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Sample records for overcome syk-mediated resistance

  1. Overcoming Resistance to Change

    Science.gov (United States)

    Hull, Ted H.; Balka, Don S.; Miles, Ruth Harbin

    2010-01-01

    Resistance to change is a major obstacle in developing and implementing effective instructional programs, yet it is rarely considered, discussed, or addressed. The school leaders who are responsible for improvement frequently feel that their efforts are being blocked or thwarted. For the most part, they are correct, but they may not realize that…

  2. 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.

  3. Using Epigenetic Therapy to Overcome Chemotherapy Resistance.

    Science.gov (United States)

    Strauss, Julius; Figg, William D

    2016-01-01

    It has been known for decades that as cancer progresses, tumors develop genetic alterations, making them highly prone to developing resistance to therapies. Classically, it has been thought that these acquired genetic changes are fixed. This has led to the paradigm of moving from one cancer therapy to the next while avoiding past therapies. However, emerging data on epigenetic changes during tumor progression and use of epigenetic therapies have shown that epigenetic modifications leading to chemotherapy resistance have the potential to be reversible with epigenetic therapy. In fact, promising clinical data exist that treatment with epigenetic agents can diminish chemotherapy resistance in a number of tumor types including chronic myelogenous leukemia, colorectal, ovarian, lung and breast cancer. The potential for epigenetic-modifying drugs to allow for treatment of resistant disease is exciting and clinical trials have just begun to evaluate this area. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  4. Anthelmintics Resistance; How to Overcome it?

    Directory of Open Access Journals (Sweden)

    Hatem A Shalaby

    2013-03-01

    Full Text Available Many parasitic helminthes of veterinary importance have genetic features that favor development of anthelmintic resistance, this becoming a major worldwide constrain in livestock production. The develop­ment of anthelmintic resistance poses a large threat to future production and welfare of graz­ing animals. Development of variable degrees of resistance among different species of gastrointes­tinal nematodes has been reported for all the major groups of anthelmintic drugs. It has been ob­served that frequent usage of the same group of anthelmintic; use of anthelmintics in sub-optimal doses, prophylactic mass treatment of domestic animals and frequent and continuous use of a single drug have contributed to the widespread development of anthelmintic resistance in helminthes. The degree and extent of this problem especially with respect to multidrug resistance in nematode popula­tions is likely to increase. Maintaining parasites in refugia and not exposed to anthelmintics, seems to be a key point in controlling and delaying the development of resistance, because the suscepti­ble genes are preserved. Targeted selective treatments attract the interest of scientists to­wards this direction. Additionally, adoption of strict quarantine measures and a combination drug strategy are two important methods of preventing of anthelmintic resistance. Experience from the development of anthelmintic resistance suggests that modern control schemes should not rely on sole use of anthelmintics, but employ other, more complex and sustainable recipes, including parasite resistant breeds, nutrition, pasture management, nematode-trapping fungi, antiparasitic vaccines and botanical dewormers. Most of them reduce reliance on the use of chemicals and are environmental friendly. Finally, if new anthelmintic products are released, an important question will be raised about how they should be used. It is suggested that slowing the development of resistance to a new

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

    OpenAIRE

    2008-01-01

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

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

    Science.gov (United States)

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

    2018-01-01

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

  7. 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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations

    Directory of Open Access Journals (Sweden)

    Nourah Mohammad Obaid

    2017-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Markus Vähä-Koskela

    2014-01-01

    Full Text Available 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.

  10. Will new antimicrobials overcome resistance among Gram-negatives?

    Science.gov (United States)

    Bassetti, Matteo; Ginocchio, Francesca; Mikulska, Małgorzata; Taramasso, Lucia; Giacobbe, Daniele Roberto

    2011-10-01

    The spread of resistance among Gram-positive and Gram-negative bacteria represents a growing challenge for the development of new antimicrobials. The pace of antibiotic drug development has slowed during the last decade and, especially for Gram-negatives, clinicians are facing a dramatic shortage in the availability of therapeutic options to face the emergency of the resistance problem throughout the world. In this alarming scenario, although there is a shortage of compounds reaching the market in the near future, antibiotic discovery remains one of the keys to successfully stem and maybe overcome the tide of resistance. Analogs of already known compounds and new agents belonging to completely new classes of antimicrobials are in early stages of development. Novel and promising anti-Gram-negative antimicrobials belong both to old (cephalosporins, carbapenems, β-lactamase inhibitors, monobactams, aminoglycosides, polymyxin analogues and tetracycline) and completely new antibacterial classes (boron-containing antibacterial protein synthesis inhibitors, bis-indoles, outer membrane synthesis inhibitors, antibiotics targeting novel sites of the 50S ribosomal subunit and antimicrobial peptides). However, all of these compounds are still far from being introduced into clinical practice. Therefore, infection control policies and optimization in the use of already existing molecules are still the most effective approaches to reduce the spread of resistance and preserve the activity of antimicrobials.

  11. A Salmonella nanoparticle mimic overcomes multidrug resistance in tumours.

    Science.gov (United States)

    Mercado-Lubo, Regino; Zhang, Yuanwei; Zhao, Liang; Rossi, Kyle; Wu, Xiang; Zou, Yekui; Castillo, Antonio; Leonard, Jack; Bortell, Rita; Greiner, Dale L; Shultz, Leonard D; Han, Gang; McCormick, Beth A

    2016-07-25

    Salmonella enterica serotype Typhimurium is a food-borne pathogen that also selectively grows in tumours and functionally decreases P-glycoprotein (P-gp), a multidrug resistance transporter. Here we report that the Salmonella type III secretion effector, SipA, is responsible for P-gp modulation through a pathway involving caspase-3. Mimicking the ability of Salmonella to reverse multidrug resistance, we constructed a gold nanoparticle system packaged with a SipA corona, and found this bacterial mimic not only accumulates in tumours but also reduces P-gp at a SipA dose significantly lower than free SipA. Moreover, the Salmonella nanoparticle mimic suppresses tumour growth with a concomitant reduction in P-gp when used with an existing chemotherapeutic drug (that is, doxorubicin). On the basis of our finding that the SipA Salmonella effector is fundamental for functionally decreasing P-gp, we engineered a nanoparticle mimic that both overcomes multidrug resistance in cancer cells and increases tumour sensitivity to conventional chemotherapeutics.

  12. Supermolecular drug challenge to overcome drug resistance in cancer cells.

    Science.gov (United States)

    Onishi, Yasuhiko; Eshita, Yuki; Ji, Rui-Cheng; Kobayashi, Takashi; Onishi, Masayasu; Mizuno, Masaaki; Yoshida, Jun; Kubota, Naoji

    2018-06-04

    Overcoming multidrug resistance (MDR) of cancer cells can be accomplished using drug delivery systems in large-molecular-weight ATP-binding cassette transporters before entry into phagolysosomes and by particle-cell-surface interactions. However, these hypotheses do not address the intratumoral heterogeneity in cancer. Anti-MDR must be related to alterations of drug targets, expression of detoxification, as well as altered proliferation. In this study, it is shown that the excellent efficacy and sustainability of anti-MDR is due to a stable ES complex because of the allosteric facilities of artificial enzymes when they are used as supramolecular complexes. The allosteric effect of supermolecular drugs can be explained by the induced-fit model and can provide stable feedback control systems through the loop transfer function of the Hill equation. Copyright © 2018 Elsevier Ltd. All rights reserved.

  13. Techniques for overcoming community resistance to family planning programs.

    Science.gov (United States)

    Palley, H A

    1968-01-01

    Methods of overcoming resistance to publicly subsidized family planning programs are discussed. The main sources of opposition include groups that oppose family planning for moral reasons, and those who object to the spending of government funds to provide services and information. Such opposition can be weakened by indicating that family planning clinics fulf: 11 important medical needs. Presenting social justification for family planning can help to lower oppostion. In order to secure participation in the programs by low income groups it is essential to have community leaders involved in policy decisions and to use indigenous community paraprofessionals in the clinics. A coalition of representatives of the poor community and the health and welfare system, aided by the community organization, can lead to an effective family planning program.

  14. Strategies to potentiate antimicrobial photoinactivation by overcoming resistant phenotypes†

    Science.gov (United States)

    Vera, D. Mariano A.; Haynes, Mark H; Ball, Anthony R.; Dai, D. Tianhong; Astrakas, Christos; Kelso, Michael J; Hamblin, Michael R; Tegos, George P.

    2012-01-01

    Conventional antimicrobial strategies have become increasingly ineffective due to the emergence of multidrug resistance among pathogenic microorganisms. The need to overcome these deficiencies has triggered the exploration of alternative treatments and unconventional approaches towards controlling microbial infections. Photodynamic therapy was originally established as an anti-cancer modality and is currently used in the treatment of age related macular degeneration. The concept of photodynamic inactivation requires cell exposure to light energy, typically wavelengths in the visible region that causes the excitation of photosensitizer molecules either exogenous or endogenous, which results in the production of reactive oxygen species. ROS produce cell inactivation and death through modification of intracellular components. The versatile characteristics of PDT prompted its investigation as an anti-infective discovery platform. Advances in understanding of microbial physiology have shed light on a series of pathways, and phenotypes that serve as putative targets for antimicrobial drug discovery. Investigations of these phenotypic elements in concert with PDT have been reported focused on multidrug efflux systems, biofilms, virulence and pathogenesis determinants. In many instances the results are promising but only preliminary and require further investigation. This review discusses the different antimicrobial PDT strategies and highlights the need for highly informative and comprehensive discovery approaches. PMID:22242675

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

    OpenAIRE

    Canonici, A; Gijsen, M; Mullooly, M; Bennett, R; Bouguern, N; Pedersen, K; O'Brien, NA; Roxanis, I; Li, J-L; Bridge, E; Finn, R; Siamon, D; McGowan, P; Duffy, MJ; O'Donovan, N

    2013-01-01

    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. ...

  16. 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.

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

    National Research Council Canada - National Science Library

    Johnson, Irene

    2004-01-01

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

  18. Overcoming cellular multidrug resistance using classical nanomedicine formulations

    Czech Academy of Sciences Publication Activity Database

    Kunjachan, S.; Blauz, A.; Möckel, D.; Theek, B.; Kiessling, F.; Etrych, Tomáš; Ulbrich, K.; van Bloois, L.; Storm, G.; Bartosz, G.; Rychlik, B.; Lammers, T.

    2012-01-01

    Roč. 45, č. 4 (2012), s. 421-428 ISSN 0928-0987 R&D Projects: GA AV ČR IAA400500806 Institutional research plan: CEZ:AV0Z40500505 Keywords : cancer * nanomedicine * multidrug resistance Subject RIV: CD - Macromolecular Chemistry Impact factor: 2.987, year: 2012

  19. Characteristics and overcome of the resistance to chemotherapeutic agents

    International Nuclear Information System (INIS)

    Hong, Weon Seon; Im, Young Hyuck; Kim, Young Sun

    1993-01-01

    Although the clinical use of colony-stimulating factor (CSF) improves the therapeutic results, there have been a lot of evidences that CSF may stimulate the growth of cancer cells. This study was conducted to investigate the effects of granulocytemacrophage(GM)-CSF and granulocyte(G)-CSF on the colony formations in eight human cancer cell lines. The stimulatory effects of GM-CSF and G-CSF on the colony formation were evaluated in human tumor colony assay against four human cancer cell lines, four sublines resistant to adriamycin or cisplatin : PC-9 and PC-14 (pulmonary adenoca), MKN-45 and KATO III (gastric adenoca), PC/ADM and PC/CDDP (sublines of PC-14 resistant to adriamycin and cisplatin, respectively), MKN/ADM and MKN/CDDP (sublines of MKN-45 resistant to adriamycin and cisplatin, respectively). Cancer cells were plated at concentrations of 1x10 3 and 1x10 5 cells/well in the upper layer. Two kinds of GM-CSF (LBD-005 and CSF 39-300) and two kinds of G-CSF (Grasin and Neutrogin) were tested by the addition of final concentrations of GM-CSF and G-CSF (0.01, 0.1 and 1.0 μg/ml) to the lower layer to allow continuous exposure for 14 days. The colony formations (%) of eight cell lines tested were 85-113% and 92-106% in wells plated at the concentrations (/well) of 1x10 3 and 1x10 5 plated, respectively, in all cell lines compared to those of control wells. These results suggest that GM-CSF and G-CSF dose not directly stimulate the growth of cancer cells in all cell lines tested. (Author)

  20. Alternatives to overcoming bacterial resistances: State-of-the-art.

    Science.gov (United States)

    Rios, Alessandra C; Moutinho, Carla G; Pinto, Flávio C; Del Fiol, Fernando S; Jozala, Angela; Chaud, Marco V; Vila, Marta M D C; Teixeira, José A; Balcão, Victor M

    2016-10-01

    Worldwide, bacterial resistance to chemical antibiotics has reached such a high level that endangers public health. Presently, the adoption of alternative strategies that promote the elimination of resistant microbial strains from the environment is of utmost importance. This review discusses and analyses several (potential) alternative strategies to current chemical antibiotics. Bacteriophage (or phage) therapy, although not new, makes use of strictly lytic phage particles as an alternative, or a complement, in the antimicrobial treatment of bacterial infections. It is being rediscovered as a safe method, because these biological entities devoid of any metabolic machinery do not possess any affinity whatsoever to eukaryotic cells. Lysin therapy is also recognized as an innovative antimicrobial therapeutic option, since the topical administration of preparations containing purified recombinant lysins with amounts in the order of nanograms, in infections caused by Gram-positive bacteria, demonstrated a high therapeutic potential by causing immediate lysis of the target bacterial cells. Additionally, this therapy exhibits the potential to act synergistically when combined with certain chemical antibiotics already available on the market. Another potential alternative antimicrobial therapy is based on the use of antimicrobial peptides (AMPs), amphiphilic polypeptides that cause disruption of the bacterial membrane and can be used in the treatment of bacterial, fungal and viral infections, in the prevention of biofilm formation, and as antitumoral agents. Interestingly, bacteriocins are a common strategy of bacterial defense against other bacterial agents, eliminating the potential opponents of the former and increasing the number of available nutrients in the environment for their own growth. They can be applied in the food industry as biopreservatives and as probiotics, and also in fighting multi-resistant bacterial strains. The use of antibacterial antibodies

  1. Overcoming EMT-driven therapeutic resistance by BH3 mimetics.

    Science.gov (United States)

    Keitel, Ulrike; Scheel, Christina; Dobbelstein, Matthias

    2014-01-01

    Epithelial-mesenchymal transition (EMT) contributes to the progression of cancer through enhanced invasion and stem-like properties of cancer cells. Additionally, EMT confers resistance towards many chemotherapeutics. We recently described a mechanism that mediates EMT-driven chemoresistance through augmented levels of Bcl-xL, an anti-apoptotic member of the Bcl-2 family (Keitel et al., Oncotarget, in press). Here, we elaborate on how these findings pertain to cancer cells dispersed in the tumor-adjacent stroma of breast cancer tissues, and how BH3-mimetics may provide a therapeutic strategy to eliminate cancer cell populations that have passed through an EMT.

  2. Rhodacyanine derivative selectively targets cancer cells and overcomes tamoxifen resistance.

    Directory of Open Access Journals (Sweden)

    John Koren

    Full Text Available MKT-077, a rhodacyanine dye, was shown to produce cancer specific cell death. However, complications prevented the use of this compound beyond clinical trials. Here we describe YM-1, a derivative of MKT-077. We found that YM-1 was more cytotoxic and localized differently than MKT-077. YM-1 demonstrated this cytotoxicity across multiple cancer cell lines. This toxicity was limited to cancer cell lines; immortalized cell models were unaffected. Brief applications of YM-1 were found to be non-toxic. Brief treatment with YM-1 restored tamoxifen sensitivity to a refractory tamoxifen-resistant MCF7 cell model. This effect is potentially due to altered estrogen receptor alpha phosphorylation, an outcome precipitated by selective reductions in Akt levels (Akt/PKB. Thus, modifications to the rhodocyanine scaffold could potentially be made to improve efficacy and pharmacokinetic properties. Moreover, the impact on tamoxifen sensitivity could be a new utility for this compound family.

  3. Understanding Supplier Resistance - Overcoming Obstacles to Supply Innovation

    Directory of Open Access Journals (Sweden)

    New Steve

    2014-11-01

    Full Text Available This paper explores an important but unexplored theme in the development of 'total quality' relationships in the supply chain: why suppliers may exhibit resistance to quality initiatives, and why what seems to customers as cooperation can appear as unwelcome interference or even exploitation to suppliers. This is a question of great relevance to all those seeking to understand current business practice, and also to those seeking to bring about practical improvements in supply chain quality. Too much of the supply chain and quality literature assumes the issue of supplier's compliance with customer initiatives is unproblematic (unable to understand this sentence; experience suggests it is one of the major obstacles in developing the quality-oriented, integrated supply chain.

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

    Science.gov (United States)

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

    2017-12-15

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

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

    Science.gov (United States)

    Moyer-Guse, Emily; Nabi, Robin L.

    2010-01-01

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

  6. Overcoming antibiotic resistance: Is siderophore Trojan horse conjugation an answer to evolving resistance in microbial pathogens?

    Science.gov (United States)

    Dhusia, Kalyani; Bajpai, Archana; Ramteke, P W

    2018-01-10

    Comparative study of siderophore biosynthesis pathway in pathogens provides potential targets for antibiotics and host drug delivery as a part of computationally feasible microbial therapy. Iron acquisition using siderophore models is an essential and well established model in all microorganisms and microbial infections a known to cause great havoc to both plant and animal. Rapid development of antibiotic resistance in bacterial as well as fungal pathogens has drawn us at a verge where one has to get rid of the traditional way of obstructing pathogen using single or multiple antibiotic/chemical inhibitors or drugs. 'Trojan horse' strategy is an answer to this imperative call where antibiotic are by far sneaked into the pathogenic cell via the siderophore receptors at cell and outer membrane. This antibiotic once gets inside, generates a 'black hole' scenario within the opportunistic pathogens via iron scarcity. For pathogens whose siderophore are not compatible to smuggle drug due to their complex conformation and stiff valence bonds, there is another approach. By means of the siderophore biosynthesis pathways, potential targets for inhibition of these siderophores in pathogenic bacteria could be achieved and thus control pathogenic virulence. Method to design artificial exogenous siderophores for pathogens that would compete and succeed the battle of intake is also covered with this review. These manipulated siderophore would enter pathogenic cell like any other siderophore but will not disperse iron due to which iron inadequacy and hence pathogens control be accomplished. The aim of this review is to offer strategies to overcome the microbial infections/pathogens using siderophore. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Comparison of Strategies to Overcome Drug Resistance: Learning from Various Kingdoms

    Directory of Open Access Journals (Sweden)

    Hiroshi Ogawara

    2018-06-01

    Full Text Available Drug resistance, especially antibiotic resistance, is a growing threat to human health. To overcome this problem, it is significant to know precisely the mechanisms of drug resistance and/or self-resistance in various kingdoms, from bacteria through plants to animals, once more. This review compares the molecular mechanisms of the resistance against phycotoxins, toxins from marine and terrestrial animals, plants and fungi, and antibiotics. The results reveal that each kingdom possesses the characteristic features. The main mechanisms in each kingdom are transporters/efflux pumps in phycotoxins, mutation and modification of targets and sequestration in marine and terrestrial animal toxins, ABC transporters and sequestration in plant toxins, transporters in fungal toxins, and various or mixed mechanisms in antibiotics. Antibiotic producers in particular make tremendous efforts for avoiding suicide, and are more flexible and adaptable to the changes of environments. With these features in mind, potential alternative strategies to overcome these resistance problems are discussed. This paper will provide clues for solving the issues of drug resistance.

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

    Science.gov (United States)

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

    2014-01-01

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

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

    International Nuclear Information System (INIS)

    Wang, Xin; Liu, Ying; Wang, Shouju; Shi, Donghong; Zhou, Xianguang; Wang, Chunyan; Wu, Jiang; Zeng, Zhiyong; Li, Yanjun; Sun, Jing; Wang, Jiandong; Zhang, Longjiang; Teng, Zhaogang; Lu, Guangming

    2015-01-01

    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

  10. Progress toward overcoming hypoxia-induced resistance to solid tumor therapy

    International Nuclear Information System (INIS)

    Karakashev, Sergey V; Reginato, Mauricio J

    2015-01-01

    Hypoxic tumors are associated with poor clinical outcome for multiple types of human cancer. This may be due, in part, to hypoxic cancer cells being resistant to anticancer therapy, including radiation therapy, chemotherapy, and targeted therapy. Hypoxia inducible factor 1, a major regulator of cellular response to hypoxia, regulates the expression of genes that are involved in multiple aspects of cancer biology, including cell survival, proliferation, metabolism, invasion, and angiogenesis. Here, we review multiple pathways regulated by hypoxia/hypoxia inducible factor 1 in cancer cells and discuss the latest advancements in overcoming hypoxia-mediated tumor resistance

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

    KAUST Repository

    Manzoor, Safia

    2018-02-13

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

  12. 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.

