. was undertaken on mRNA of samples and cell lines. Also we purchased unrestricted somatic stem cells from Bonyakhte Company to evaluate the effect of soluble factors from myeloma cell lines on osteogenic differentiation medium.Results: Our results showed that SOST is expressed significantly in primary myeloma cells derived from MM patients and myeloma cell lines. In other words, patients with more bone problems, express SOST in their plasma cells at a higher level. In addition, myeloma cells inhibit osteoblast differentiation in progenitor cells from umbilical cord blood stem cell (UCSC in osteogenic inducing medium.Conclusion: There are many osteoblast maturation inhibitory factors such as DKK, Sfrp and Sclerostin that inhibit maturation of osteoblast in bone. Among osteoblast inhibitory agents (DKK, Sfrp, Sclerostin sclerostin has the highest specificity and therefore will have less side effect versus non-specific inhibitory agents. Our

  15. Sym004, a novel EGFR antibody mixture, can overcome acquired resistance to cetuximab.

    Science.gov (United States)

    Iida, Mari; Brand, Toni M; Starr, Megan M; Li, Chunrong; Huppert, Evan J; Luthar, Neha; Pedersen, Mikkel W; Horak, Ivan D; Kragh, Michael; Wheeler, Deric L

    2013-10-01

    The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in a variety of human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for head and neck and colorectal cancer treatment, but many patients treated with cetuximab don't respond or eventually acquire resistance. To determine how tumor cells acquire resistance to cetuximab, we previously developed a model of acquired resistance using the non-small cell lung cancer line NCI-H226. These cetuximab-resistant (Ctx(R)) cells exhibit increased steady-state EGFR expression secondary to alterations in EGFR trafficking and degradation and, further, retained dependence on EGFR signaling for enhanced growth potential. Here, we examined Sym004, a novel mixture of antibodies directed against distinct epitopes on the extracellular domain of EGFR, as an alternative therapy for Ctx(R) tumor cells. Sym004 treatment of Ctx(R) clones resulted in rapid EGFR degradation, followed by robust inhibition of cell proliferation and down-regulation of several mitogen-activated protein kinase pathways. To determine whether Sym004 could have therapeutic benefit in vivo, we established de novo Ctx(R) NCI-H226 mouse xenografts and subsequently treated Ctx(R) tumors with Sym004. Sym004 treatment of mice harboring Ctx(R) tumors resulted in growth delay compared to mice continued on cetuximab. Levels of total and phospho-EGFR were robustly decreased in Ctx(R) tumors treated with Sym004. Immunohistochemical analysis of these Sym004-treated xenograft tumors further demonstrated decreased expression of Ki67, and phospho-rpS6, as well as a modest increase in cleaved caspase-3. These results indicate that Sym004 may be an effective targeted therapy for Ctx(R) tumors. PMID:24204198

  16. Sym004, a Novel EGFR Antibody Mixture, Can Overcome Acquired Resistance to Cetuximab

    Directory of Open Access Journals (Sweden)

    Mari Iida

    2013-10-01

    Full Text Available The epidermal growth factor receptor (EGFR is a central regulator of tumor progression in a variety of human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for head and neck and colorectal cancer treatment, but many patients treated with cetuximab don't respond or eventually acquire resistance. To determine how tumor cells acquire resistance to cetuximab, we previously developed a model of acquired resistance using the non-small cell lung cancer line NCI-H226. These cetuximab-resistant (CtxR cells exhibit increased steady-state EGFR expression secondary to alterations in EGFR trafficking and degradation and, further, retained dependence on EGFR signaling for enhanced growth potential. Here, we examined Sym004, a novel mixture of antibodies directed against distinct epitopes on the extracellular domain of EGFR, as an alternative therapy for CtxR tumor cells. Sym004 treatment of CtxR clones resulted in rapid EGFR degradation, followed by robust inhibition of cell proliferation and down-regulation of several mitogen-activated protein kinase pathways. To determine whether Sym004 could have therapeutic benefit in vivo, we established de novo CtxR NCI-H226 mouse xenografts and subsequently treated CtxR tumors with Sym004. Sym004 treatment of mice harboring CtxR tumors resulted in growth delay compared to mice continued on cetuximab. Levels of total and phospho-EGFR were robustly decreased in CtxR tumors treated with Sym004. Immunohistochemical analysis of these Sym004-treated xenograft tumors further demonstrated decreased expression of Ki67, and phospho-rpS6, as well as a modest increase in cleaved caspase-3. These results indicate that Sym004 may be an effective targeted therapy for CtxR tumors.

  17. Targeting head and neck cancer stem cells to overcome resistance to photon and carbon ion radiation.

    Science.gov (United States)

    Bertrand, Gérald; Maalouf, Mira; Boivin, Antony; Battiston-Montagne, Priscillia; Beuve, Michael; Levy, Antonin; Jalade, Patrice; Fournier, Claudia; Ardail, Dominique; Magné, Nicolas; Alphonse, Gersende; Rodriguez-Lafrasse, Claire