  13. Inhibition of BMP signaling overcomes acquired resistance to cetuximab in oral squamous cell carcinomas.

    Science.gov (United States)

    Yin, Jinlong; Jung, Ji-Eun; Choi, Sun Il; Kim, Sung Soo; Oh, Young Taek; Kim, Tae-Hoon; Choi, Eunji; Lee, Sun Joo; Kim, Hana; Kim, Eun Ok; Lee, Yu Sun; Chang, Hee Jin; Park, Joo Yong; Kim, Yeejeong; Yun, Tak; Heo, Kyun; Kim, Youn-Jae; Kim, Hyunggee; Kim, Yun-Hee; Park, Jong Bae; Choi, Sung Weon

    2018-02-01

    Despite expressing high levels of the epidermal growth factor receptor (EGFR), a majority of oral squamous cell carcinoma (OSCC) patients show limited response to cetuximab and ultimately develop drug resistance. However, mechanism underlying cetuximab resistance in OSCC is not clearly understood. Here, using a mouse orthotopic xenograft model of OSCC, we show that bone morphogenic protein-7-phosphorylated Smad-1, -5, -8 (BMP7-p-Smad1/5/8) signaling contributes to cetuximab resistance. Tumor cells isolated from the recurrent cetuximab-resistant xenograft models exhibited low EGFR expression but extremely high levels of p-Smad1/5/8. Treatment with the bone morphogenic protein receptor type 1 (BMPRI) inhibitor, DMH1 significantly reduced cetuximab-resistant OSCC tumor growth, and combined treatment of DMH1 and cetuximab remarkably reduced relapsed tumor growth in vivo. Importantly, p-Smad1/5/8 level was elevated in cetuximab-resistant patients and this correlated with poor prognosis. Collectively, our results indicate that the BMP7-p-Smad1/5/8 signaling is a key pathway to acquired cetuximab resistance, and demonstrate that combination therapy of cetuximab and a BMP signaling inhibitor as potentially a new therapeutic strategy for overcoming acquired resistance to cetuximab in OSCC. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Overcoming Resistance to Cetuximab with Honokiol, A Small-Molecule Polyphenol.

    Science.gov (United States)

    Pearson, Hannah E; Iida, Mari; Orbuch, Rachel A; McDaniel, Nellie K; Nickel, Kwangok P; Kimple, Randall J; Arbiser, Jack L; Wheeler, Deric L

    2018-01-01

    Overexpression and activation of the EGFR have been linked to poor prognosis in several human cancers. Cetuximab is a mAb against EGFR that is used for the treatment in head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer. Unfortunately, most tumors have intrinsic or will acquire resistance to cetuximab during the course of therapy. Honokiol is a natural compound found in the bark and leaves of the Chinese Magnolia tree and is established to have several anticancer properties without appreciable toxicity. In this study, we hypothesized that combining cetuximab and honokiol treatments could overcome acquired resistance to cetuximab. We previously developed a model of acquired resistance to cetuximab in non-small cell lung cancer H226 cell line. Treatment of cetuximab-resistant clones with honokiol and cetuximab resulted in a robust antiproliferative response. Immunoblot analysis revealed the HER family and their signaling pathways were downregulated after combination treatment, most notably the proliferation (MAPK) and survival (AKT) pathways. In addition, we found a decrease in phosphorylation of DRP1 and reactive oxygen species after combination treatment in cetuximab-resistant clones, which may signify a change in mitochondrial function. Furthermore, we utilized cetuximab-resistant HNSCC patient-derived xenografts (PDX) to test the benefit of combinatorial treatment in vivo There was significant growth delay in PDX tumors after combination treatment with a subsequent downregulation of active MAPK, AKT, and DRP1 signaling as seen in vitro Collectively, these data suggest that honokiol is a promising natural compound in overcoming acquired resistance to cetuximab. Mol Cancer Ther; 17(1); 204-14. ©2017 AACR . ©2017 American Association for Cancer Research.

  15. Etanercept overcomes P-glycoprotein-induced drug resistance in lymphocytes of patients with intractable rheumatoid arthritis.

    Science.gov (United States)

    Tsujimura, Shizuyo; Saito, Kazuyoshi; Nakayamada, Shingo; Tanaka, Yoshiya

    2010-04-01

    P-glycoprotein (P-gp) on activated lymphocytes is an adenosine triphosphate (ATP)-binding cassette transporter that causes drug resistance by exclusion of intracellular drugs in patients with active rheumatoid arthritis (RA). However, infliximab with methotrexate (MTX) can overcome P-gp-mediated drug resistance. We encounter patients who cannot continue infliximab or MTX. Here we tested how etanercept affected P-gp-mediated drug resistance in such intractable RA patients. Peripheral lymphocytes of 11 RA patients (3 switched from infliximab and 8 who could not be treated with MTX) were analyzed for P-gp expression by flow cytometry and for drug exclusion using radioisotope-labeled dexamethasone. Activated lymphocytes of RA patients overexpressed P-gp and coexpressed CD69. Incubation of these lymphocytes with dexamethasone in vitro reduced intracellular dexamethasone levels. Two-week etanercept therapy significantly reduced P-gp expression and eliminated such P-gp- and CD69-high-expressing subgroup. The reduction in P-gp resulted in recovery of intracellular dexamethasone levels in lymphocytes and improvement of disease activity, thus allowing tapering of corticosteroids. None of the patients experienced any severe adverse effects. Etanercept is useful for overcoming P-gp-mediated treatment resistance in intractable RA patients who have to discontinue infliximab or are intolerant to MTX.

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

    Science.gov (United States)

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

    2016-11-20

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

  17. PI3K inhibition to overcome endocrine resistance in breast cancer.

    Science.gov (United States)

    Keegan, Niamh M; Gleeson, Jack P; Hennessy, Bryan T; Morris, Patrick G

    2018-01-01

    Activation of the phosphatidylinositol-3 kinase (PI3K) pathway is a critical step in oncogenesis and plays a role in the development of treatment resistance for both estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) positive breast cancers. Hence, there have been efforts to therapeutically inhibit this pathway. Areas covered: Several inhibitors of PI3K are now progressing through clinical trials with varying degrees of efficacy and toxicity to date. Numerous unresolved questions remain concerning the optimal isoform selectivity of PI3K inhibitors and use of predictive biomarkers. This review examines the most important PI3K inhibitors in ER positive breast cancer to date, with a particular focus on their role in overcoming endocrine therapy resistance and the possible use of PIK3CA mutations as a predictive biomarker. Expert opinion: We discuss some of the emerging challenges and questions encountered during the development of PI3K inhibitors from preclinical to phase III studies, including other novel biomarkers and future combinations to overcome endocrine resistance.

  18. Novel Holistic Approaches for Overcoming Therapy Resistance in Pancreatic and Colon Cancers.

    Science.gov (United States)

    Sarkar, Fazlul H

    2016-01-01

    Gastrointestinal (GI) cancers, such as of the colon and pancreas, are highly resistant to both standard and targeted therapeutics. Therapy-resistant and heterogeneous GI cancers harbor highly complex signaling networks (the resistome) that resist apoptotic programming. Commonly used gemcitabine or platinum-based regimens fail to induce meaningful (i.e. disease-reversing) perturbations in the resistome, resulting in high rates of treatment failure. The GI cancer resistance networks are, in part, due to interactions between parallel signaling and aberrantly expressed microRNAs (miRNAs) that collectively promote the development and survival of drug-resistant cancer stem cells with epithelial-to-mesenchymal transition (EMT) characteristics. The lack of understanding of the resistance networks associated with this subpopulation of cells as well as reductionist, single protein-/pathway-targeted approaches have made 'effective drug design' a difficult task. We propose that the successful design of novel therapeutic regimens to target drug-resistant GI tumors is only possible if network-based drug avenues and agents, in particular 'natural agents' with no known toxicity, are correctly identified. Natural agents (dietary agents or their synthetic derivatives) can individually alter miRNA profiles, suppress EMT pathways and eliminate cancer stem-like cells that derive from pancreatic cancer and colon cancer, by partially targeting multiple yet meaningful networks within the GI cancer resistome. However, the efficacy of these agents as combinations (e.g. consumed in the diet) against this resistome has never been studied. This short review article provides an overview of the different challenges involved in the understanding of the GI resistome, and how novel computational biology can help in the design of effective therapies to overcome resistance. © 2015 S. Karger AG, Basel.

  19. Pristimerin overcomes adriamycin resistance in breast cancer cells through suppressing Akt signaling

    Science.gov (United States)

    XIE, GUI'E; YU, XINPEI; LIANG, HUICHAO; CHEN, JINGSONG; TANG, XUEWEI; WU, SHAOQING; LIAO, CAN

    2016-01-01

    Breast cancer remains a major public health problem worldwide. Chemotherapy serves an important role in the treatment of breast cancer. However, resistance to chemotherapeutic agents, in particular, multi-drug resistance (MDR), is a major cause of treatment failure in cancer. Agents that can either enhance the effects of chemotherapeutics or overcome chemoresistance are urgently needed for the treatment of breast cancer. Pristimerin, a quinonemethide triterpenoid compound isolated from Celastraceae and Hippocrateaceae, has been shown to possess antitumor, anti-inflammatory, antioxidant and insecticidal properties. The aim of the present study was to investigate whether pristimerin can override chemoresistance in MCF-7/adriamycin (ADR)-resistant human breast cancer cells. The results demonstrated that pristimerin indeed displayed potent cytocidal effect on multidrug-resistant MCF-7/ADR breast cancer cells, and that these effects occurred through the suppression of Akt signaling, which in turn led to the downregulation of antiapoptotic effectors and increased apoptosis. These findings indicate that use of pristimerin may represent a potentially promising approach for the treatment of ADR-resistant breast cancer. PMID:27123073

  20. Strategies to overcome or circumvent P-glycoprotein mediated multidrug resistance.

    Science.gov (United States)

    Yuan, Hongyu; Li, Xun; Wu, Jifeng; Li, Jinpei; Qu, Xianjun; Xu, Wenfang; Tang, Wei

    2008-01-01

    Cancer patients who receive chemotherapy often experience intrinsic or acquired resistance to a broad spectrum of chemotherapeutic agents. The phenomenon, termed multidrug resistance (MDR), is often associated with the over-expression of P-glycoprotein, a transmembrane protein pump, which can enhance efflux of a various chemicals structurally unrelated at the expense of ATP depletion, resulting in decrease of the intracellular cytotoxic drug accumulation. The MDR has been a big threaten to the human health and the war fight for it continues. Although several other mechanisms for MDR are elucidated in recent years, considerable efforts attempting to inverse MDR are involved in exploring P-glycoprotein modulators and suppressing P-glycoprotein expression. In this review, we will report on the recent advances in various strategies for overcoming or circumventing MDR mediated by P-glycoprotein.

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

    Directory of Open Access Journals (Sweden)

    Laura Pisarsky

    2016-05-01

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

  2. 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.

  3. Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance in vitro.

    Science.gov (United States)

    Khdair, Ayman; Handa, Hitesh; Mao, Guangzhao; Panyam, Jayanth

    2009-02-01

    Drug resistance limits the success of many anticancer drugs. Reduced accumulation of the drug at its intracellular site of action because of overexpression of efflux transporters such as P-glycoprotein (P-gp) is a major mechanism of drug resistance. In this study, we investigated whether photodynamic therapy (PDT) using methylene blue, also a P-gp inhibitor, can be used to enhance doxorubicin-induced cytotoxicity in drug-resistant tumor cells. Aerosol OT (AOT)-alginate nanoparticles were used as a carrier for the simultaneous cellular delivery of doxorubicin and methylene blue. Methylene blue was photoactivated using light of 665 nm wavelength. Induction of apoptosis and necrosis following treatment with combination chemotherapy and PDT was investigated in drug-resistant NCI/ADR-RES cells using flow cytometry and fluorescence microscopy. Effect of encapsulation in nanoparticles on the intracellular accumulation of doxorubicin and methylene blue was investigated qualitatively using fluorescence microscopy and was quantitated using HPLC. Encapsulation in AOT-alginate nanoparticles significantly enhanced the cytotoxicity of combination therapy in resistant tumor cells. Nanoparticle-mediated combination therapy resulted in a significant induction of both apoptosis and necrosis. Improvement in cytotoxicity could be correlated with enhanced intracellular and nuclear delivery of the two drugs. Further, nanoparticle-mediated combination therapy resulted in significantly elevated reactive oxygen species (ROS) production compared to single drug treatment. In conclusion, nanoparticle-mediated combination chemotherapy and PDT using doxorubicin and methylene blue was able to overcome resistance mechanisms and resulted in improved cytotoxicity in drug-resistant tumor cells.

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

    International Nuclear Information System (INIS)

    Susa, Michiro; Iyer, Arun K; Ryu, Keinosuke; Hornicek, Francis J; Mankin, Henry; Amiji, Mansoor M; Duan, Zhenfeng

    2009-01-01

    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, KHOS R2 , U-2OS, and U-2OS R2 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

  5. Zinc Finger Nuclease: A New Approach to Overcome Beta-Lactam Antibiotic Resistance

    Science.gov (United States)

    Shahbazi Dastjerdeh, Mansoureh; Kouhpayeh, Shirin; Sabzehei, Faezeh; Khanahmad, Hossein; Salehi, Mansour; Mohammadi, Zahra; Shariati, Laleh; Hejazi, Zahra; Rabiei, Parisa; Manian, Mostafa

    2016-01-01

    Background: The evolution of antibiotic-resistant bacteria (ARB) and antibiotic-resistance genes (ARGs) has been accelerated recently by the indiscriminate application of antibiotics. Antibiotic resistance has challenged the success of medical interventions and therefore is considered a hazardous threat to human health. Objectives: The present study aimed to describe the use of zinc finger nuclease (ZFN) technology to target and disrupt a plasmid-encoded β-lactamase, which prevents horizontal gene transfer-mediated evolution of ARBs. Materials and Methods: An engineered ZFN was designed to target a specific sequence in the ampicillin resistance gene (ampR) of the pTZ57R plasmid. The Escherichia coli bacteria already contained the pZFN kanamycin-resistant (kanaR) plasmid as the case or the pP15A, kanaR empty vector as the control, were transformed with the pTZ57R; the ability of the designed ZFN to disrupt the β-lactamase gene was evaluated with the subsequent disturbed ability of the bacteria to grow on ampicillin (amp) and ampicillin-kanamycin (amp-kana)-containing media. The effect of mild hypothermia on the ZFN gene targeting efficiency was also evaluated. Results: The growth of bacteria in the case group on the amp and amp-kana-containing media was significantly lower compared with the control group at 37°C (P < 0.001). Despite being more efficient in hypothermic conditions at 30°C (P < 0.001), there were no significant associations between the incubation temperature and the ZFN gene targeting efficiency. Conclusions: Our findings revealed that the ZFN technology could be employed to overcome ampicillin resistance by the targeted disruption of the ampicillin resistance gene, which leads to inactivation of β-lactam synthesis. Therefore, ZFN technology could be engaged to decrease the antibiotic resistance issue with the construction of a ZFN archive against different ARGs. To tackle the resistance issue at the environmental level, recombinant phages

  6. Green Tea Catechin-Based Complex Micelles Combined with Doxorubicin to Overcome Cardiotoxicity and Multidrug Resistance

    Science.gov (United States)

    Cheng, Tangjian; Liu, Jinjian; Ren, Jie; Huang, Fan; Ou, Hanlin; Ding, Yuxun; Zhang, Yumin; Ma, Rujiang; An, Yingli; Liu, Jianfeng; Shi, Linqi

    2016-01-01

    Chemotherapy for cancer treatment has been demonstrated to cause some side effects on healthy tissues and multidrug resistance of the tumor cells, which greatly limits therapeutic efficacy. To address these limitations and achieve better therapeutic efficacy, combination therapy based on nanoparticle platforms provides a promising approach through delivering different agents simultaneously to the same destination with synergistic effect. In this study, a novel green tea catechin-based polyion complex (PIC) micelle loaded with doxorubicin (DOX) and (-)-Epigallocatechin-3-O-gallate (EGCG) was constructed through electrostatic interaction and phenylboronic acid-catechol interaction between poly(ethylene glycol)-block-poly(lysine-co-lysine-phenylboronic acid) (PEG-PLys/PBA) and EGCG. DOX was co-loaded in the PIC micelles through π-π stacking interaction with EGCG. The phenylboronic acid-catechol interaction endowed the PIC micelles with high stability under physiological condition. Moreover, acid cleavability of phenylboronic acid-catechol interaction in the micelle core has significant benefits for delivering EGCG and DOX to same destination with synergistic effects. In addition, benefiting from the oxygen free radicals scavenging activity of EGCG, combination therapy with EGCG and DOX in the micelle core could protect the cardiomyocytes from DOX-mediated cardiotoxicity according to the histopathologic analysis of hearts. Attributed to modulation of EGCG on P-glycoprotein (P-gp) activity, this kind of PIC micelles could effectively reverse multidrug resistance of cancer cells. These results suggested that EGCG based PIC micelles could effectively overcome DOX induced cardiotoxicity and multidrug resistance. PMID:27375779

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

    International Nuclear Information System (INIS)

    Yoshimoto, Koji; Mizoguchi, Masahiro; Hata, Nobuhiro; Murata, Hideki; Hatae, Ryusuke; Amano, Toshiyuki; Nakamizo, Akira; Sasaki, Tomio

    2012-01-01

    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 (GBM). Although the activity of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) has been described as the main modulator to determine the sensitivity of GBM to TMZ, a subset of GBM 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 repair and double-strand break 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Yoshimoto, Koji; Mizoguchi, Masahiro; Hata, Nobuhiro; Murata, Hideki; Hatae, Ryusuke; Amano, Toshiyuki; Nakamizo, Akira; Sasaki, Tomio, E-mail: kyoshimo@ns.med.kyushu-u.ac.jp [Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan)

    2012-12-05

    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 (GBM). Although the activity of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) has been described as the main modulator to determine the sensitivity of GBM to TMZ, a subset of GBM 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 repair and double-strand break 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.

  9. Encapsulation in lipid-core nanocapsules overcomes lung cancer cell resistance to tretinoin.

    Science.gov (United States)

    Schultze, Eduarda; Ourique, Aline; Yurgel, Virginia Campello; Begnini, Karine Rech; Thurow, Helena; de Leon, Priscila Marques Moura; Campos, Vinicius Farias; Dellagostin, Odir Antônio; Guterres, Silvia R; Pohlmann, Adriana R; Seixas, Fabiana Kömmling; Beck, Ruy Carlos Ruver; Collares, Tiago

    2014-05-01

    Tretinoin is a retinoid derivative that has an antiproliferative effect on several kinds of tumours. Human lung adenocarcinoma epithelial cell lines (A549) exhibit a profound resistance to the effects of tretinoin. Nanocarriers seem to be a good alternative to overcomecellular resistance to drugs. The aim of this study was to test whether tretinoin-loaded lipid-core nanocapsules exert anantitumor effect on A549 cells. A549 cells were incubated with free tretinoin (TTN), blank nanocapsules (LNC) and tretinoin-loaded lipid-core nanocapsules (TTN-LNC). Data from evaluation of DNA content and Annexin V binding assay by flow cytometry showed that TTN-LNC induced apoptosis and cell cycle arrest at the G1-phase while TTN did not. TTN-LNC showed higher cytotoxic effects than TTN on A549 cells evaluated by MTT and LIVE/DEAD cell viability assay. Gene expression profiling identified up-regulated expression of gene p21 by TTN-LNC, supporting the cell cycle arrest effect. These results showed for the first time that TTN-LNC are able to overcome the resistance of adenocarcinoma cell line A549 to treatment with TTN by inducing apoptosis and cell cycle arrest, providing support for their use in applications in lung cancer therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2018-03-05

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

  11. Overcoming Antimicrobial Resistance in Bacteria Using Bioactive Magnetic Nanoparticles and Pulsed Electromagnetic Fields

    Directory of Open Access Journals (Sweden)

    Vitalij Novickij

    2018-01-01

    Full Text Available Nisin is a known bacteriocin, which exhibits a wide spectrum of antimicrobial activity, while commonly being inefficient against Gram-negative bacteria. In this work, we present a proof of concept of novel antimicrobial methodology using targeted magnetic nisin-loaded nano-carriers [iron oxide nanoparticles (NPs (11–13 nm capped with citric, ascorbic, and gallic acids], which are activated by high pulsed electric and electromagnetic fields allowing to overcome the nisin-resistance of bacteria. As a cell model the Gram-positive bacteria Bacillus subtilis and Gram-negative Escherichia coli were used. We have applied 10 and 30 kV cm-1 electric field pulses (100 μs × 8 separately and in combination with two pulsed magnetic field protocols: (1 high dB/dt 3.3 T × 50 and (2 10 mT, 100 kHz, 2 min protocol to induce additional permeabilization and local magnetic hyperthermia. We have shown that the high dB/dt pulsed magnetic fields increase the antimicrobial efficiency of nisin NPs similar to electroporation or magnetic hyperthermia methods and a synergistic treatment is also possible. The results of our work are promising for the development of new methods for treatment of the drug-resistant foodborne pathogens to minimize the risks of invasive infections.

  12. SUCCESSION PROCESS IN A FAMILY BUSINESS: KNOWLEDGE MANAGEMENT OVERCOMING RESISTANCE TO ORGANIZATIONAL CHANGES

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    Patricia de Sá Freire

    2010-12-01

    Full Text Available This study examined the perception of a family business’ employees over changes brought about by the company’s succession procsess through the identification of existing problems and the probabilities of overcoming them. The company was classified as a family business organization as per Bernhoeft´s (1991 definition, and the perspectives proposed by Motta (2001 were used as a basis for change analysis. The succession challenges were studied through the knowledge management viewpoint. The methodological approach is characterized as a qualitative descriptive study done through interviews and document analysis. Quantitative data was used, with the application of questionnaires in order to obtain primary data. Data analysis is mainly characterized by its qualitative and descriptive content. After data analysis, the following issues were detected: (1 lack of or inneficient internal communication, (2 the decision making process was either slow or not committed to the desired results and (3 there was either dual leadership or no leadership. It was concluded that in order to achieve the objectives of the changes, it would require a new look into the intraorganizational integration to eliminate features of the family business such as lack of dialogue and unilateral decisions. It is finally suggested the use of strategies for sharing information and knowledge that will pave the way for understanding the entire succession process, overcoming uncertainties and individual resistance. Thus, the inclusion of Knowledge Management in the family business succession process will result in more aware leaders, managers and employees in terms of change of power during the mentioned process.

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

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    Weideman, Albert

    2002-12-01

    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

  14. Overcoming Multidrug Resistance via Photodestruction of ABCG2-Rich Extracellular Vesicles Sequestering Photosensitive Chemotherapeutics

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    Goler-Baron, Vicky; Assaraf, Yehuda G.

    2012-01-01

    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 preventing

  15. Enhancing pharmacists' role in developing countries to overcome the challenge of antimicrobial resistance: a narrative review.

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    Sakeena, M H F; Bennett, Alexandra A; McLachlan, Andrew J

    2018-01-01

    Antimicrobial resistance (AMR) is a global health challenge and developing countries are more vulnerable to the adverse health impacts of AMR. Health care workers including pharmacists can play a key role to support the appropriate use of antimicrobials in developing countries and reduce AMR. The aim of this review is to investigate the role of pharmacists in the appropriate use of antibiotics and to identify how the pharmacists' role can be enhanced to combat AMR in developing countries. The databases MEDLINE, EMBASE, Web of Science and Google Scholar were searched for articles published between 2000 and the end of August 2017 that involved studies on the role of pharmacists in developing countries, the expanded services of pharmacists in patient care in developed countries and pharmacists' contributions in antimicrobial use in both developed and developing nations. In developing countries pharmacists role in patient care are relatively limited. However, in developed nations, the pharmacists' role has expanded to provide multifaceted services in patient care resulting in improved health outcomes from clinical services and reduced health care costs. Success stories of pharmacist-led programs in combating AMR demonstrates that appropriately trained pharmacists can be part of the solution to overcome the global challenge of AMR. Pharmacists can provide education to patients enabling them to use antibiotics appropriately. They can also provide guidance to their healthcare colleagues on appropriate antibiotic prescribing. This review highlights that appropriately trained pharmacists integrated into the health care system can make a significant impact in minimising inappropriate antibiotic use in developing countries. Strengthening and enhancing the pharmacists' role in developing countries has the potential to positively impact the global issue of AMR.

  16. Tumor-specific apoptotic gene targeting overcomes radiation resistance in esophageal adenocarcinoma

    International Nuclear Information System (INIS)

    Chang, Joe Y.; Zhang Xiaochun; Komaki, Ritsuko; Cheung, Rex; Fang Bingliang

    2006-01-01

    Purpose: To overcome radiation resistance in esophageal adenocarcinoma by tumor-specific apoptotic gene targeting using tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Methods and Materials: Adenoviral vector Ad/TRAIL-F/RGD with a tumor-specific human telomerase reverse transcription promoter was used to transfer TRAIL gene to human esophageal adenocarcinoma and normal human lung fibroblastic cells (NHLF). Activation of apoptosis was analyzed by Western blot, fluorescent activated cell sorting, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate labeling (TUNEL) assay. A human esophageal adenocarcinoma mouse model was treated with intratumoral injections of Ad/TRAIL-F/RGD plus local radiotherapy. Results: The combination of Ad/TRAIL-F/RGD and radiotherapy increased the cell-killing effect in all esophageal adenocarcinoma cell lines but not in NHLF cells. This combination also significantly reduced clonogenic formation (p < 0.05) and increased sub-G1 deoxyribonucleic acid accumulation in cancer cells (p < 0.05). Activation of apoptosis by Ad/TRAIL-F/RGD plus radiotherapy was demonstrated by activation of caspase-9, caspase-8, and caspase-3 and cleaved poly (adenosine diphosphate-ribose) polymerase in vitro and TUNEL assay in vivo. Combined Ad/TRAIL-F/RGD and radiotherapy dramatically inhibited tumor growth and prolonged mean survival in the esophageal adenocarcinoma model to 31.6 days from 16.7 days for radiotherapy alone and 21.5 days for Ad/TRAIL-F/RGD alone (p < 0.05). Conclusions: The combination of tumor-specific TRAIL gene targeting and radiotherapy enhances the effect of suppressing esophageal adenocarcinoma growth and prolonging survival

  17. A simple reduction-sensitive micelles co-delivery of paclitaxel and dasatinib to overcome tumor multidrug resistance

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    Li J

    2017-11-01

    Full Text Available Jun Li,1,* Ruitong Xu,2,* Xiao Lu,3 Jing He,1 Shidai Jin1 1Department of Medical Oncology, 2Department of General Practice, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 3Department of Medical Oncology, Changshu No 1 People’s Hospital, Changshu, People’s Republic of China *These authors contributed equally to this work Abstract: Multidrug resistance (MDR is one of the major obstacles in successful chemotherapy. The combination of chemotherapy drugs and multidrug-resistant reversing agents for treating MDR tumor is a good strategy to overcome MDR. In this work, we prepared the simple redox-responsive micelles based on mPEG-SS-C18 as a co-delivery system to load the paclitaxel (PTX and dasatinib (DAS for treatment of MCF-7/ADR cells. The co-loaded micelles had a good dispersity and a spherical shape with a uniform size distribution, and they could quickly disassemble and rapidly release drugs under the reduction environment. Compared with MCF-7 cells, the DAS and PTX co-loaded redox-sensitive micelle (SS-PDNPs showed stronger cytotoxicity and a more improving intracellular drug concentration than other drug formulations in MCF-7/ADR cells. In summary, the results suggested that the simple co-delivery micelles of PTX and DAS possessed significant potential to overcome drug resistance in cancer therapy. Keywords: redox responsive, overcoming multidrug resistant, co-delivery, paclitaxel, dasatinib 

  18. Novel Holistic Approaches for Overcoming Therapy Resistance in Pancreatic and Colon Cancers

    OpenAIRE

    Sarkar, Fazlul H.

    2015-01-01

    Gastrointestinal (GI) cancers, such as of the colon and pancreas, are highly resistant to both standard and targeted therapeutics. Therapy-resistant and heterogeneous GI cancers harbor highly complex signaling networks (the resistome) that resist apoptotic programming. Commonly used gemcitabine or platinum-based regimens fail to induce meaningful (i.e. disease-reversing) perturbations in the resistome, resulting in high rates of treatment failure. The GI cancer resistance networks are, in par...

  19. Super-Penetrant Androgen Receptor: Overcoming Enzalutamide Sensitivity in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2016-07-01

    Prostate Cancer Research Symposium- Prostate Cancer Epigenetic Reprogramming of the Androgen Receptor in Castration Resistant Prostate Cancer , May19... cancer cells rely critically on the androgen receptor (AR) for initiation, growth and progression to castration resistant prostate cancer (CRPC...Androgen receptor, castration resistant prostate cancer , Enzalutamide , kinases. 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER

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

    Science.gov (United States)

    Burmester, Elizabeth

    2017-01-01

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

  1. A Novel Docetaxel-Loaded Poly (ɛ-Caprolactone)/Pluronic F68 Nanoparticle Overcoming Multidrug Resistance for Breast Cancer Treatment

    Science.gov (United States)

    Mei, Lin; Zhang, Yangqing; Zheng, Yi; Tian, Ge; Song, Cunxian; Yang, Dongye; Chen, Hongli; Sun, Hongfan; Tian, Yan; Liu, Kexin; Li, Zhen; Huang, Laiqiang

    2009-12-01

    Multidrug resistance (MDR) in tumor cells is a significant obstacle to the success of chemotherapy in many cancers. The purpose of this research is to test the possibility of docetaxel-loaded poly (ɛ-caprolactone)/Pluronic F68 (PCL/Pluronic F68) nanoparticles to overcome MDR in docetaxel-resistance human breast cancer cell line. Docetaxel-loaded nanoparticles were prepared by modified solvent displacement method using commercial PCL and self-synthesized PCL/Pluronic F68, respectively. PCL/Pluronic F68 nanoparticles were found to be of spherical shape with a rough and porous surface. The nanoparticles had an average size of around 200 nm with a narrow size distribution. The in vitro drug release profile of both nanoparticle formulations showed a biphasic release pattern. There was an increased level of uptake of PCL/Pluronic F68 nanoparticles in docetaxel-resistance human breast cancer cell line, MCF-7 TAX30, when compared with PCL nanoparticles. The cytotoxicity of PCL nanoparticles was higher than commercial Taxotere® in the MCF-7 TAX30 cell culture, but the differences were not significant ( p > 0.05). However, the PCL/Pluronic F68 nanoparticles achieved significantly higher level of cytotoxicity than both of PCL nanoparticles and Taxotere® ( p < 0.05), indicating docetaxel-loaded PCL/Pluronic F68 nanoparticles could overcome multidrug resistance in human breast cancer cells and therefore have considerable potential for treatment of breast cancer.

  2. 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.

  3. Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

    Science.gov (United States)

    Iida, Mari; Bahrar, Harsh; Brand, Toni M; Pearson, Hannah E; Coan, John P; Orbuch, Rachel A; Flanigan, Bailey G; Swick, Adam D; Prabakaran, Prashanth; Lantto, Johan; Horak, Ivan D.; Kragh, Michael; Salgia, Ravi; Kimple, Randy J; Wheeler, Deric L

    2016-01-01

    Cetuximab, an antibody against the Epidermal Growth Factor Receptor (EGFR) has shown efficacy in treating head and neck squamous cell carcinoma (HNSCC), metastatic colorectal cancer and non-small cell lung cancer (NSCLC). Despite the clinical success of cetuximab, many patients do not respond to cetuximab. Furthermore, virtually all patients who do initially respond become refractory, highlighting both intrinsic and acquired resistance to cetuximab as significant clinical problems. To understand mechanistically how cancerous cells acquire resistance, we previously developed models of acquired resistance using the H226 NSCLC and UM-SCC1 HNSCC cell lines. Cetuximab-resistant clones showed a robust upregulation and dependency on the HER family receptors EGFR, HER2 and HER3. Here, we examined Pan-HER, a mixture of six antibodies targeting these receptors on cetuximab-resistant clones. In cells exhibiting acquired or intrinsic resistance to cetuximab, Pan-HER treatment decreased all three receptors’ protein levels and down-stream activation of AKT and MAPK. This correlated with decreased cell proliferation in cetuximab-resistant clones. To determine whether Pan-HER had a therapeutic benefit in vivo, we established de novo cetuximab-resistant mouse xenografts and treated resistant tumors with Pan-HER. This regimen resulted in a superior growth delay of cetuximab-resistant xenografts compared to mice continued on cetuximab. Furthermore, intrinsically cetuximab-resistant HNSCC patient-derived xenograft tumors treated with Pan-HER exhibited significant growth delay compared to vehicle/cetuximab controls. These results suggest that targeting HER family receptors simultaneously with Pan-HER is a promising treatment strategy for tumors displaying intrinsic or acquired resistance to cetuximab. PMID:27422810

  4. Current scenario of antibiotic resistance and latest strategies to overcome it

    Directory of Open Access Journals (Sweden)

    Mohankumar J Megha

    2014-09-01

    Full Text Available Antibiotic resistance in microorganisms has become a critical health issue these days and has evolved to become a worldwide health threat. Over a decade, the resistance level of bacteria has increased many folds due to various factors, accounting to the added pressure on the environmental resistome. Infections that are resistant to these antibiotics show potentially devastating effects on public health, often affecting developing countries. This review focuses on the present scenario of antibiotic resistance and enlists some of the strategies to combat this global community threat.

  5. Overcoming cetuximab resistance in Ewing's sarcoma by inhibiting lactate dehydrogenase-A.

    Science.gov (United States)

    Fu, Jiaxin; Jiang, Han; Wu, Chenxuan; Jiang, Yi; Xiao, Lianping; Tian, Yonggang

    2016-07-01

    Ewing's sarcoma, the second most common type of malignant bone tumor, generally occurs in children and young adults. The current treatment of Ewing's sarcoma comprises systemic anti‑cancer chemotherapy with complete surgical resection. However, the majority of patients with Ewing's sarcoma develop resistance to chemotherapy. The present study revealed an oncogenic role of lactate dehydrogenase‑A (LDHA) in the resistance of Ewing's sarcoma to cetuximab. LDHA was shown to be upregulated at the protein and mRNA level in cetuximab‑resistant Ewing's sarcoma tissues and a cell line. In addition, a link between LDHA‑induced glycolysis and cetuximab resistance in Ewing's sarcoma cells was revealed. Of note, inhibition of LDHA by either small interfering RNA or LDHA inhibitor oxamate significantly re‑sensitized cetuximab‑resistant cells to cetuximab. Combined treatment with LDHA inhibitor and cetuximab synergistically reduced the viability of cetuximab-resistant cells through the suppression of LDHA. The present study revealed a novel mechanism of cetuximab resistance from the perspective of cancer‑cell metabolism and provided a sensitization approach, which may aid in the development of anti-chemoresistance strategies for the treatment of cetuximab-resistant Ewing's sarcoma.

  6. Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance.

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    Con Dogovski

    2015-04-01

    Full Text Available Successful control of falciparum malaria depends greatly on treatment with artemisinin combination therapies. Thus, reports that resistance to artemisinins (ARTs has emerged, and that the prevalence of this resistance is increasing, are alarming. ART resistance has recently been linked to mutations in the K13 propeller protein. We undertook a detailed kinetic analysis of the drug responses of K13 wild-type and mutant isolates of Plasmodium falciparum sourced from a region in Cambodia (Pailin. We demonstrate that ART treatment induces growth retardation and an accumulation of ubiquitinated proteins, indicative of a cellular stress response that engages the ubiquitin/proteasome system. We show that resistant parasites exhibit lower levels of ubiquitinated proteins and delayed onset of cell death, indicating an enhanced cell stress response. We found that the stress response can be targeted by inhibiting the proteasome. Accordingly, clinically used proteasome inhibitors strongly synergize ART activity against both sensitive and resistant parasites, including isogenic lines expressing mutant or wild-type K13. Synergy is also observed against Plasmodium berghei in vivo. We developed a detailed model of parasite responses that enables us to infer, for the first time, in vivo parasite clearance profiles from in vitro assessments of ART sensitivity. We provide evidence that the clinical marker of resistance (delayed parasite clearance is an indirect measure of drug efficacy because of the persistence of unviable parasites with unchanged morphology in the circulation, and we suggest alternative approaches for the direct measurement of viability. Our model predicts that extending current three-day ART treatment courses to four days, or splitting the doses, will efficiently clear resistant parasite infections. This work provides a rationale for improving the detection of ART resistance in the field and for treatment strategies that can be employed in areas

  7. Harnessing the p53-PUMA Axis to Overcome DNA Damage Resistance in Renal Cell Carcinoma

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    Xiaoguang Zhou

    2014-12-01

    Full Text Available Resistance to DNA damage–induced apoptosis is a hallmark of cancer and a major cause of treatment failure and lethal disease outcome. A tumor entity that is largely resistant to DNA-damaging therapies including chemo- or radiotherapy is renal cell carcinoma (RCC. This study was designed to explore the underlying molecular mechanisms of DNA damage resistance in RCC to develop strategies to resensitize tumor cells to DNA damage–induced apoptosis. Here, we show that apoptosis-resistant RCC cells have a disconnect between activation of p53 and upregulation of the downstream proapoptotic protein p53 upregulated modulator of apoptosis (PUMA. We demonstrate that this disconnect is not caused by gene-specific repression through CCCTC-binding factor (CTCF but instead by aberrant chromatin compaction. Treatment with an HDAC inhibitor was found to effectively reactivate PUMA expression on the mRNA and protein level and to revert resistance to DNA damage–induced cell death. Ectopic expression of PUMA was found to resensitize a panel of RCC cell lines to four different DNA-damaging agents tested. Remarkably, all RCC cell lines analyzed were wild-type for p53, and a knockdown was likewise able to sensitize RCC cells to acute genotoxic stress. Taken together, our results indicate that DNA damage resistance in RCC is reversible, involves the p53-PUMA axis, and is potentially targetable to improve the oncological outcomes of RCC patients.

  8. Targeting NF-κB RelA/p65 phosphorylation overcomes RITA resistance.

    Science.gov (United States)

    Bu, Yiwen; Cai, Guoshuai; Shen, Yi; Huang, Chenfei; Zeng, Xi; Cao, Yu; Cai, Chuan; Wang, Yuhong; Huang, Dan; Liao, Duan-Fang; Cao, Deliang

    2016-12-28

    Inactivation of p53 occurs frequently in various cancers. RITA is a promising anticancer small molecule that dissociates p53-MDM2 interaction, reactivates p53 and induces exclusive apoptosis in cancer cells, but acquired RITA resistance remains a major drawback. This study found that the site-differential phosphorylation of nuclear factor-κB (NF-κB) RelA/p65 creates a barcode for RITA chemosensitivity in cancer cells. In naïve MCF7 and HCT116 cells where RITA triggered vast apoptosis, phosphorylation of RelA/p65 increased at Ser536, but decreased at Ser276 and Ser468; oppositely, in RITA-resistant cells, RelA/p65 phosphorylation decreased at Ser536, but increased at Ser276 and Ser468. A phosphomimetic mutation at Ser536 (p65/S536D) or silencing of endogenous RelA/p65 resensitized the RITA-resistant cells to RITA while the phosphomimetic mutant at Ser276 (p65/S276D) led to RITA resistance of naïve cells. In mouse xenografts, intratumoral delivery of the phosphomimetic p65/S536D mutant increased the antitumor activity of RITA. Furthermore, in the RITA-resistant cells ATP-binding cassette transporter ABCC6 was upregulated, and silencing of ABCC6 expression in these cells restored RITA sensitivity. In the naïve cells, ABCC6 delivery led to RITA resistance and blockage of p65/S536D mutant-induced RITA sensitivity. Taken together, these data suggest that the site-differential phosphorylation of RelA/p65 modulates RITA sensitivity in cancer cells, which may provide an avenue to manipulate RITA resistance. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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

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    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.