    2014-02-01

    Although promising new radiation therapy techniques such as hadrontherapy are currently being evaluated in the treatment of head and neck malignancies, local control of head and neck squamous cell carcinoma (HNSCC) remains low. Here, we investigated the involvement of cancer stem-like cells (CSCs) in a radioresistant HNSCC cell line (SQ20B). Stem-like cells SQ20B/SidePopulation(SP)/CD44(+)/ALDH(high) were more resistant to both photon and carbon ion irradiation compared with non-CSCs. This was confirmed by a BrdU labeling experiment, which suggests that CSCs were able to proliferate and to induce tumorigenicity after irradiation. SQ20B/SP/CD44(+)/ALDH(high) were capable of an extended G2/M arrest phase in response to photon or carbon ion irradiation compared with non-CSCs. Moreover, our data strongly suggest that resistance of CSCs may result from an imbalance between exacerbated self-renewal and proliferative capacities and the decrease in apoptotic cell death triggering. In order to modulate these processes, two targeted pharmacological strategies were tested. Firstly, UCN-01, a checkpoint kinase (Chk1) inhibitor, induced the relapse of G2/M arrest and radiosensitization of SQ20B-CSCs. Secondly, all-trans retinoic acid (ATRA) resulted in an inhibition of ALDH activity, and induction of the differentiation and radiosensitization of SQ20B/SP/CD44(+)/ALDH(high) cells. The combination of ATRA and UCN-01 treatments with irradiation drastically decreased the surviving fraction at 2Gy of SQ20B-CSCs from 0.85 to 0.38 after photon irradiation, and from 0.45 to 0.21 in response to carbon ions. Taken together, our results suggest that the combination of UCN-01 and ATRA represent a promising pharmacological-targeted strategy that significantly sensitizes CSCs to photon or carbon ion radiation. PMID:23955575

  18. Fallopia japonica, a Natural Modulator, Can Overcome Multidrug Resistance in Cancer Cells.

    Science.gov (United States)

    Eid, Safaa Yehia; El-Readi, Mahmoud Zaki; Ashour, Mohamed Lotfy; Wink, Michael

    2015-01-01

    Resistance of cancer cells to chemotherapy is controlled by the decrease of intracellular drug accumulation, increase of detoxification, and diminished propensity of cancer cells to undergo apoptosis. ATP-binding cassette (ABC) membrane transporters with intracellular metabolic enzymes contribute to the complex and unresolved phenomenon of multidrug resistance (MDR). Natural products as alternative medicine have great potential to discover new MDR inhibitors with diverse modes of action. In this study, we characterized several extracts of traditional Chinese medicine (TCM) plants (N = 16) for their interaction with ABC transporters, cytochrome P3A4 (CYP3A4), and glutathione-S-transferase (GST) activities and their cytotoxic effect on different cancer cell lines. Fallopia japonica (FJ) (Polygonaceae) shows potent inhibitory effect on CYP3A4 P-glycoprotein activity about 1.8-fold when compared to verapamil as positive control. FJ shows significant inhibitory effect (39.81%) compared with the known inhibitor ketoconazole and 100 μg/mL inhibited GST activity to 14 μmol/min/mL. FJ shows moderate cytotoxicity in human Caco-2, HepG-2, and HeLa cell lines; IC50 values were 630.98, 198.80, and 317.37 µg/mL, respectively. LC-ESI-MS were used to identify and quantify the most abundant compounds, emodin, polydatin, and resveratrol, in the most active extract of FJ. Here, we present the prospect of using Fallopia japonica as natural products to modulate the function of ABC drug transporters. We are conducting future study to evaluate the ability of the major active secondary metabolites of Fallopia japonica to modulate MDR and their impact in case of failure of chemotherapy. PMID:26346937

  19. Fallopia japonica, a Natural Modulator, Can Overcome Multidrug Resistance in Cancer Cells

    Directory of Open Access Journals (Sweden)

    Safaa Yehia Eid

    2015-01-01

    Full Text Available Resistance of cancer cells to chemotherapy is controlled by the decrease of intracellular drug accumulation, increase of detoxification, and diminished propensity of cancer cells to undergo apoptosis. ATP-binding cassette (ABC membrane transporters with intracellular metabolic enzymes contribute to the complex and unresolved phenomenon of multidrug resistance (MDR. Natural products as alternative medicine have great potential to discover new MDR inhibitors with diverse modes of action. In this study, we characterized several extracts of traditional Chinese medicine (TCM plants (N = 16 for their interaction with ABC transporters, cytochrome P3A4 (CYP3A4, and glutathione-S-transferase (GST activities and their cytotoxic effect on different cancer cell lines. Fallopia japonica (FJ (Polygonaceae shows potent inhibitory effect on CYP3A4 P-glycoprotein activity about 1.8-fold when compared to verapamil as positive control. FJ shows significant inhibitory effect (39.81% compared with the known inhibitor ketoconazole and 100 μg/mL inhibited GST activity to 14 μmol/min/mL. FJ shows moderate cytotoxicity in human Caco-2, HepG-2, and HeLa cell lines; IC50 values were 630.98, 198.80, and 317.37 µg/mL, respectively. LC-ESI-MS were used to identify and quantify the most abundant compounds, emodin, polydatin, and resveratrol, in the most active extract of FJ. Here, we present the prospect of using Fallopia japonica as natural products to modulate the function of ABC drug transporters. We are conducting future study to evaluate the ability of the major active secondary metabolites of Fallopia japonica to modulate MDR and their impact in case of failure of chemotherapy.

  20. Rossijskij jeksklav na Baltike: jevoljucija jeksklavnosti i poisk putej ee preodolenija [Russian Exclave on the Baltic Sea: Evolution of Exclavity and Ways to Overcome It

    Directory of Open Access Journals (Sweden)

    Klemeshev Andrey

    2009-01-01

    Full Text Available The author considers peculiarities of the emergence and evolution of exclavity of the Kaliningrad region. The article analyses the influence of exclavity on the connections of the region with the Russian mainland, its economic development, exclave administration, and Kaliningrad identity and examines the ways the existing disadvantages can be overcome. Methods of overcoming these disadvantages are suggested in the article.