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

    Science.gov (United States)

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

    2018-04-01

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

  11. A novel HDAC inhibitor, CG200745, inhibits pancreatic cancer cell growth and overcomes gemcitabine resistance.

    Science.gov (United States)

    Lee, Hee Seung; Park, Soo Been; Kim, Sun A; Kwon, Sool Ki; Cha, Hyunju; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung; Song, Si Young

    2017-01-30

    Pancreatic cancer is predominantly lethal, and is primarily treated using gemcitabine, with increasing resistance. Therefore, novel agents that increase tumor sensitivity to gemcitabine are needed. Histone deacetylase (HDAC) inhibitors are emerging therapeutic agents, since HDAC plays an important role in cancer initiation and progression. We evaluated the antitumor effect of a novel HDAC inhibitor, CG200745, combined with gemcitabine/erlotinib on pancreatic cancer cells and gemcitabine-resistant pancreatic cancer cells. Three pancreatic cancer-cell lines were used to evaluate the antitumor effect of CG200745 combined with gemcitabine/erlotinib. CG200745 induced the expression of apoptotic proteins (PARP and caspase-3) and increased the levels of acetylated histone H3. CG200745 with gemcitabine/erlotinib showed significant growth inhibition and synergistic antitumor effects in vitro. In vivo, gemcitabine/erlotinib and CG200745 reduced tumor size up to 50%. CG200745 enhanced the sensitivity of gemcitabine-resistant pancreatic cancer cells to gemcitabine, and decreased the level of ATP-binding cassette-transporter genes, especially multidrug resistance protein 3 (MRP3) and MRP4. The novel HDAC inhibitor, CG200745, with gemcitabine/erlotinib had a synergistic anti-tumor effect on pancreatic cancer cells. CG200745 significantly improved pancreatic cancer sensitivity to gemcitabine, with a prominent antitumor effect on gemcitabine-resistant pancreatic cancer cells. Therefore, improved clinical outcome is expected in the future.

  12. A Novel Submicron Emulsion System Loaded with Doxorubicin Overcome Multi-Drug Resistance in MCF-7/ADR Cells.

    Science.gov (United States)

    Zhou, W P; Hua, H Y; Sun, P C; Zhao, Y X

    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 after autoclaving. The doxorubicin submicron emulsion significantly increased the intracellular accumulation of doxorubicin submicron emulsion and enhanced cytotoxic activity and apoptotic effects of doxorubicin. These results may be correlated to doxorubicin submicron emulsion inhibitory effects on efflux pumps through the progressive release of intracellular free Solutol HS15 from doxorubicin submicron emulsion. Furthermore, these in vitro results suggest that the Solutol HS15-based submicron emulsion may be a potentially useful drug delivery system to circumvent multi-drug resistance of tumor cells.

  13. New antibiotic agents in the pipeline and how they can help overcome microbial resistance.

    Science.gov (United States)

    Gould, Ian M; Bal, Abhijit M

    2013-02-15

    Bacterial resistance is a growing threat and yet few new antibiotics active against multi-resistant bacteria are being explored. A combination of falling profits, regulatory mechanisms and irrational and injudicious use of antibiotics has led to an alarming situation where some infections have no cure. In this article, we summarize the new developments that have been suggested to incentivize the pharmaceutical industries toward the field of infections. We also briefly mention the new compounds on the horizon and some newly approved compounds that might help us tide over this crisis.

  14. 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. ©2016 American Association for Cancer Research.

  15. The Use of Metaphor to Overcome Inmate Resistance to Mental Health Counseling.

    Science.gov (United States)

    Romig, Charles A.; Gruenke, Carol

    1991-01-01

    Provides an overview of prison inmate resistance to mental health counseling and describes ways that indirect, metaphorical communication can be used to establish rapport with this client population. Establishing rapport is difficult because of the suspicion that inmate clients have toward mental health professionals and the correctional system…

  16. Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer.

    LENUS (Irish Health Repository)

    Mohd Sharial, M S N

    2012-12-01

    Approximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival. HER2-targeted therapy has substantially improved outcomes in patients with HER2-positive breast cancer. However, both de novo and acquired resistance are observed.

  17. Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance.

    Science.gov (United States)

    Khdair, Ayman; Chen, Di; Patil, Yogesh; Ma, Linan; Dou, Q Ping; Shekhar, Malathy P V; Panyam, Jayanth

    2010-01-25

    Tumor drug resistance significantly limits the success of chemotherapy in the clinic. Tumor cells utilize multiple mechanisms to prevent the accumulation of anticancer drugs at their intracellular site of action. In this study, we investigated the anticancer efficacy of doxorubicin in combination with photodynamic therapy using methylene blue in a drug-resistant mouse tumor model. Surfactant-polymer hybrid nanoparticles formulated using an anionic surfactant, Aerosol-OT (AOT), and a naturally occurring polysaccharide polymer, sodium alginate, were used for synchronized delivery of the two drugs. Balb/c mice bearing syngeneic JC tumors (mammary adenocarcinoma) were used as a drug-resistant tumor model. Nanoparticle-mediated combination therapy significantly inhibited tumor growth and improved animal survival. Nanoparticle-mediated combination treatment resulted in enhanced tumor accumulation of both doxorubicin and methylene blue, significant inhibition of tumor cell proliferation, and increased induction of apoptosis. These data suggest that nanoparticle-mediated combination chemotherapy and photodynamic therapy using doxorubicin and methylene blue has significant therapeutic potential against drug-resistant tumors. Copyright 2009 Elsevier B.V. All rights reserved.

  18. Resistance to Change: Overcoming Institutional and Individual Limitations for Improving Student Behavior through PLCs

    Science.gov (United States)

    Maag, John W.

    2009-01-01

    Many public schools currently have organizational structures that form barriers for dealing more effectively with students' challenging behaviors even though positive school-wide approaches exist and provide empirical support for their use. Nevertheless, resistance to change occurs at both institutional and individual levels. Improving student…

  19. The Imipridone ONC201 Induces Apoptosis and Overcomes Chemotherapy Resistance by Up-Regulation of Bim in Multiple Myeloma.

    Science.gov (United States)

    Tu, Yong-Sheng; He, Jin; Liu, Huan; Lee, Hans C; Wang, Hua; Ishizawa, Jo; Allen, Joshua E; Andreeff, Michael; Orlowski, Robert Z; Davis, Richard E; Yang, Jing

    2017-10-01

    In multiple myeloma, despite recent improvements offered by new therapies, disease relapse and drug resistance still occur in the majority of patients. Therefore, there is an urgent need for new drugs that can overcome drug resistance and prolong patient survival after failure of standard therapies. The imipridone ONC201 causes downstream inactivation of ERK1/2 signaling and has tumoricidal activity against a variety of tumor types, while its efficacy in preclinical models of myeloma remains unclear. In this study, we treated human myeloma cell lines and patient-derived tumor cells with ONC201. Treatment decreased cellular viability and induced apoptosis in myeloma cell lines, with IC50 values of 1 to 1.5 μM, even in those with high risk features or TP53 loss. ONC201 increased levels of the pro-apoptotic protein Bim in myeloma cells, resulting from decreased phosphorylation of degradation-promoting Bim Ser69 by ERK1/2. In addition, myeloma cell lines made resistant to several standard-of-care agents (by chronic exposure) were equally sensitive to ONC201 as their drug-naïve counterparts, and combinations of ONC201 with proteasome inhibitors had synergistic anti-myeloma activity. Overall, these findings demonstrate that ONC201 kills myeloma cells regardless of resistance to standard-of-care therapies, making it promising for clinical testing in relapsed/refractory myeloma. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  20. The Imipridone ONC201 Induces Apoptosis and Overcomes Chemotherapy Resistance by Up-Regulation of Bim in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Yong-sheng Tu

    2017-10-01

    Full Text Available In multiple myeloma, despite recent improvements offered by new therapies, disease relapse and drug resistance still occur in the majority of patients. Therefore, there is an urgent need for new drugs that can overcome drug resistance and prolong patient survival after failure of standard therapies. The imipridone ONC201 causes downstream inactivation of ERK1/2 signaling and has tumoricidal activity against a variety of tumor types, while its efficacy in preclinical models of myeloma remains unclear. In this study, we treated human myeloma cell lines and patient-derived tumor cells with ONC201. Treatment decreased cellular viability and induced apoptosis in myeloma cell lines, with IC50 values of 1 to 1.5 μM, even in those with high risk features or TP53 loss. ONC201 increased levels of the pro-apoptotic protein Bim in myeloma cells, resulting from decreased phosphorylation of degradation-promoting Bim Ser69 by ERK1/2. In addition, myeloma cell lines made resistant to several standard-of-care agents (by chronic exposure were equally sensitive to ONC201 as their drug-naïve counterparts, and combinations of ONC201 with proteasome inhibitors had synergistic anti-myeloma activity. Overall, these findings demonstrate that ONC201 kills myeloma cells regardless of resistance to standard-of-care therapies, making it promising for clinical testing in relapsed/refractory myeloma.

  1. Sym004, a Novel EGFR Antibody Mixture, Can Overcome Acquired Resistance to Cetuximab1

    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

    2013-01-01

    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 (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. PMID:24204198

  2. A novel HDAC inhibitor, CG200745, inhibits pancreatic cancer cell growth and overcomes gemcitabine resistance

    OpenAIRE

    Lee, Hee Seung; Park, Soo Been; Kim, Sun A; Kwon, Sool Ki; Cha, Hyunju; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung; Song, Si Young

    2017-01-01

    Pancreatic cancer is predominantly lethal, and is primarily treated using gemcitabine, with increasing resistance. Therefore, novel agents that increase tumor sensitivity to gemcitabine are needed. Histone deacetylase (HDAC) inhibitors are emerging therapeutic agents, since HDAC plays an important role in cancer initiation and progression. We evaluated the antitumor effect of a novel HDAC inhibitor, CG200745, combined with gemcitabine/erlotinib on pancreatic cancer cells and gemcitabine-resis...

  3. The necrotic signal induced by mycophenolic acid overcomes apoptosis-resistance in tumor cells.

    Directory of Open Access Journals (Sweden)

    Gwendaline Guidicelli

    Full Text Available BACKGROUND: The amount of inosine monophosphate dehydrogenase (IMPDH, a pivotal enzyme for the biosynthesis of the guanosine tri-phosphate (GTP, is frequently increased in tumor cells. The anti-viral agent ribavirin and the immunosuppressant mycophenolic acid (MPA are potent inhibitors of IMPDH. We recently showed that IMPDH inhibition led to a necrotic signal requiring the activation of Cdc42. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we strengthened the essential role played by this small GTPase in the necrotic signal by silencing Cdc42 and by the ectopic expression of a constitutive active mutant of Cdc42. Since resistance to apoptosis is an essential step for the tumorigenesis process, we next examined the effect of the MPA-mediated necrotic signal on different tumor cells demonstrating various mechanisms of resistance to apoptosis (Bcl2-, HSP70-, Lyn-, BCR-ABL-overexpressing cells. All tested cells remained sensitive to MPA-mediated necrotic signal. Furthermore, inhibition of IMPDH activity in Chronic Lymphocytic Leukemia cells was significantly more efficient at eliminating malignant cells than apoptotic inducers. CONCLUSIONS/SIGNIFICANCE: These findings indicate that necrosis and apoptosis are split signals that share few if any common hub of signaling. In addition, the necrotic signaling pathway induced by depletion of the cellular amount of GTP/GDP would be of great interest to eliminate apoptotic-resistant tumor cells.

  4. A co-delivery nanosystem of chemotherapeutics and DNAzyme overcomes cancer drug resistance and metastasis

    Science.gov (United States)

    Sun, Shu-Pin; Liu, Ching-Ping; Huang, I.-Ping; Chu, Chia-Hui; Chung, Ming-Fang; Cheng, Shih-Hsun; Lin, Shu-Yi; Lo, Leu-Wei

    2017-12-01

    Multidrug resistance (MDR) constitutes a major problem in the management of cancer and cancer metastasized from primary-source tumor causes cancer-related deaths. Our new approach is the co-delivery of chemotherapy drugs with a transcription-factor-targeting genetic agent to simultaneously inhibit the growth and metastasis of cancer cells. C-Jun is a transcription factor that regulates multidrug resistance-associated protein 1 (MRP1) pump efflux transcription and tumor metastasis. In this work, we reported that mesoporous silica nanoparticles (MSNs) can be functionalized to co-deliver doxorubicin (Dox) and DNAzyme (Dz) to increase cancer cell killing in an additive fashion. The MSNs were sequentially conjugated with Dox into the MSNs’ nanochannels and Dz onto the MSNs’ outermost surface to target c-Jun as the Dox@MSN-Dz co-delivery system. The Dox-resistant PC-3 cells treated with Dox@MSN-Dz efficiently enhanced the intracellular Dox concentration due to the abrogation of Dox-induced MRP1 expression through the downregulation of c-Jun expression by Dz. Additionally, significant reductions in invasion and migration related to metastasis were also observed in cells treated with Dox@MSN-Dz. Therefore, our results contribute new insight to the treatment of MDR combined metastatic cancer cells, worthwhile for studying its potential for development in clinical translation.

  5. Neutralization resistance of hepatitis C virus can be overcome by recombinant human monoclonal antibodies

    DEFF Research Database (Denmark)

    Pedersen, Jannie L; Carlsen, Thomas H R; Prentoe, Jannick

    2013-01-01

    Immunotherapy and vaccine development for hepatitis C virus (HCV) will depend on broadly reactive neutralizing antibodies (NAbs). However, studies in infectious strain JFH1-based culture systems expressing patient-derived Core-NS2 proteins have suggested neutralization resistance for specific HCV...... demonstrated that the novel genotype 2 viruses as well as prototype strains J6/JFH1(2a) and J8/JFH1(2b), all with authentic envelope proteins, were resistant to neutralization by genotype 2a, 2b, 2c, 2j, 2i, and 2q patient sera. However, these patient sera had high titers of HCV-specific NAbs, because...... they efficiently reduced the infectivity of J6(2a) and J8(2b) with deleted hypervariable region 1. The genotype 2a, 2b, and 2c viruses, found resistant to polyclonal patient sera neutralization, were efficiently neutralized by two lead HMAbs (AR4A and HC84.26). Conclusion: Using novel 2a, 2b, and 2c cell...

  6. Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells

    Science.gov (United States)

    Lai, I-Lu; Chou, Chih-Chien; Lai, Po-Ting; Fang, Chun-Sheng; Shirley, Lawrence A.; Yan, Ribai; Mo, Xiaokui; Bloomston, Mark; Kulp, Samuel K.; Bekaii-Saab, Tanios; Chen, Ching-Shih

    2014-01-01

    Gemcitabine resistance remains a significant clinical challenge. Here, we used a novel glucose transporter (Glut) inhibitor, CG-5, as a proof-of-concept compound to investigate the therapeutic utility of targeting the Warburg effect to overcome gemcitabine resistance in pancreatic cancer. The effects of gemcitabine and/or CG-5 on viability, survival, glucose uptake and DNA damage were evaluated in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cell lines. Mechanistic studies were conducted to determine the molecular basis of gemcitabine resistance and the mechanism of CG-5-induced sensitization to gemcitabine. The effects of CG-5 on gemcitabine sensitivity were investigated in a xenograft tumor model of gemcitabine-resistant pancreatic cancer. In contrast to gemcitabine-sensitive pancreatic cancer cells, the resistant Panc-1 and Panc-1GemR cells responded to gemcitabine by increasing the expression of ribonucleotide reductase M2 catalytic subunit (RRM2) through E2F1-mediated transcriptional activation. Acting as a pan-Glut inhibitor, CG-5 abrogated this gemcitabine-induced upregulation of RRM2 through decreased E2F1 expression, thereby enhancing gemcitabine-induced DNA damage and inhibition of cell survival. This CG-5-induced inhibition of E2F1 expression was mediated by the induction of a previously unreported E2F1-targeted microRNA, miR-520f. The addition of oral CG-5 to gemcitabine therapy caused greater suppression of Panc-1GemR xenograft tumor growth in vivo than either drug alone. Glut inhibition may be an effective strategy to enhance gemcitabine activity for the treatment of pancreatic cancer. PMID:24879635

  7. Ability of polymer-bound P-glycoprotein inhibitor ritonavir to overcome multidrug resistance in various resistant neuroblastoma cell lines

    Czech Academy of Sciences Publication Activity Database

    Koziolová, Eva; Chytil, Petr; Etrych, Tomáš; Janoušková, Olga

    2017-01-01

    Roč. 28, č. 10 (2017), s. 1126-1130 ISSN 0959-4973 R&D Projects: GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : drug-delivery polymers * multidrug resistance * N-(2-hydroxypropyl) methacrylamide Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 2.320, year: 2016

  8. Does the use of melatonin overcome drug resistance in cancer chemotherapy?

    Science.gov (United States)

    Asghari, Mohammad Hossein; Ghobadi, Emad; Moloudizargari, Milad; Fallah, Marjan; Abdollahi, Mohammad

    2018-03-01

    Our knowledge regarding the implications of melatonin in the therapy of numerous medical conditions, including cancer is constantly expanding. Melatonin can variably affect cancer pathology via targeting several key aspects of any neoplastic condition, including the very onset of carcinogenesis as well as tumor growth, differentiation, and dissemination. Numerous studies have examined the effects of melatonin in the context of various cancers reporting the enhanced efficacy of chemo/radiotherapy in combination with this compound. Reduced sensitivity and also resistance of cancer cells to antineoplastic agents are common events which might arise as a result of genomic instability of the malignant cells. Genetic mutations provide numerous mechanisms for these cells to resist cytotoxic therapies. Melatonin, due to its pleitropic effects, is able to correct these alterations in favour of sensitization to antineoplastic agents as evident by increased response to treatment via modulating the expression and phosphorylation status of drug targets, the reduced clearance of drugs by affecting their metabolism and transport within the body, decreased survival of malignant cells via altering DNA repair and telomerase activity, and enhanced responsiveness to cell death-associated mechanisms such as apoptosis and autophagy. These effects are presumably governed by melatonin's interventions in the main signal transduction pathways such as Akt and MAPK, independent of its antioxidant properties. Possessing such a signaling altering nature, melatonin can considerably affect the drug-resistance mechanisms employed by the malignant cells in breast, lung, hepatic, and colon cancers as well as different types of leukemia which are the subject of the current review. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. Mitochondrial targeting overcomes ABCA1-dependent resistance of lung carcinoma to alpha-tocopheryl succinate

    Czech Academy of Sciences Publication Activity Database

    Procházka, L.; Koudelka, Š.; Dong, L. F.; Štursa, Jan; Goodwin, J.; Neca, J.; Slavík, J.; Cigánek, M.; Mašek, J.; Klučková, Katarína; Nguyen, M.; Turánek, J.; Neužil, Jiří

    2013-01-01

    Roč. 18, č. 3 (2013), s. 286-299 ISSN 1360-8185 R&D Projects: GA ČR GAP301/10/1937; GA ČR(CZ) GAP304/10/1951 Grant - others:GA ČR(CZ) GP204/09/P632 Institutional research plan: CEZ:AV0Z50520701; CEZ:AV0Z40550506 Keywords : vitamin E analogues * apoptosis * mitochondrial targeting * ABCA1 * acquired resistance Subject RIV: CE - Biochemistry; EA - Cell Biology (BTO-N) Impact factor: 3.614, year: 2013

  10. The Panitumumab EGFR Complex Reveals a Binding Mechanism That Overcomes Cetuximab Induced Resistance.

    Directory of Open Access Journals (Sweden)

    E Allen Sickmier

    Full Text Available Panitumumab and cetuximab target the epidermal growth factor receptor for the treatment of metastatic colorectal cancer. These therapies provide a significant survival benefit to patients with metastatic colorectal cancer with wild-type RAS. A single point mutation in the ectodomain of EGFR (S468R confers acquired or secondary resistance in cetuximab treated patients, which is not observed in panitumumab-treated patients. Structural and biophysical studies presented here show this mutation directly blocks cetuximab binding to EGFR domain III and describes a unique mechanism by which panitumumab uses a central cavity to accommodate this mutation.

  11. Tumor-targeted micelle-forming block copolymers for overcoming of multidrug resistance

    Czech Academy of Sciences Publication Activity Database

    Braunová, Alena; Kostka, Libor; Sivák, Ladislav; Cuchalová, Lucie; Hvězdová, Zuzana; Laga, Richard; Filippov, Sergey K.; Černoch, Peter; Pechar, Michal; Janoušková, Olga; Šírová, Milada; Etrych, Tomáš

    2017-01-01

    Roč. 245, 10 January (2017), s. 41-51 ISSN 0168-3659 R&D Projects: GA MZd(CZ) NV16-28600A; GA MŠk(CZ) LO1507; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : multidrug resistance * P-glycoprotein inhibitor * EPR effect Subject RIV: CD - Macromolecular Chemistry; EE - Microbiology, Virology (MBU-M) OBOR OECD: Polymer science; Microbiology (MBU-M) Impact factor: 7.786, year: 2016

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

    International Nuclear Information System (INIS)

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

    2013-01-01

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

  13. Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs).

    Science.gov (United States)

    Rathore, Rama; McCallum, Jennifer E; Varghese, Elizabeth; Florea, Ana-Maria; Büsselberg, Dietrich

    2017-07-01

    Inhibitors of apoptosis (IAPs) are a family of proteins that play a significant role in the control of programmed cell death (PCD). PCD is essential to maintain healthy cell turnover within tissue but also to fight disease or infection. Uninhibited, IAPs can suppress apoptosis and promote cell cycle progression. Therefore, it is unsurprising that cancer cells demonstrate significantly elevated expression levels of IAPs, resulting in improved cell survival, enhanced tumor growth and subsequent metastasis. Therapies to target IAPs in cancer has garnered substantial scientific interest and as resistance to anti-cancer agents becomes more prevalent, targeting IAPs has become an increasingly attractive strategy to re-sensitize cancer cells to chemotherapies, antibody based-therapies and TRAIL therapy. Antagonism strategies to modulate the actions of XIAP, cIAP1/2 and survivin are the central focus of current research and this review highlights advances within this field with particular emphasis upon the development and specificity of second mitochondria-derived activator of caspase (SMAC) mimetics (synthetic analogs of endogenously expressed inhibitors of IAPs SMAC/DIABLO). While we highlight the potential of SMAC mimetics as effective single agent or combinatory therapies to treat cancer we also discuss the likely clinical implications of resistance to SMAC mimetic therapy, occasionally observed in cancer cell lines.

  14. NANOMEDICINE: will it offer possibilities to overcome multiple drug resistance in cancer?

    Science.gov (United States)

    Friberg, Sten; Nyström, Andreas M

    2016-03-09

    This review is written with the purpose to review the current nanomedicine literature and provide an outlook on the developments in utilizing nanoscale drug constructs in treatment of solid cancers as well as in the potential treatment of multi-drug resistant cancers. No specific design principles for this review have been utilized apart from our active choice to avoid results only based on in vitro studies. Few drugs based on nanotechnology have progressed to clinical trials, since most are based only on in vitro experiments which do not give the necessary data for the research to progress towards pre-clinical studies. The area of nanomedicine has indeed spark much attention and holds promise for improved future therapeutics in the treatment of solid cancers. However, despite much investment few targeted therapeutics have successfully progressed to early clinical trials, indicating yet again that the human body is complicated and that much more understanding of the fundamentals of receptor interactions, physics of nanomedical constructs and their circulation in the body is indeed needed. We believe that nanomedical therapeutics can allow for more efficient treatments of resistant cancers, and may well be a cornerstone for RNA based therapeutics in the future given their general need for shielding from the harsh environment in the blood stream.

  15. Functionalized graphene oxide mediated adriamycin delivery and miR-21 gene silencing to overcome tumor multidrug resistance in vitro.

    Directory of Open Access Journals (Sweden)

    Feng Zhi

    Full Text Available Multidrug resistance (MDR is a major impediment to successful cancer chemotherapy. Co-delivery of novel MDR-reversing agents and anticancer drugs to cancer cells holds great promise for cancer treatment. MicroRNA-21 (miR-21 overexpression is associated with the development and progression of MDR in breast cancer, and it is emerging as a novel and promising MDR-reversing target. In this study, a multifunctional nanocomplex, composed of polyethylenimine (PEI/poly(sodium 4-styrenesulfonates (PSS/graphene oxide (GO and termed PPG, was prepared using the layer-by-layer assembly method to evaluate the reversal effects of PPG as a carrier for adriamycin (ADR along with miR-21 targeted siRNA (anti-miR-21 in cancer drug resistance. ADR was firstly loaded onto the PPG surface (PPGADR by physical mixing and anti-miR-21 was sequentially loaded onto PPGADR through electric absorption to form (anti-miR-21PPGADR. Cell experiments showed that PPG significantly enhanced the accumulation of ADR in MCF-7/ADR cells (an ADR resistant breast cancer cell line and exhibited much higher cytotoxicity than free ADR, suggesting that PPG could effectively reverse ADR resistance of MCF-7/ADR. Furthermore, the enhanced therapeutic efficacy of PPG could be correlated with effective silencing of miR-21 and with increased accumulation of ADR in drug-resistant tumor cells. The endocytosis study confirmed that PPG could effectively carry drug molecules into cells via the caveolae and clathrin-mediated endocytosis pathways. These results suggest that this PPG could be a potential and efficient non-viral vector for reversing MDR, and the strategy of combining anticancer drugs with miRNA therapy to overcome MDR could be an attractive approach in cancer treatment.

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

    Science.gov (United States)

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

    2017-06-15

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

  17. Multi-agent chemotherapy overcomes glucocorticoid resistance conferred by a BIM deletion polymorphism in pediatric acute lymphoblastic leukemia.

    Directory of Open Access Journals (Sweden)

    Sheila Xinxuan Soh

    Full Text Available A broad range of anti-cancer agents, including glucocorticoids (GCs and tyrosine kinase inhibitors (TKIs, kill cells by upregulating the pro-apoptotic BCL2 family member, BIM. A common germline deletion in the BIM gene was recently shown to favor the production of non-apoptotic BIM isoforms, and to predict inferior responses in TKI-treated chronic myeloid leukemia (CML and EGFR-driven lung cancer patients. Given that both in vitro and in vivo GC resistance are predictive of adverse outcomes in acute lymphoblastic leukemia (ALL, we hypothesized that this polymorphism would mediate GC resistance, and serve as a biomarker of poor response in ALL. Accordingly, we used zinc finger nucleases to generate ALL cell lines with the BIM deletion, and confirmed the ability of the deletion to mediate GC resistance in vitro. In contrast to CML and lung cancer, the BIM deletion did not predict for poorer clinical outcome in a retrospective analysis of 411 pediatric ALL patients who were uniformly treated with GCs and chemotherapy. Underlying the lack of prognostic significance, we found that the chemotherapy agents used in our cohort (vincristine, L-asparaginase, and methotrexate were each able to induce ALL cell death in a BIM-independent fashion, and resensitize BIM deletion-containing cells to GCs. Together, our work demonstrates how effective therapy can overcome intrinsic resistance in ALL patients, and suggests the potential of using combinations of drugs that work via divergent mechanisms of cell killing to surmount BIM deletion-mediated drug resistance in other cancers.

  18. Creating value in health by understanding and overcoming resistance to de-innovation.

    Science.gov (United States)

    Ubel, Peter A; Asch, David A

    2015-02-01

    As hard as it may be for clinicians to adopt new practices, it is often harder for them to "de-innovate," or give up old practices, even when new evidence reveals that those practices offer little value. In this article we explore recent controversies over screening for breast and prostate cancer and testing for sleep disorders. We show that these controversies are not caused solely by a lack of clinical data on the harms and benefits of these tests but are also influenced by several psychological biases that make it difficult for clinicians to de-innovate. De-innovation could be fostered by making sure that advisory panels and guideline committees include experts who have competing biases; emphasizing evidence over clinical judgment; resisting "indication creep," or the premature extension of innovations into unproven areas; and encouraging clinicians to explicitly consider how their experiences bias their interpretations of clinical evidence. Project HOPE—The People-to-People Health Foundation, Inc.

  19. Inhibition of IGF1-R overcomes IGFBP7-induced chemotherapy resistance in T-ALL

    International Nuclear Information System (INIS)

    Bartram, Isabelle; Erben, Ulrike; Ortiz-Tanchez, Jutta; Blunert, Katja; Schlee, Cornelia; Neumann, Martin; Heesch, Sandra; Baldus, Claudia D.

    2015-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease with the need for treatment optimization. Previously, high expression of Insulin-like growth factor binding protein 7 (IGFBP7), a member of the IGF system, was identified as negative prognostic factor in adult T-ALL patients. Since aberrant IGFBP7 expression was observed in a variety of neoplasia and was relevant for prognosis in T-ALL, we investigated the functional role of IGFBP7 in Jurkat and Molt-4 cells as in vitro models for T-ALL. Jurkat and Molt-4 cells were stably transfected with an IGFBP7 over-expression vector or the empty vector as control. Proliferation of the cells was assessed by WST-1 assays and cell cycle status was measured by flow-cytometry after BrDU/7-AAD staining. The effect of IGFBP7 over-expression on sensitivity to cytostatic drugs was determined in AnnexinV/7-AAD assays. IGF1-R protein expression was measured by Western Blot and flow-cytometric analysis. IGF1-R associated gene expression profiles were generated from microarray gene expression data of 86 T-ALL patients from the Microarrays Innovations in Leukemia (MILE) multicenter study. IGFBP7-transfected Jurkat cells proliferated less, leading to a longer survival in a nutrient–limited environment. Both IGFBP7-transfected Jurkat and Molt-4 cells showed an arrest in the G0/G1 cell cycle phase. Furthermore, Jurkat IGFBP7-transfected cells were resistant to vincristine and asparaginase treatment. Surface expression and whole protein measurement of IGF1-R protein expression showed a reduced abundance of the receptor after IGFBP7 transfection in Jurkat cells. Interestingly, combination of the IGF1-R inhibitor NPV-AEW541 restored sensitivity to vincristine in IGFBP7-transfected cells. Additionally, IGF1-R associated GEP revealed an up-regulation of important drivers of T-ALL pathogenesis and regulators of chemo-resistance and apoptosis such as NOTCH1, BCL-2, PRKCI, and TP53. This study revealed a

  20. 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.

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

    Science.gov (United States)

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

    2013-01-01

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

  2. ErbB2 and NFκB overexpression as predictors of chemoradiation resistance and putative targets to overcome resistance in muscle-invasive bladder cancer.

    Directory of Open Access Journals (Sweden)

    Fumitaka Koga

    Full Text Available Radical cystectomy for muscle-invasive bladder cancer (MIBC patients frequently impairs their quality of life (QOL due to urinary diversion. To improve their QOL, a bladder-sparing alternative strategy using chemoradiation has been developed. In bladder-sparing protocols, complete response (CR to induction chemoradiation is a prerequisite for bladder preservation and favorable survival. Thus predicting chemoradiation resistance and overcoming it would increase individual MIBC patients' chances of bladder preservation. The aim of this study is to investigate putative molecular targets for treatment aimed at improving chemoradiation response. Expression levels of erbB2, NFκB, p53, and survivin were evaluated immunohistochemically in pretreatment biopsy samples from 35 MIBC patients in whom chemoradiation sensitivity had been pathologically evaluated in cystectomy specimens, and associations of these expression levels with chemoradiation sensitivity and cancer-specific survival (CSS were investigated. Of the 35 patients, 11 (31% achieved pathological CR, while tumors in the remaining 24 patients (69% were chemoradiation-resistant. Multivariate analysis identified erbB2 and NFκB overexpression and hydronephrosis as significant and independent risk factors for chemoradiation resistance with respective relative risks of 11.8 (P = 0.014, 15.4 (P = 0.024 and 14.3 (P = 0.038. The chemoradiation resistance rate was 88.5% for tumors overexpressing erbB2 and/or NFκB, but only 11.1% for those negative for both (P <0.0001. The 5-year CSS rate was 74% overall. Through multivariate analysis, overexpression of erbB2 and/or NFκB was identified as an independent risk factor for bladder cancer death with marginal significance (hazard ratio 21.5, P = 0.056 along with chemoradiation resistance (P = 0.003 and hydronephrosis (P = 0.018. The 5-year CSS rate for the 11 patients achieving pathological CR was 100%, while that for the 24 with

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

    International Nuclear Information System (INIS)

    Horsman, M.

    1996-01-01

    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

  4. Transforming growth factor β signaling overcomes dasatinib resistance in lung cancer.

    Directory of Open Access Journals (Sweden)

    Edna Gordian

    Full Text Available Lung cancer is the second most common cancer and the leading cause of cancer-related deaths. Despite recent advances in the development of targeted therapies, patients with advanced disease remain incurable, mostly because metastatic non-small cell lung carcinomas (NSCLC eventually become resistant to tyrosine kinase inhibitors (TKIs. Kinase inhibitors have the potential for target promiscuity because the kinase super family is the largest family of druggable genes that binds to a common substrate (ATP. As a result, TKIs often developed for a specific purpose have been found to act on other targets. Drug affinity chromatography has been used to show that dasatinib interacts with the TGFβ type I receptor (TβR-I, a serine-threonine kinase. To determine the potential biological relevance of this association, we studied the combined effects of dasatinib and TGFβ on lung cancer cell lines. We found that dasatinib treatment alone had very little effect; however, when NSCLC cell lines were treated with a combination of TGFβ and dasatinib, apoptosis was induced. Combined TGFβ-1 + dasatinib treatment had no effect on the activity of Smad2 or other non-canonical TGFβ intracellular mediators. Interestingly, combined TGFβ and dasatinib treatment resulted in a transient increase in p-Smad3 (seen after 3 hours. In addition, when NSCLC cells were treated with this combination, the pro-apoptotic protein BIM was up-regulated. Knockdown of the expression of Smad3 using Smad3 siRNA also resulted in a decrease in BIM protein, suggesting that TGFβ-1 + dasatinib-induced apoptosis is mediated by Smad3 regulation of BIM. Dasatinib is only effective in killing EGFR mutant cells, which is shown in only 10% of NSCLCs. Therefore, the observation that wild-type EGFR lung cancers can be manipulated to render them sensitive to killing by dasatinib could have important implications for devising innovative and potentially more efficacious treatment strategies for this

  5. Multi-targeted therapy for leprosy: insilico strategy to overcome multi drug resistance and to improve therapeutic efficacy.

    Science.gov (United States)

    Anusuya, Shanmugam; Natarajan, Jeyakumar

    2012-12-01

    Leprosy remains a major public health problem, since single and multi-drug resistance has been reported worldwide over the last two decades. In the present study, we report the novel multi-targeted therapy for leprosy to overcome multi drug resistance and to improve therapeutic efficacy. If multiple enzymes of an essential metabolic pathway of a bacterium were targeted, then the therapy would become more effective and can prevent the occurrence of drug resistance. The MurC, MurD, MurE and MurF enzymes of peptidoglycan biosynthetic pathway were selected for multi targeted therapy. The conserved or class specific active site residues important for function or stability were predicted using evolutionary trace analysis and site directed mutagenesis studies. Ten such residues which were present in at least any three of the four Mur enzymes (MurC, MurD, MurE and MurF) were identified. Among the ten residues G125, K126, T127 and G293 (numbered based on their position in MurC) were found to be conserved in all the four Mur enzymes of the entire bacterial kingdom. In addition K143, T144, T166, G168, H234 and Y329 (numbered based on their position in MurE) were significant in binding substrates and/co-factors needed for the functional events in any three of the Mur enzymes. These are the probable residues for designing newer anti-leprosy drugs in an attempt to reduce drug resistance. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. Novel Mutations Detected in Avirulence Genes Overcoming Tomato Cf Resistance Genes in Isolates of a Japanese Population of Cladosporium fulvum.

    Directory of Open Access Journals (Sweden)

    Yuichiro Iida

    Full Text Available Leaf mold of tomato is caused by the biotrophic fungus Cladosporium fulvum which complies with the gene-for-gene system. The disease was first reported in Japan in the 1920s and has since been frequently observed. Initially only race 0 isolates were reported, but since the consecutive introduction of resistance genes Cf-2, Cf-4, Cf-5 and Cf-9 new races have evolved. Here we first determined the virulence spectrum of 133 C. fulvum isolates collected from 22 prefectures in Japan, and subsequently sequenced the avirulence (Avr genes Avr2, Avr4, Avr4E, Avr5 and Avr9 to determine the molecular basis of overcoming Cf genes. Twelve races of C. fulvum with a different virulence spectrum were identified, of which races 9, 2.9, 4.9, 4.5.9 and 4.9.11 occur only in Japan. The Avr genes in many of these races contain unique mutations not observed in races identified elsewhere in the world including (i frameshift mutations and (ii transposon insertions in Avr2, (iii point mutations in Avr4 and Avr4E, and (iv deletions of Avr4E, Avr5 and Avr9. New races have developed by selection pressure imposed by consecutive introductions of Cf-2, Cf-4, Cf-5 and Cf-9 genes in commercially grown tomato cultivars. Our study shows that molecular variations to adapt to different Cf genes in an isolated C. fulvum population in Japan are novel but overall follow similar patterns as those observed in populations from other parts of the world. Implications for breeding of more durable C. fulvum resistant varieties are discussed.

  7. A Continuous 3D-Graphene Network to Overcome Threshold Issues and Contact Resistance in Thermally Conductive Graphene Nanocomposites

    Directory of Open Access Journals (Sweden)

    Federico Conrado

    2017-01-01

    Full Text Available In order to overcome thermal resistance issues in polymeric matrix composites, self-standing graphene aerogels were synthetized and infiltrated with an epoxy resin, in order to create conductive preferential pathways through which heat can be easily transported. These continuous highly thermally conductive 3D-structures show, due to the high interconnection degree of graphene flakes, enhanced transport properties. Two kinds of aerogels were investigated, obtained by hydrothermal synthesis (HS and ice-templated direct freeze synthesis (DFS. Following HS method an isotropic structure is obtained, and following DFS method instead an anisotropic arrangement of graphene flakes results. The density of the structure can be tuned leading to a different amount of graphene inside the final composite. The residual oxygen, known to be detrimental to thermal properties, was removed by thermal treatment before the infiltration process. With 1,25 wt.% of graphene, using HS method, the thermal conductivity of the polymeric resin was increased by 80%, suggesting that this technique is a valid route to improve the thermal performance of graphene-based composites. When preferential orientation of the filler was present (DFS case, thermal conductivity was increased more than 25% with a graphene content of only 0,27 wt.%, demonstrating that oriented structures can further improve the thermal transport efficiency.

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

    International Nuclear Information System (INIS)

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

    2012-01-01

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

  9. Positive practice routines in overcoming resistance to the treatment of school phobia: a case study with follow-up.

    Science.gov (United States)

    Kolko, D J; Ayllon, T; Torrence, C

    1987-09-01

    The treatment is described of a 6-year-old first grade girl who refused to attend her classroom without adult accompaniment. For eight weeks an attempt was made, using different adult escorts, to prompt/shape classroom attendence through classroom exposure. However, the outcome was the development of an unwavering preference to remain in the principal's office after the child would not tolerate separation from these adults. Rather then continue to take her to the classroom, an intervention was initiated designed to structure her daily experiences and provide instruction. In this she was expected to practice several educational activities at designated times in the principal's office. This intervention resulted in a complete elimination of the child's classroom avoidance within five weeks and concomitant improvements in both social and academic functioning. Although the child's mother suddenly died during intervention, follow-up at one and 12 months in a different school indicated the maintenance of all therapeutic gains. Unique aspects of the procedures pertaining to refractory problems and some tentative behavioral guidelines to overcoming resistance to treatment are discussed.

  10. Overcoming challenges

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    Full Text Available ... breastfeeding Overcoming challenges Common questions about breastfeeding and pain Breastfeeding checklist: How to get a good latch Finding ... myths Overcoming challenges Common questions about breastfeeding and pain Breastfeeding checklist: How to get a good latch Finding ...

  11. Overcoming challenges

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

  12. Overcoming resistance to beta-lactamase inhibitors: comparing sulbactam to novel inhibitors against clavulanate resistant SHV enzymes with substitutions at Ambler position 244.

    Science.gov (United States)

    Thomson, Jodi M; Distler, Anne M; Bonomo, Robert A

    2007-10-09

    Amino acid changes at Ambler position R244 in class A TEM and SHV beta-lactamases confer resistance to ampicillin/clavulanate, a beta-lactam/beta-lactamase inhibitor combination used to treat serious infections. To gain a deeper understanding of this resistance phenotype, we investigated the activities of sulbactam and two novel penem beta-lactamase inhibitors with sp2 hybridized C3 carboxylates and bicyclic R1 side chains against a library of SHV beta-lactamase variants at the 244 position. Compared to SHV-1 expressed in Escherichia coli, all 19 R244 variants exhibited increased susceptibility to ampicillin/sulbactam, an important difference compared to ampicillin/clavulanate. Kinetic analyses of SHV-1 and three SHV R244 (-S, -Q, and -L) variants revealed the Ki for sulbactam was significantly elevated for the R244 variants, but the partition ratios, kcat/kinact, were markedly reduced (13 000 --> resistance can be overcome by designing penem inhibitors with strategic chemical properties that improve affinity and impair turnover.

  13. HSA-based multi-target combination therapy: regulating drugs' release from HSA and overcoming single drug resistance in a breast cancer model.

    Science.gov (United States)

    Gou, Yi; Zhang, Zhenlei; Li, Dongyang; Zhao, Lei; Cai, Meiling; Sun, Zhewen; Li, Yongping; Zhang, Yao; Khan, Hamid; Sun, Hongbing; Wang, Tao; Liang, Hong; Yang, Feng

    2018-11-01

    Multi-drug delivery systems, which may be promising solution to overcome obstacles, have limited the clinical success of multi-drug combination therapies to treat cancer. To this end, we used three different anticancer agents, Cu(BpT)Br, NAMI-A, and doxorubicin (DOX), to build human serum albumin (HSA)-based multi-drug delivery systems in a breast cancer model to investigate the therapeutic efficacy of overcoming single drug (DOX) resistance to cancer cells in vivo, and to regulate the drugs' release from HSA. The HSA complex structure revealed that NAMI-A and Cu(BpT)Br bind to the IB and IIA sub-domain of HSA by N-donor residue replacing a leaving group and coordinating to their metal centers, respectively. The MALDI-TOF mass spectra demonstrated that one DOX molecule is conjugated with lysine of HSA by a pH-sensitive linker. Furthermore, the release behavior of three agents form HSA can be regulated at different pH levels. Importantly, in vivo results revealed that the HSA-NAMI-A-Cu(BpT)Br-DOX complex not only increases the targeting ability compared with a combination of the three agents (the NAMI-A/Cu(BpT)Br/DOX mixture), but it also overcomes DOX resistance to drug-resistant breast cancer cell lines.

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

    Science.gov (United States)

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

    2017-05-02

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

  15. The HDAC inhibitor SB939 overcomes resistance to BCR-ABL kinase Inhibitors conferred by the BIM deletion polymorphism in chronic myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Muhammad Rauzan

    Full Text Available Chronic myeloid leukemia (CML treatment has been improved by tyrosine kinase inhibitors (TKIs such as imatinib mesylate (IM but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the BCL2-like 11 (BIM gene which impairs the expression of pro-apoptotic splice isoforms of BIM. SB939 (pracinostat is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome BIM deletion polymorphism-induced TKI resistance. We found that SB939 corrects BIM pre-mRNA splicing in CML cells with the BIM deletion polymorphism, and induces apoptotic cell death in CML cell lines and primary cells with the BIM deletion polymorphism. More importantly, SB939 both decreases the viability of CML cell lines and primary CML progenitors with the BIM deletion and restores TKI-sensitivity. Our results demonstrate that SB939 overcomes BIM deletion polymorphism-induced TKI resistance, and suggest that SB939 may be useful in treating CML patients with BIM deletion-associated TKI resistance.

  16. 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

    Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The 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.Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The

  17. Overcoming challenges

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

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    Full Text Available ... menu It's Only Natural Planning ahead Breastfeeding and baby basics Making breastfeeding work for you Addressing breastfeeding ... in the African-American community Incredible facts about babies, breastmilk, and breastfeeding Overcoming challenges Common questions about ...

  19. Overcoming challenges

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

  20. Overcoming challenges

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    Full Text Available ... facts about babies, breastmilk, and breastfeeding Overcoming challenges Common questions about breastfeeding and pain Breastfeeding checklist: How to get a good latch Finding support It takes a village: Building ...

  1. Overcoming challenges

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    Full Text Available ... breastfeeding means to them. Subscribe To receive Breastfeeding email updates Enter email Submit Overcoming challenges Breastfeeding has a long list ... breastfeeding means to them. Subscribe To receive Breastfeeding email updates Enter email Submit All material contained on ...

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

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

    Science.gov (United States)

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

    2017-06-28

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

  4. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK

    Science.gov (United States)

    Katayama, Ryohei; Khan, Tahsin M.; Benes, Cyril; Lifshits, Eugene; Ebi, Hiromichi; Rivera, Victor M.; Shakespeare, William C.; Iafrate, A. John; Engelman, Jeffrey A.; Shaw, Alice T.

    2011-01-01

    The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion oncogene represents a molecular target in a small subset of non-small cell lung cancers (NSCLCs). This fusion leads to constitutive ALK activation with potent transforming activity. In a pivotal phase 1 clinical trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib (PF-02341066) demonstrated impressive antitumor activity in the majority of patients with NSCLC harboring ALK fusions. However, despite these remarkable initial responses, cancers eventually develop resistance to crizotinib, usually within 1 y, thereby limiting the potential clinical benefit. To determine how cancers acquire resistance to ALK inhibitors, we established a model of acquired resistance to crizotinib by exposing a highly sensitive EML4-ALK–positive NSCLC cell line to increasing doses of crizotinib until resistance emerged. We found that cells resistant to intermediate doses of crizotinib developed amplification of the EML4-ALK gene. Cells resistant to higher doses (1 μM) also developed a gatekeeper mutation, L1196M, within the kinase domain, rendering EML4-ALK insensitive to crizotinib. This gatekeeper mutation was readily detected using a unique and highly sensitive allele-specific PCR assay. Although crizotinib was ineffectual against EML4-ALK harboring the gatekeeper mutation, we observed that two structurally different ALK inhibitors, NVP-TAE684 and AP26113, were highly active against the resistant cancer cells in vitro and in vivo. Furthermore, these resistant cells remained highly sensitive to the Hsp90 inhibitor 17-AAG. Thus, we have developed a model of acquired resistance to ALK inhibitors and have shown that second-generation ALK TKIs or Hsp90 inhibitors are effective in treating crizotinib-resistant tumors harboring secondary gatekeeper mutations. PMID:21502504

  5. Fisetin, a dietary phytochemical, overcomes Erlotinib-resistance of lung adenocarcinoma cells through inhibition of MAPK and AKT pathways.

    Science.gov (United States)

    Zhang, Liang; Huang, Yi; Zhuo, Wenlei; Zhu, Yi; Zhu, Bo; Chen, Zhengtang

    2016-01-01

    Erlotinib (Tarceva) is a selective epidermal growth factor receptor tyrosine kinase inhibitor for treatment of non-small cell lung cancer (NSCLC). However, its efficacy is usually reduced by the occurrence of drug resistance. Our recent study showed that a flavonoid found in many plants, Fisetin, might have a potential to reverse the acquired Cisplatin-resistance of lung adenocarcinoma. In the present study, we aimed to test whether Fisetin could have the ability to reverse Erlotinib-resistance of lung cancer cells. Erlotinib-resistant lung adenocarcinoma cells, HCC827-ER, were cultured from the cell line HCC827, and the effects of Fisetin and Erlotinib on the cell viability and apoptosis were evaluated. The possible signaling pathways in this process were also detected. As expected, the results showed that Fisetin effectively increased sensitivity of Erlotinib-resistant lung cancer cells to Erlotinib, possibly by inhibiting aberrant activation of MAPK and AKT signaling pathways resulted from AXL suppression. In conclusion, Fisetin was a potential agent for reversing acquired Erlotinib-resistance of lung adenocarcinoma. Inactivation of AXL, MAPK and AKT pathways might play a partial role in this process.

  6. Overcoming challenges

    Medline Plus

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

  7. Overcoming challenges

    Medline Plus

    Full Text Available ... we are What we do Programs and activities Work with us Contact Us Blog Popular topics Vision and mission Leadership Programs and activities In your community Funding opportunities Internships and jobs View all pages in this section Home It's Only Natural Overcoming challenges It's Only Natural ...

  8. Vinblastine 20' Amides: Synthetic Analogues That Maintain or Improve Potency and Simultaneously Overcome Pgp-Derived Efflux and Resistance.

    Science.gov (United States)

    Lukesh, John C; Carney, Daniel W; Dong, Huijun; Cross, R Matthew; Shukla, Vyom; Duncan, Katharine K; Yang, Shouliang; Brody, Daniel M; Brütsch, Manuela M; Radakovic, Aleksandar; Boger, Dale L

    2017-09-14

    A series of 180 vinblastine 20' amides were prepared in three steps from commercially available starting materials, systematically exploring a typically inaccessible site in the molecule enlisting a powerful functionalization strategy. Clear structure-activity relationships and a structural model were developed in the studies which provided many such 20' amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogues that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines. The improvements in potency directly correlated with target tubulin binding affinity, and the reduction in differential functional activity against the sensitive and Pgp overexpressing resistant cell lines was found to correlate directly with an impact on Pgp-derived efflux.

  9. Overcoming STC2 mediated drug resistance through drug and gene co-delivery by PHB-PDMAEMA cationic polyester in liver cancer cells.

    Science.gov (United States)

    Cheng, Hongwei; Wu, Zhixian; Wu, Caisheng; Wang, Xiaoyuan; Liow, Sing Shy; Li, Zibiao; Wu, Yun-Long

    2018-02-01

    Stanniocalcin 2 (STC2) overexpression in hepatocellular carcinoma (HCC) could lead to poor prognosis, which might be due to its induced P-glycoprotein and Bcl-2 protein expression level increase. P-glycoprotein or membrane pump induced drug efflux and altered prosurvival Bcl-2 expression are key mechanisms for drug resistance leading to failure of chemotherapy in HCC. However, current strategy to overcome both P-glycoprotein and Bcl-2 protein induced drug resistance was rarely reported. In this work, we utilized an amphiphilic poly[(R)-3-hydroxybutyrate] (PHB)-b-poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) cationic polyester to encapsulate chemotherapeutic paclitaxel (PTX) in hydrophobic PHB domain and Bcl-2 convertor Nur77/ΔDBD gene (Nur77 without DNA binding domain for mitochondria localization) by formation of polyplex due to cationic PDMAEMA segment, to effectively inhibit the drug resistant HepG2/STC2 and SMCC7721/STC2 liver cancer cell growth. Thanks to the cationic nanoparticle complex formation ability and high transfection efficiency to express Bcl-2 conversion proteins, PHB-PDMAEMA/PTX@polyplex could partially impair P-glycoprotein induced PTX efflux and activate the apoptotic function of previous prosurvival Bcl-2 protein. This is the pioneer report of cationic amphiphilic polyester PHB-PDMAEMA to codeliver anticancer drug and therapeutic plasmid to overcome both pump and non-pump mediated chemotherapeutic resistance in liver cancer cells, which might be inspiring for the application of polyester in personalized cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. LA-12 overcomes confluence-dependent resistance of HT-29 colon cancer cells to Pt (II) compounds

    Czech Academy of Sciences Publication Activity Database

    Šindlerová, Lenka; Foltinová, V.; Vaculová, Alena; Horváth, Viktor; Souček, Karel; Sova, P.; Hofmanová, Jiřina; Kozubík, Alois

    2010-01-01

    Roč. 30, č. 4 (2010), s. 1183-1188 ISSN 0250-7005 R&D Projects: GA ČR(CZ) GA301/07/1557 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : LA-12 * resistance * HT-29 Subject RIV: BO - Biophysics Impact factor: 1.656, year: 2010

  11. Ovatodiolide Targets β-Catenin Signaling in Suppressing Tumorigenesis and Overcoming Drug Resistance in Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Jar-Yi Ho

    2013-01-01

    Full Text Available Dysregulated β-catenin signaling is intricately involved in renal cell carcinoma (RCC carcinogenesis and progression. Determining potential β-catenin signaling inhibitors would be helpful in ameliorating drug resistance in advanced or metastatic RCC. Screening for β-catenin signaling inhibitors involved in silico inquiry of the PubChem Bioactivity database followed by TCF/LEF reporter assay. The biological effects of ovatodiolide were evaluated in 4 RCC cell lines in vitro and 2 RCC cell lines in a mouse xenograft model. The synergistic effects of ovatodiolide and sorafenib or sunitinib were examined in 2 TKI-resistant RCC cell lines. Ovatodiolide, a pure compound of Anisomeles indica, inhibited β-catenin signaling and reduced RCC cell viability, survival, migration/invasion, and in vitro cell or in vivo mouse tumorigenicity. Cytotoxicity was significantly reduced in a normal kidney epithelial cell line with the treatment. Ovatodiolide reduced phosphorylated β-catenin (S552 that inhibited β-catenin nuclear translocation. Moreover, ovatodiolide decreased β-catenin stability and impaired the association of β-catenin and transcription factor 4. Ovatodiolide combined with sorafenib or sunitinib overcame drug resistance in TKI-resistant RCC cells. Ovatodiolide may be a potent β-catenin signaling inhibitor, with synergistic effects with sorafenib or sunitinib, and therefore, a useful candidate for improving RCC therapy.

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

    Science.gov (United States)

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

    2015-03-01

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

  13. Overcoming cisplatin resistance in non-small cell lung cancer with Mad2 silencing siRNA delivered systemically using EGFR-targeted chitosan nanoparticles.

    Science.gov (United States)

    Nascimento, Ana Vanessa; Singh, Amit; Bousbaa, Hassan; Ferreira, Domingos; Sarmento, Bruno; Amiji, Mansoor M

    2017-01-01

    Efficiency of chemotherapy is often limited by low therapeutic index of the drug as well as emergence of inherent and acquired drug resistance in cancer cells. As a common strategy to overcome drug resistance, higher doses of chemo-agents are administered. However, adverse side effects are usually increased as a consequence. A potentially effective approach is to combine chemotherapy with other therapeutic strategies such as small interfering RNAs (siRNAs) that allow the use of lower yet efficient doses of the anticancer drugs. We previously developed epidermal growth factor receptor (EGFR)-targeted chitosan (CS) nanoparticles as a versatile delivery system for silencing the essential mitotic checkpoint gene Mad2, and induce cell death. Here, we tested this system as a single therapy and in combination with cisplatin in cisplatin sensitive and resistant lung cancer models, and characterized its in vivo efficacy and safety. Combination treatment resulted in significant improvement in tumor inhibition that was strikingly more effective in cisplatin-resistant tumors. Importantly, effective cisplatin dosage was dramatically reduced in the co-therapy regimen resulting in negligible toxic effects from the drug as confirmed by parameters such as body weight gain, biochemical markers of hepatic and renal function, and histopathology of liver/kidney/spleen tissues. Overall, we demonstrate that the combination of Mad2 siRNA-loaded CS nanoparticles strategy with chemotherapeutic agents such as cisplatin constitutes an efficient and safe approach for the treatment of drug resistant tumors. Lung cancer remains one of the leading killers in the United States and around the world. Platinum agents, including cisplatin, are the first line treatment in lung cancer, including non-small cell lung cancer (NSCLC), which is the predominant form of lung cancer. In this study, we have evaluated Mad2 cell-cycle checkpoint gene silencing using small interfering RNA (siRNA) delivered

  14. The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells

    International Nuclear Information System (INIS)

    Kuwatsuka, Y; Minami, M; Minami, Y; Sugimoto, K; Hayakawa, F; Miyata, Y; Abe, A; Goff, D J; Kiyoi, H; Naoe, T

    2011-01-01

    In Ph-positive (Ph + ) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph + acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγ null (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G 0 cells in the CD34 + CD38 − population compared with the CD34 + CD38 + and CD34 − populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34 + CD38 − population than in the other populations. Although slow-cycling G 0 cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34 + CD38 − population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34 + cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph + leukemia due to quiescence

  15. 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

  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 Absence

    DEFF Research Database (Denmark)

    Paldam, Camilla Skovbjerg

    2017-01-01

    In this chapter, I address the rhetoric of modern love correspondence – its various purposes, modes of communication, and meta-reflections on writing and media – from the beginning of the 20th century till today. I analyze how love and the beloved are mediated in the articulated desire and longing...... of love letters, and how love letters are used as a medium to overcome absence. I also reflect on the material status of love letters in relation to the technological development and subsequently the replacement of traditional letters by their digital counterparts such as email, text messages and real...

  18. CM363, a novel naphthoquinone derivative which acts as multikinase modulator and overcomes imatinib resistance in chronic myelogenous leukemia

    Science.gov (United States)

    Díaz-Chico, Juan Carlos; McNaughton-Smith, Grant; Jiménez-Alonso, Sandra; Hueso-Falcón, Idaira; Montero, Juan Carlos; Blanco, Raquel; León, Javier; Rodríguez-González, Germán; Estévez-Braun, Ana; Pandiella, Atanasio; Díaz-Chico, Bonifacio Nicolás; Fernández-Pérez, Leandro

    2017-01-01

    Human Chronic Myelogenous Leukemia (CML) is a hematological stem cell disorder which is associated with activation of Bcr-Abl-Stat5 oncogenic pathway. Direct Bcr-Abl inhibitors are initially successful for the treatment of CML but over time many patients develop drug resistance. In the present study, the effects of CM363, a novel naphthoquinone (NPQ) derivative, were evaluated on human CML-derived K562 cells. CM363 revealed an effective cell growth inhibition (IC50 = 0.7 ± 0.5 μM) by inducing cancer cells to undergo cell cycle arrest and apoptosis. CM363 caused a dose- and time-dependent reduction of cells in G0/G1 and G2/M phases. This cell cycle arrest was associated with increased levels of cyclin E, pChk1 and pChk2 whereas CM363 downregulated cyclin B, cyclin D3, p27, pRB, Wee1, and BUBR1. CM363 increased the double-strand DNA break marker γH2AX. CM363 caused a time-dependent increase of annexin V-positive cells, DNA fragmentation and increased number of apoptotic nuclei. CM363 triggered the mitochondrial apoptotic pathway as reflected by a release of cytochrome C from mitochondria and induction of the cleavage of caspase-3 and -9, and PARP. CM363 showed multikinase modulatory effects through an early increased JNK phosphorylation followed by inhibition of pY-Bcrl-Abl and pY-Stat5. CM363 worked synergistically with imatinib to inhibit cell viability and maintained its activity in imatinib-resistant cells. Finally, CM363 (10 mg/Kg) suppressed the growth of K562 xenograft tumors in athymic mice. In summary, CM363 is a novel multikinase modulator that offers advantages to circumvent imanitib resistance and might be therapeutically effective in Bcrl-Abl-Stat5 related malignancies. PMID:27557509

  19. Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?

    Science.gov (United States)

    Marshall, Steven; Hujer, Andrea M; Rojas, Laura J; Papp-Wallace, Krisztina M; Humphries, Romney M; Spellberg, Brad; Hujer, Kristine M; Marshall, Emma K; Rudin, Susan D; Perez, Federico; Wilson, Brigid M; Wasserman, Ronald B; Chikowski, Linda; Paterson, David L; Vila, Alejandro J; van Duin, David; Kreiswirth, Barry N; Chambers, Henry F; Fowler, Vance G; Jacobs, Michael R; Pulse, Mark E; Weiss, William J; Bonomo, Robert A

    2017-04-01

    Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram-negative bacteria, we tested the efficacy of the combination of ceftazidime-avibactam (CAZ-AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk diffusion and agar-based antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ-AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included bla IMP , bla NDM , bla OXA-48 , bla CTX-M , bla AmpC , and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ-AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ-AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥21 mm. All isolates demonstrated a reduction in CAZ-AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥4-log 10 -CFU decrease for all groups that had CAZ-AVI with ATM (8 μg/ml) added, compared to the group treated with CAZ-AVI alone. In the murine neutropenic thigh infection model, an almost 4-log 10 -CFU reduction was noted at 24 h for CAZ-AVI (32 mg/kg every 8 h [q8h]) plus ATM (32 mg/kg q8h) versus CAZ-AVI (32 mg/kg q8h) alone. The data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae . Copyright © 2017 American Society for Microbiology.

  20. The Role of Interferon Regulatory Factor-1 (IRF1) in Overcoming Antiestrogen Resistance in the Treatment of Breast Cancer

    International Nuclear Information System (INIS)

    Schwartz, J.L.; Shajahan, A.N.; Clarke, R.

    2011-01-01

    Resistance to endocrine therapy is common among breast cancer patients with estrogen receptor alpha-positive (ER+) tumors and limits the success of this therapeutic strategy. While the mechanisms that regulate endocrine responsiveness and cell fate are not fully understood, interferon regulatory factor-1 (IRF1) is strongly implicated as a key regulatory node in the underlying signaling network. IRF1 is a tumor suppressor that mediates cell fate by facilitating apoptosis and can do so with or without functional p53. Expression of IRF1 is down regulated in endocrine-resistant breast cancer cells, protecting these cells from IRF1-induced inhibition of proliferation and/or induction of cell death. Nonetheless, when IRF1 expression is induced following IFN treatment, antiestrogen sensitivity is restored by a process that includes the inhibition of pro survival BCL2 family members and caspase activation. These data suggest that a combination of endocrine therapy and compounds that effectively induce IRF1 expression may be useful for the treatment of many ER+ breast cancers. By understanding IRF1 signaling in the context of endocrine responsiveness, we may be able to develop novel therapeutic strategies and better predict how patients will respond to endocrine therapy

  1. Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Tianjun; Commodore, Lois; Huang, Wei-Sheng; Wang, Yihan; Thomas, Mathew; Keats, Jeff; Xu, Qihong; Rivera, Victor M.; Shakespeare, William C.; Clackson, Tim; Dalgarno, David C.; Zhu, Xiaotian (ARIAD)

    2012-01-20

    The BCR-ABL inhibitor imatinib has revolutionized the treatment of chronic myeloid leukemia. However, drug resistance caused by kinase domain mutations has necessitated the development of new mutation-resistant inhibitors, most recently against the T315I gatekeeper residue mutation. Ponatinib (AP24534) inhibits both native and mutant BCR-ABL, including T315I, acting as a pan-BCR-ABL inhibitor. Here, we undertook a combined crystallographic and structure-activity relationship analysis on ponatinib to understand this unique profile. While the ethynyl linker is a key inhibitor functionality that interacts with the gatekeeper, virtually all other components of ponatinib play an essential role in its T315I inhibitory activity. The extensive network of optimized molecular contacts found in the DFG-out binding mode leads to high potency and renders binding less susceptible to disruption by single point mutations. The inhibitory mechanism exemplified by ponatinib may have broad relevance to designing inhibitors against other kinases with mutated gatekeeper residues.

  2. Targeted delivery of CD44s-siRNA by ScFv overcomes de novo resistance to cetuximab in triple negative breast cancer.

    Science.gov (United States)

    Fu, Wenyan; Sun, Hefen; Zhao, Yang; Chen, Mengting; Yang, Lipeng; Yang, Xueli; Jin, Wei

    2018-05-16

    The overexpression of EGFR often occurs in TNBC, and the anti-EGFR receptor antibody cetuximab is used widely to treat metastatic cancer in the clinic. However, EGFR-targeted therapies have been developed for TNBC without clinical success. In this study, we show that impaired EGFR degradation is crucial for resistance to cetuximab, which depends on the cell surface molecule CD44. To further investigate the role of CD44 in EGFR signaling and its treatment potential, we developed a targeting fusion protein composed of an anti-EGFR scFv generated from cetuximab and truncated protamine, called Ce-tP. CD44 siRNA can be specifically delivered into EGFR-positive TNBC cells by Ce-tP. Efficient knockdown of CD44 and suppression of both EGFR and downstream signaling by the Ce-tP/siRNA complex were observed in EGFR-positive TNBC cells. More importantly, our results also showed that targeted delivery of siRNA specific for CD44 can efficiently overcome resistance to EGFR targeting in TNBC cells both in vitro and in vivo. Overall, our results establish a new principle to achieve EGFR inhibition in TNBC and limit drug resistance. Copyright © 2018 Elsevier Ltd. All rights reserved.

  3. Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma.

    Science.gov (United States)

    Chiron, David; Dousset, Christelle; Brosseau, Carole; Touzeau, Cyrille; Maïga, Sophie; Moreau, Philippe; Pellat-Deceunynck, Catherine; Le Gouill, Steven; Amiot, Martine

    2015-04-20

    The aggressive biological behavior of mantle cell lymphoma (MCL) and its short response to current treatment highlight a great need for better rational therapy. Herein, we investigate the ability of ABT-199, the Bcl-2-selective BH3 mimetic, to kill MCL cells. Among MCL cell lines tested (n = 8), only three were sensitive (LD50 < 200 nM). In contrast, all primary MCL samples tested (n = 11) were highly sensitive to ABT-199 (LD50 < 10 nM). Mcl-1 and Bcl-xL both confer resistance to ABT-199-specific killing and BCL2/(BCLXL+MCL1) mRNA ratio is a strong predictor of sensitivity. By mimicking the microenvironment through CD40 stimulation, we show that ABT-199 sensitivity is impaired through activation of NF-kB pathway and Bcl-x(L) up-regulation. We further demonstrate that resistance is rapidly lost when MCL cells detach from CD40L-expressing fibroblasts. It has been reported that ibrutinib induces lymphocytosis in vivo holding off malignant cells from their protective microenvironment. We show here for two patients undergoing ibrutinib therapy that mobilized MCL cells are highly sensitive to ABT-199. These results provide evidence that in situ ABT-199 resistance can be overcome when MCL cells escape from the lymph nodes. Altogether, our data support the clinical application of ABT-199 therapy both as a single agent and in sequential combination with BTK inhibitors.

  4. γ-Glutamylcysteine synthetase (γ-GCS) as a target for overcoming chemo- and radio-resistance of human hepatocellular carcinoma cells.

    Science.gov (United States)

    Lin, Li-Ching; Chen, Chi-Fen; Ho, Chun-Te; Liu, Jun-Jen; Liu, Tsan-Zon; Chern, Chi-Liang

    2018-04-01

    This study uncovered that the genetically endowed intracellular glutathione contents (iGSH) regulated by the catalytic subunit of γ‑glutamylcysteine synthetase heavy chain (γ‑GCSh) as a prime target for overcoming both the inherited and stimuli-activated chemo- and radio-resistance of hepatocellular carcinoma (HCC) cells. Reactive oxygen species (ROS) production and mitochondrial membrane potential (Δψm) were determined by the probe-based flow cytometry. The TUNEL assay was used as an index of radio-sensitivity and the MTT assay was used as an index of chemo-sensitivity against various anti-cancer agents. iGSH and γ‑GCSh activity were measured by HPLC methods. γ‑GCSh-overexpressing GCS30 cell line was established by tetracycline-controlled Tet-OFF gene expression system in SK-Hep-1 cells. The relative radio-sensitivities of a panel of five HCC cells were found to be correlated negatively with both the contents of iGSH and their corresponding γ‑GCSh activities with an order of abundance being Hep G2 > Hep 3B > J5 > Mahlavu > SK-Hep-1, respectively. Similarly, the cytotoxicity response patterns of these HCC cells against arsenic trioxide (ATO), a ROS-producing anti-cancer drug, were exactly identical to the order of ranking instigated by the radiotherapy (RT) treatment. Next, γ‑GCSh-overexpressing GCS30 cells were found to possess excellent ability to profoundly mitigate both the drop of Δψm and apoptotic TUNEL-positive cell population engendered by ATO, cisplatin, doxorubicin, and RT treatments. Our data unequivocally demonstrate that γ‑GCSh may represent a prime target for overcoming anti-cancer drugs and RT resistance for HCC cells. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. Altered Cross-linking of HSP27 by Zerumbone as a Novel Strategy for Overcoming HSP27- mediated Resistance

    International Nuclear Information System (INIS)

    Choi, Seo Hyun; Lee, Yoon Jin; Lee, Hae June; Lee, Yun Sil; Kim, Joon; Seo, Woo Duck; Nam, Joo Won; Lee, Yoo Jin; Seo, Eun Kyung

    2010-01-01

    HSPs have diverse roles in the regulation of signal transduction and in numerous aspects of cell growth and death. Indeed, HSP90, HSP70, and HSP27 have each been implicated in promoting cancer. Most HSP27 exists as large oligomeric complexes ranging from 100- 800 kDa, which are probably stabilized by complex interactions between dimeric building blocks. The functional properties of HSP27 are dependent on the quaternary structure of the protein. For example, HSP27 acts as a chaperone and binds to cytochrome c or Daxx as a dimer. Therefore, the oligomerization pattern of HPS27 is believed to have HSP27-mediated protective functions. In this study, zerumbone (ZER), the cytotoxic component isolated from Zingiber zerumbet Smith, induced cross-linking of HSP27 protein by its insertion between the disulfide bond of HSP27, and ZERmediated altered cross-linking of HSP27 modified normal HSP27 dimerization, which resulted in a sensitizing effect to tumors after treatment with radiation. Therefore, altered cross-linking by ZER may be a novel strategy for inhibition of HSP27-mediated resistance

  6. Quantitative and Qualitative Involvement of P3N-PIPO in Overcoming Recessive Resistance against Clover Yellow Vein Virus in Pea Carrying the cyv1 Gene

    Science.gov (United States)

    Choi, Sun Hee; Hagiwara-Komoda, Yuka; Atsumi, Go; Shimada, Ryoko; Hisa, Yusuke; Naito, Satoshi

    2013-01-01

    In pea carrying cyv1, a recessive gene for resistance to Clover yellow vein virus (ClYVV), ClYVV isolate Cl-no30 was restricted to the initially infected cells, whereas isolate 90-1 Br2 overcame this resistance. We mapped the region responsible for breaking of cyv1-mediated resistance by examining infection of cyv1 pea with chimeric viruses constructed from parts of Cl-no30 and 90-1 Br2. The breaking of resistance was attributed to the P3 cistron, which is known to produce two proteins: P3, from the main open reading frame (ORF), and P3N-PIPO, which has the N-terminal part of P3 fused to amino acids encoded by a small open reading frame (ORF) called PIPO in the +2 reading frame. We introduced point mutations that were synonymous with respect to the P3 protein but nonsynonymous with respect to the P3N-PIPO protein, and vice versa, into the chimeric viruses. Infection of plants with these mutant viruses revealed that both P3 and P3N-PIPO were involved in overcoming cyv1-mediated resistance. Moreover, P3N-PIPO quantitatively affected the virulence of Cl-no30 in cyv1 pea. Additional expression in trans of the P3N-PIPO derived from Cl-no30, using White clover mosaic virus as a vector, enabled Cl-no30 to move to systemic leaves in cyv1 pea. Susceptible pea plants infected with chimeric ClYVV possessing the P3 cistron of 90-1 Br2, and which were therefore virulent toward cyv1 pea, accumulated more P3N-PIPO than did those infected with Cl-no30, suggesting that the higher level of P3N-PIPO in infected cells contributed to the breaking of resistance by 90-1 Br2. This is the first report showing that P3N-PIPO is a virulence determinant in plants resistant to a potyvirus. PMID:23616656

  7. The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Kuwatsuka, Y; Minami, M; Minami, Y; Sugimoto, K; Hayakawa, F; Miyata, Y; Abe, A [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan); Goff, D J [Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA (United States); Kiyoi, H [Department of Infectious Diseases, Nagoya University Hospital, Nagoya (Japan); Naoe, T [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan)

    2011-05-01

    In Ph-positive (Ph{sup +}) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph{sup +} acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγ{sup null} (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G{sub 0} cells in the CD34{sup +}CD38{sup −} population compared with the CD34{sup +}CD38{sup +} and CD34{sup −} populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34{sup +}CD38{sup −} population than in the other populations. Although slow-cycling G{sub 0} cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34{sup +}CD38{sup −} population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34{sup +} cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph{sup +} leukemia due to quiescence.

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

    Directory of Open Access Journals (Sweden)

    Michiro Susa

    2010-05-01

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

  9. Overcoming multidrug resistance in 2D and 3D culture models by controlled drug chitosan-graft poly(caprolactone)-based nanoparticles.

    Science.gov (United States)

    Shi, Wei-Bin; Le, Van-Minh; Gu, Chun-Hua; Zheng, Yuan-Hong; Lang, Mei-Dong; Lu, Yan-Hua; Liu, Jian-Wen

    2014-04-01

    The principal limitations of chemotherapy are dose-limiting systemic toxicity and the development of multidrug-resistant phenotypes. The aim of this study was to investigate the efficiency of a new sustained drug delivery system based on chitosan and ε-caprolactone to overcome multidrug resistance in monolayer and drug resistance associated with the three-dimensional (3D) tumor microenvironment in our established 3D models. The 5-fluorouracil (5-FU)-loaded nanoparticles (NPs) were characterized by transmission electron microscope and dynamic light scattering, and its released property was determined at different pH values. 5-FU/NPs exhibited well-sustained release properties and markedly enhanced the cytotoxicity of 5-FU against HCT116/L-OHP or HCT8/VCR MDR cells in two-dimensional (2D) and its parental cells in 3D collagen gel culture with twofold to threefold decrease in the IC50 values, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Hoechst/propidium iodide staining and flow cytometry analysis. Furthermore, the possible mechanism was explored by high-performance liquid chromatography and rhodamine 123 accumulation experiment. Overall, the results demonstrated that 5-FU/NPs increase intracellular concentration of 5-FU and enhance its anticancer efficiency by inducing apoptosis. It was suggested that this novel NPs are a promising carrier to decrease toxic of 5-FU and has the potential to reverse the forms of both intrinsic and acquired drug resistance in 2D and 3D cultures. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  10. Options for small and medium sized reactors (SMRs) to overcome loss of economies of scale and incorporate increased proliferation resistance and energy security

    International Nuclear Information System (INIS)

    Kuznetsov, Vladimir

    2008-01-01

    The designers of innovative small and medium sized reactors pursue new design and deployment strategies making use of certain advantages provided by smaller reactor size and capacity to achieve reduced design complexity and simplified operation and maintenance requirements, and to provide for incremental capacity increase through multi-module plant clustering. Competitiveness of SMRs depends on the incorporated strategies to overcome loss of economies of scale but equally it depends on finding appropriate market niches for such reactors. For many less developed countries, these are the features of enhanced proliferation resistance and increased robustness of barriers for sabotage protection that may ensure the progress of nuclear power. For such countries, small reactors without on-site refuelling, designed for infrequent replacement of well-contained fuel cassette(s) in a manner that impedes clandestine diversion of nuclear fuel material, may provide a solution. Based on the outputs of recent IAEA activities for innovative SMRs, the paper provides a summary of the state-of-the-art in approaches to improve SMR competitiveness and incorporate enhanced proliferation resistance and energy security. (author)

  11. Cafestol overcomes ABT-737 resistance in Mcl-1-overexpressed renal carcinoma Caki cells through downregulation of Mcl-1 expression and upregulation of Bim expression.

    Science.gov (United States)

    Woo, S M; Min, K-J; Seo, B R; Nam, J-O; Choi, K S; Yoo, Y H; Kwon, T K

    2014-11-06

    Although ABT-737, a small-molecule Bcl-2/Bcl-xL inhibitor, has recently emerged as a novel cancer therapeutic agent, ABT-737-induced apoptosis is often blocked in several types of cancer cells with elevated expression of Mcl-1. Cafestol, one of the major compounds in coffee beans, has been reported to have anti-carcinogenic activity and tumor cell growth-inhibitory activity, and we examined whether cafestol could overcome resistance against ABT-737 in Mcl-1-overexpressed human renal carcinoma Caki cells. ABT-737 alone had no effect on apoptosis, but cafestol markedly enhanced ABT-737-mediated apoptosis in Mcl-1-overexpressed Caki cells, human glioma U251MG cells, and human breast carcinoma MDA-MB231 cells. By contrast, co-treatment with ABT-737 and cafestol did not induce apoptosis in normal human skin fibroblast. Furthermore, combined treatment with cafestol and ABT-737 markedly reduced tumor growth compared with either drug alone in xenograft models. We found that cafestol inhibited Mcl-1 protein expression, which is important for ABT-737 resistance, through promotion of protein degradation. Moreover, cafestol increased Bim expression, and siRNA-mediated suppression of Bim expression reduced the apoptosis induced by cafestol plus ABT-737. Taken together, cafestol may be effectively used to enhance ABT-737 sensitivity in cancer therapy via downregulation of Mcl-1 expression and upregulation of Bim expression.

  12. pH-Dependent doxorubicin release from terpolymer of starch, polymethacrylic acid and polysorbate 80 nanoparticles for overcoming multi-drug resistance in human breast cancer cells.

    Science.gov (United States)

    Shalviri, Alireza; Raval, Gaurav; Prasad, Preethy; Chan, Carol; Liu, Qiang; Heerklotz, Heiko; Rauth, Andrew Michael; Wu, Xiao Yu

    2012-11-01

    This work investigated the capability of a new nanoparticulate system, based on terpolymer of starch, polymethacrylic acid and polysorbate 80, to load and release doxorubicin (Dox) as a function of pH and to evaluate the anticancer activity of Dox-loaded nanoparticles (Dox-NPs) to overcome multidrug resistance (MDR) in human breast cancer cells in vitro. The Dox-NPs were characterized by Fourier transform infrared spectroscopy (FTIR), isothermal titration calorimetry (ITC), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The cellular uptake and cytotoxicity of the Dox-loaded nanoparticles were investigated using fluorescence microscopy, flow cytometry, and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay. The nanoparticles were able to load up to 49.7±0.3% of Dox with a high loading efficiency of 99.9±0.1%, while maintaining good colloidal stability. The nanoparticles released Dox at a higher rate at acidic pH attributable to weaker Dox-polymer molecular interactions evidenced by ITC. The Dox-NPs were taken up by the cancer cells in vitro and significantly enhanced the cytotoxicity of Dox against human MDR1 cells with up to a 20-fold decrease in the IC50 values. The results suggest that the new terpolymeric nanoparticles are a promising vehicle for the controlled delivery of Dox for treatment of drug resistant breast cancer. Copyright © 2012 Elsevier B.V. All rights reserved.

  13. Design and deployment strategies for small and medium sized reactors (SMRs) to overcome loss of economies of scale and incorporate increased proliferation resistance

    International Nuclear Information System (INIS)

    Kuznetsov, V.

    2007-01-01

    The designers of innovative small and medium sized reactors pursue new design and deployment strategies making use of certain advantages provided by smaller reactor size and capacity to achieve reduced design complexity and simplified operation and maintenance requirements, and to provide for incremental capacity increase through multi-module plant clustering. Competitiveness of SMRs (Small and Medium size Reactor) depends on the incorporated strategies to overcome loss of economies of scale but equally it depends on finding appropriate market niches for such reactors. For many less developed countries, these are the features of enhanced proliferation resistance and increased robustness of barriers for sabotage protection that may ensure the progress of nuclear power. For such countries, small reactors without on-site refuelling, designed for infrequent replacement of well-contained fuel cassette(s) in a manner that impedes clandestine diversion of nuclear fuel material, may provide a solution. Based on the outputs of recent IAEA activities for innovative SMRs, the paper provides a summary of the state-of-the-art in approaches to improve SMR competitiveness and incorporate enhanced proliferation resistance and energy security. (author)

  14. Overcoming multidrug resistance in Dox-resistant neuroblastoma cell lines via treatment with HPMA copolymer conjugates containing anthracyclines and P-gp inhibitors

    Czech Academy of Sciences Publication Activity Database

    Koziolová, Eva; Janoušková, Olga; Cuchalová, Lucie; Hvězdová, Zuzana; Hraběta, J.; Eckschlager, T.; Sivák, Ladislav; Ulbrich, Karel; Etrych, Tomáš; Šubr, Vladimír

    2016-01-01

    Roč. 233, 10 July (2016), s. 136-146 ISSN 0168-3659 R&D Projects: GA ČR(CZ) GAP301/12/1254; GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : N-(2-hydroxypropyl)methacrylamide copolymers * multidrug resistance * P-glycoprotein inhibitors Subject RIV: CD - Macromolecular Chemistry ; FD - Oncology ; Hematology (MBU-M) Impact factor: 7.786, year: 2016

  15. Inability of p53-reactivating compounds Nutlin-3 and RITA to overcome p53 resistance in tumor cells deficient in p53Ser46 phosphorylation.

    Science.gov (United States)

    Ma, Teng; Yamada, Shumpei; Ichwan, Solachuddin J A; Iseki, Sachiko; Ohtani, Kiyoshi; Otsu, Megumi; Ikeda, Masa-Aki

    2012-01-20

    The p53 tumor suppressor protein plays key roles in protecting cells from tumorigenesis. Phosphorylation of p53 at Ser46 (p53Ser46) is considered to be a crucial modification regulating p53-mediated apoptosis. Because the activity of p53 is impaired in most human cancers, restoration of wild-type p53 (wt-p53) function by its gene transfer or by p53-reactivating small molecules has been extensively investigated. The p53-reactivating compounds Nutlin-3 and RITA activate p53 in the absence of genotoxic stress by antagonizing the action of its negative regulator Mdm2. Although controversial, Nutlin-3 was shown to induce p53-mediated apoptosis in a manner independent of p53 phosphorylation. Recently, RITA was shown to induce apoptosis by promoting p53Ser46 phosphorylation. Here we examined whether Nutlin-3 or RITA can overcome resistance to p53-mediated apoptosis in p53-resistant tumor cell lines lacking the ability to phosphorylate p53Ser46. We show that Nutlin-3 did not rescue the apoptotic defect of a Ser46 phosphorylation-defective p53 mutant in p53-sensitive tumor cells, and that RITA neither restored p53Ser46 phosphorylation nor induced apoptosis in p53Ser46 phosphorylation-deficient cells retaining wt-p53. Furthermore, treatment with Nutlin-3 or RITA together with adenoviral p53 gene transfer also failed to induce apoptosis in p53Ser46 phosphorylation-deficient cells either expressing or lacking wt-p53. These results indicate that neither Nutlin-3 nor RITA in able to induce p53-mediated apoptosis in the absence of p53Ser46 phosphorylation. Thus, the dysregulation of this phosphorylation in tumor cells may be a critical factor that limits the efficacy of these p53-based cancer therapies. Copyright © 2011 Elsevier Inc. All rights reserved.

  16. 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.

  17. The small molecule inhibitor YK-4-279 disrupts mitotic progression of neuroblastoma cells, overcomes drug resistance and synergizes with inhibitors of mitosis.

    Science.gov (United States)

    Kollareddy, Madhu; Sherrard, Alice; Park, Ji Hyun; Szemes, Marianna; Gallacher, Kelli; Melegh, Zsombor; Oltean, Sebastian; Michaelis, Martin; Cinatl, Jindrich; Kaidi, Abderrahmane; Malik, Karim

    2017-09-10

    Neuroblastoma is a biologically and clinically heterogeneous pediatric malignancy that includes a high-risk subset for which new therapeutic agents are urgently required. As well as MYCN amplification, activating point mutations of ALK and NRAS are associated with high-risk and relapsing neuroblastoma. As both ALK and RAS signal through the MEK/ERK pathway, we sought to evaluate two previously reported inhibitors of ETS-related transcription factors, which are transcriptional mediators of the Ras-MEK/ERK pathway in other cancers. Here we show that YK-4-279 suppressed growth and triggered apoptosis in nine neuroblastoma cell lines, while BRD32048, another ETV1 inhibitor, was ineffective. These results suggest that YK-4-279 acts independently of ETS-related transcription factors. Further analysis reveals that YK-4-279 induces mitotic arrest in prometaphase, resulting in subsequent cell death. Mechanistically, we show that YK-4-279 inhibits the formation of kinetochore microtubules, with treated cells showing a broad range of abnormalities including multipolar, fragmented and unseparated spindles, together leading to disrupted progression through mitosis. Notably, YK-4-279 does not affect microtubule acetylation, unlike the conventional mitotic poisons paclitaxel and vincristine. Consistent with this, we demonstrate that YK-4-279 overcomes vincristine-induced resistance in two neuroblastoma cell-line models. Furthermore, combinations of YK-4-279 with vincristine, paclitaxel or the Aurora kinase A inhibitor MLN8237/Alisertib show strong synergy, particularly at low doses. Thus, YK-4-279 could potentially be used as a single-agent or in combination therapies for the treatment of high-risk and relapsing neuroblastoma, as well as other cancers. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  18. In vitro experimental (211)At-anti-CD33 antibody therapy of leukaemia cells overcomes cellular resistance seen in vivo against gemtuzumab ozogamicin.

    Science.gov (United States)

    Petrich, Thorsten; Korkmaz, Zekiye; Krull, Doris; Frömke, Cornelia; Meyer, Geerd J; Knapp, Wolfram H

    2010-05-01

    Monoclonal anti-CD33 antibodies conjugated with toxic calicheamicin derivative (gemtuzumab ozogamicin, GO) are a novel therapy option for acute myeloid leukaemia (AML). Key prognostic factors for patients with AML are high CD33 expression on the leukaemic cells and the ability to overcome mechanisms of resistance to cytotoxic chemotherapies, including drug efflux or other mechanisms decreasing apoptosis. Alpha particle-emitting radionuclides overwhelm such anti-apoptotic mechanisms by producing numerous DNA double-stranded breaks (DSBs) accompanied by decreased DNA repair. We labelled anti-CD33 antibodies with the alpha-emitter (211)At and compared survival of leukaemic HL-60 and K-562 cells treated with the (211)At-labelled antibodies, GO or unlabelled antibodies as controls. We also measured caspase-3/7 activity, DNA fragmentation and necrosis in HL-60 cells after treatment with the different antibodies or with free (211)At. The mean labelling ratio of (211)At-labelled antibodies was 1:1,090 +/- 364 (range: 1:738-1:1,722) in comparison to 2-3:1 for GO. Tumour cell binding of (211)At-anti-CD33 was high in the presence of abundant CD33 expression and could be specifically blocked by unlabelled anti-CD33. (211)At-anti-CD33 decreased survival significantly more than did GO at comparable dilution (1:1,000). No significant differences in induction of apoptosis or necrosis or DNA DSB or in decreased survival were observed after (211)At-anti-CD33 (1:1,090) versus GO (1:1) treatment. Our results suggest that (211)At is a promising, highly cytotoxic radioimmunotherapy in CD33-positive leukaemia and kills tumour cells more efficiently than does calicheamicin-conjugated antibody. Labelling techniques leading to higher chemical yield and specific activities must be developed to increase (211)At-anti-CD33 therapeutic effects.

  19. In vitro experimental {sup 211}At-anti-CD33 antibody therapy of leukaemia cells overcomes cellular resistance seen in vivo against gemtuzumab ozogamicin

    Energy Technology Data Exchange (ETDEWEB)

    Petrich, Thorsten; Korkmaz, Zekiye; Krull, Doris; Meyer, Geerd J.; Knapp, Wolfram H. [Hanover University School of Medicine, Department of Nuclear Medicine, Hanover (Germany); Froemke, Cornelia [Hanover University School of Medicine, Department of Biometry, Hanover (Germany)

    2010-05-15

    Monoclonal anti-CD33 antibodies conjugated with toxic calicheamicin derivative (gemtuzumab ozogamicin, GO) are a novel therapy option for acute myeloid leukaemia (AML). Key prognostic factors for patients with AML are high CD33 expression on the leukaemic cells and the ability to overcome mechanisms of resistance to cytotoxic chemotherapies, including drug efflux or other mechanisms decreasing apoptosis. Alpha particle-emitting radionuclides overwhelm such anti-apoptotic mechanisms by producing numerous DNA double-stranded breaks (DSBs) accompanied by decreased DNA repair. We labelled anti-CD33 antibodies with the alpha-emitter {sup 211}At and compared survival of leukaemic HL-60 and K-562 cells treated with the {sup 211}At-labelled antibodies, GO or unlabelled antibodies as controls. We also measured caspase-3/7 activity, DNA fragmentation and necrosis in HL-60 cells after treatment with the different antibodies or with free {sup 211}At. The mean labelling ratio of {sup 211}At-labelled antibodies was 1:1,090 {+-} 364 (range: 1:738-1:1,722) in comparison to 2-3:1 for GO. Tumour cell binding of {sup 211}At-anti-CD33 was high in the presence of abundant CD33 expression and could be specifically blocked by unlabelled anti-CD33. {sup 211}At-anti-CD33 decreased survival significantly more than did GO at comparable dilution (1:1,000). No significant differences in induction of apoptosis or necrosis or DNA DSB or in decreased survival were observed after {sup 211}At-anti-CD33 (1:1,090) versus GO (1:1) treatment. Our results suggest that {sup 211}At is a promising, highly cytotoxic radioimmunotherapy in CD33-positive leukaemia and kills tumour cells more efficiently than does calicheamicin-conjugated antibody. Labelling techniques leading to higher chemical yield and specific activities must be developed to increase {sup 211}At-anti-CD33 therapeutic effects. (orig.)

  20. Alternative signaling pathways as potential therapeutic targets for overcoming EGFR and c-Met inhibitor resistance in non-small cell lung cancer.

    Directory of Open Access Journals (Sweden)

    Jason T Fong

    Full Text Available The use of tyrosine kinase inhibitors (TKIs against EGFR/c-Met in non-small cell lung cancer (NSCLC has been shown to be effective in increasing patient progression free survival (PFS, but their efficacy is limited due to the development of resistance and tumor recurrence. Therefore, understanding the molecular mechanisms underlying development of drug resistance in NSCLC is necessary for developing novel and effective therapeutic approaches to improve patient outcome. This study aims to understand the mechanism of EGFR/c-Met tyrosine kinase inhibitor (TKI resistance in NSCLC. H2170 and H358 cell lines were made resistant to SU11274, a c-Met inhibitor, and erlotinib, an EGFR inhibitor, through step-wise increases in TKI exposure. The IC50 concentrations of resistant lines exhibited a 4-5 and 11-22-fold increase for SU11274 and erlotinib, respectively, when compared to parental lines. Furthermore, mTOR and Wnt signaling was studied in both cell lines to determine their roles in mediating TKI resistance. We observed a 2-4-fold upregulation of mTOR signaling proteins and a 2- to 8-fold upregulation of Wnt signaling proteins in H2170 erlotinib and SU11274 resistant cells. H2170 and H358 cells were further treated with the mTOR inhibitor everolimus and the Wnt inhibitor XAV939. H358 resistant cells were inhibited by 95% by a triple combination of everolimus, erlotinib and SU11274 in comparison to 34% by a double combination of these drugs. Parental H2170 cells displayed no sensitivity to XAV939, while resistant cells were significantly inhibited (39% by XAV939 as a single agent, as well as in combination with SU11274 and erlotinib. Similar results were obtained with H358 resistant cells. This study suggests a novel molecular mechanism of drug resistance in lung cancer.

  1. Hypoxia-induced tumor cell resistance is overcome by synergistic GAPDH-siRNA and chemotherapy co-delivered by long-circulating and cationic-interior liposomes

    NARCIS (Netherlands)

    Guan, J.; Sun, J.; Sun, F.; Lou, B.; Zhang, D.; Mashayekhi, V.; Sadeghi, N.; Storm, G.; Mastrobattista, E.; He, Z.

    2017-01-01

    Chemotherapeutic drug resistance of tumor cells under hypoxic conditions is caused by the inhibition of apoptosis by autophagy and drug efflux via adenosine triphosphate (ATP)-dependent transporter activation, among other factors. Here, we demonstrate that disrupting glyceraldehyde-3-phosphate

  2. Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells

    International Nuclear Information System (INIS)

    Fuchs, Dominik; Daniel, Volker; Sadeghi, Mahmoud; Opelz, Gerhard; Naujokat, Cord

    2010-01-01

    Leukemia stem cells are known to exhibit multidrug resistance by expression of ATP-binding cassette (ABC) transporters which constitute transmembrane proteins capable of exporting a wide variety of chemotherapeutic drugs from the cytosol. We show here that human promyeloblastic leukemia KG-1a cells exposed to the histone deacetylase inhibitor phenylbutyrate resemble many characteristics of leukemia stem cells, including expression of functional ABC transporters such as P-glycoprotein, BCRP and MRP8. Consequently, KG-1a cells display resistance to the induction of apoptosis by various chemotherapeutic drugs. Resistance to apoptosis induction by chemotherapeutic drugs can be reversed by cyclosporine A, which effectively inhibits the activity of P-glycoprotein and BCRP, thus demonstrating ABC transporter-mediated drug resistance in KG-1a cells. However, KG-1a are highly sensitive to apoptosis induction by salinomycin, a polyether ionophore antibiotic that has recently been shown to kill human breast cancer stem cell-like cells and to induce apoptosis in human cancer cells displaying multiple mechanisms of drug and apoptosis resistance. Whereas KG-1a cells can be adapted to proliferate in the presence of apoptosis-inducing concentrations of bortezomib and doxorubicin, salinomycin does not permit long-term adaptation of the cells to apoptosis-inducing concentrations. Thus, salinomycin should be regarded as a novel and effective agent for the elimination of leukemia stem cells and other tumor cells exhibiting ABC transporter-mediated multidrug resistance.

  3. Synergistic Combinations of a Pyrethroid Insecticide and an Emulsifiable Oil Formulation of Beauveria bassiana to Overcome Insecticide Resistance in Listronotus maculicollis (Coleoptera: Curculionidae).

    Science.gov (United States)

    Wu, Shaohui; Kostromytska, Olga S; Koppenhöfer, Albrecht M

    2017-08-01

    The annual bluegrass weevil, Listronotus maculicollis (Kirby), is a major pest of golf course turf in eastern North America and has become particularly problematic owing to widespread development of insecticide resistance. As an alternative option to manage resistant adult L. maculicollis, we explored combinations of the pyrethroid insecticide bifenthrin with an emulsifiable oil formulation of the entomopathogenic fungus Beauveria bassiana strain GHA (Bb ES). Combinations synergistically enhanced mortality in both insecticide-susceptible and insecticide-resistant L. maculicollis adults in the laboratory when bifenthrin was used at LC50s for each population. To determine the component behind the synergism, technical spores of B. bassiana GHA and the emulsifiable oil carrier in the fungal formulation were tested separately or in combination with bifenthrin. In both separate and combined applications, the emulsifiable oil carrier was responsible for high mortality within 3 d after treatment and interacted synergistically with bifenthrin, whereas fungus-induced mortality started later. Strong synergism was also observed in three field experiments with a relatively resistant L. maculicollis population. Combinations of Bb ES and bifenthrin hold promise as an effective L. maculicollis management tool, particularly of pyrethroid-resistant populations. © The Authors 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. Overcoming of P-glycoprotein mediated vincristine resistance of L1210/VCR mouse leukemic cells could be induced by pentoxifylline but not by theophylline and caffeine

    International Nuclear Information System (INIS)

    Stefankova, Z.; Barancik, M.; Breier, A.

    1996-01-01

    Effects of xanthine derivatives (pentoxifylline (PTX), caffeine, theophylline, 1-methyl-3-isobutylxanthine) on P-glycoprotein mediated vincristine resistance of L1210/VCR mouse leukemic cell sub-line were studied. From the applied xanthines only PTX was found to reverse the vincristine resistance of the above cells. Moreover, only PTX, but not other xanthine, increased the accumulation of [ 3 H]vincristine by L1210/VCR cells. Thus it may be concluded that PTX-induced reversal of vincristine (VCR) resistance could not be explained from the point of known pharmacological effects of PTX that are common for other xanthines such as inhibition of phosphodiesterase activity, calcium mobilizing effect, inhibition of tumor necrosis factor α (TNF), etc. (author)

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

    Science.gov (United States)

    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, 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

    2009-01-01

    SUMMARY 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-ABLT315I mutation and compound mutants selected on sequential inhibitor therapy remain major clinical challenges. We report design and pre-clinical evaluation of AP24534, a potent, orally available multi-targeted kinase inhibitor active against T315I and other BCR-ABL mutants. AP24534 inhibited all tested BCR-ABL mutants in cellular and biochemical assays, suppressed BCR-ABLT315I-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. PMID:19878872

  6. 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.

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

    OpenAIRE

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

    2015-01-01

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

  8. Hypoxia-Induced Cisplatin Resistance in Non-Small Cell Lung Cancer Cells Is Mediated by HIF-1α and Mutant p53 and Can Be Overcome by Induction of Oxidative Stress.

    Science.gov (United States)

    Deben, Christophe; Deschoolmeester, Vanessa; De Waele, Jorrit; Jacobs, Julie; Van den Bossche, Jolien; Wouters, An; Peeters, Marc; Rolfo, Christian; Smits, Evelien; Lardon, Filip; Pauwels, Patrick

    2018-04-21

    The compound APR-246 (PRIMA-1 MET ) is a known reactivator of (mutant) p53 and inducer of oxidative stress which can sensitize cancer cells to platinum-based chemotherapeutics. However, the effect of a hypoxic tumor environment has been largely overlooked in this interaction. This study focusses on the role of hypoxia-inducible factor-1α (HIF-1α) and the p53 tumor suppressor protein in hypoxia-induced cisplatin resistance in non-small cell lung cancer (NSCLC) cells and the potential of APR-246 to overcome this resistance. We observed that hypoxia-induced cisplatin resistance only occurred in the p53 mutant NCI-H2228 Q331 * cell line, and not in the wild type A549 and mutant NCI-H1975 R273H cell lines. Cisplatin reduced HIF-1α protein levels in NCI-H2228 Q331 * cells, leading to a shift in expression from HIF-1α-dependent to p53-dependent transcription targets under hypoxia. APR-246 was able to overcome hypoxia-induced cisplatin resistance in NCI-H2228 Q331 * cells in a synergistic manner without affecting mutant p53 Q331 * transcriptional activity, but significantly depleting total glutathione levels more efficiently under hypoxic conditions. Synergism was dependent on the presence of mutant p53 Q331 * and the induction of reactive oxygen species, with depletion of one or the other leading to loss of synergism. Our data further support the rationale of combining APR-246 with cisplatin in NSCLC, since their synergistic interaction is retained or enforced under hypoxic conditions in the presence of mutant p53.

  9. Hypoxia-Induced Cisplatin Resistance in Non-Small Cell Lung Cancer Cells Is Mediated by HIF-1α and Mutant p53 and Can Be Overcome by Induction of Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Christophe Deben

    2018-04-01

    Full Text Available The compound APR-246 (PRIMA-1MET is a known reactivator of (mutant p53 and inducer of oxidative stress which can sensitize cancer cells to platinum-based chemotherapeutics. However, the effect of a hypoxic tumor environment has been largely overlooked in this interaction. This study focusses on the role of hypoxia-inducible factor-1α (HIF-1α and the p53 tumor suppressor protein in hypoxia-induced cisplatin resistance in non-small cell lung cancer (NSCLC cells and the potential of APR-246 to overcome this resistance. We observed that hypoxia-induced cisplatin resistance only occurred in the p53 mutant NCI-H2228Q331* cell line, and not in the wild type A549 and mutant NCI-H1975R273H cell lines. Cisplatin reduced HIF-1α protein levels in NCI-H2228Q331* cells, leading to a shift in expression from HIF-1α-dependent to p53-dependent transcription targets under hypoxia. APR-246 was able to overcome hypoxia-induced cisplatin resistance in NCI-H2228Q331* cells in a synergistic manner without affecting mutant p53Q331* transcriptional activity, but significantly depleting total glutathione levels more efficiently under hypoxic conditions. Synergism was dependent on the presence of mutant p53Q331* and the induction of reactive oxygen species, with depletion of one or the other leading to loss of synergism. Our data further support the rationale of combining APR-246 with cisplatin in NSCLC, since their synergistic interaction is retained or enforced under hypoxic conditions in the presence of mutant p53.

  10. The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models.

    Science.gov (United States)

    Zhang, Sen; Anjum, Rana; Squillace, Rachel; Nadworny, Sara; Zhou, Tianjun; Keats, Jeff; Ning, Yaoyu; Wardwell, Scott D; Miller, David; Song, Youngchul; Eichinger, Lindsey; Moran, Lauren; Huang, Wei-Sheng; Liu, Shuangying; Zou, Dong; Wang, Yihan; Mohemmad, Qurish; Jang, Hyun Gyung; Ye, Emily; Narasimhan, Narayana; Wang, Frank; Miret, Juan; Zhu, Xiaotian; Clackson, Tim; Dalgarno, David; Shakespeare, William C; Rivera, Victor M

    2016-11-15

    Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK + ) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Here, we report the structure and first comprehensive preclinical evaluation of the next-generation ALK TKI brigatinib. A kinase screen was performed to evaluate the selectivity profile of brigatinib. The cellular and in vivo activities of ALK TKIs were compared using engineered and cancer-derived cell lines. The brigatinib-ALK co-structure was determined. Brigatinib potently inhibits ALK and ROS1, with a high degree of selectivity over more than 250 kinases. Across a panel of ALK + cell lines, brigatinib inhibited native ALK (IC 50 , 10 nmol/L) with 12-fold greater potency than crizotinib. Superior efficacy of brigatinib was also observed in mice with ALK + tumors implanted subcutaneously or intracranially. Brigatinib maintained substantial activity against all 17 secondary ALK mutants tested in cellular assays and exhibited a superior inhibitory profile compared with crizotinib, ceritinib, and alectinib at clinically achievable concentrations. Brigatinib was the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses. Brigatinib is a highly potent and selective ALK inhibitor. These findings provide the molecular basis for the promising activity being observed in ALK + , crizotinib-resistant patients with NSCLC being treated with brigatinib in clinical trials. Clin Cancer Res; 22(22); 5527-38. ©2016 AACR. ©2016 American Association for Cancer Research.

  11. NVP-BEZ235 overcomes gefitinib-acquired resistance by down-regulating PI3K/AKT/ mTOR phosphorylation

    Directory of Open Access Journals (Sweden)

    Sun ZH

    2015-01-01

    Full Text Available Zhihua Sun,2,* Qiuhui li,1,* Sheng Zhang,1 Jing Chen,1 Lili Huang,3 Jinghua Ren,1 Yu Chang,1 Yichen Liang,1 Gang Wu1 1Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2Oncology department, Xiangyang central Hospital, Xiangyang, Hubei, People’s Republic of China; 3Radiation Oncology Department, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People's Republic of China *These authors contributed equally to this work Background: Patients harboring activating mutations in epidermal growth factor receptors (EGFR are particularly sensitive to EGFR tyrosine kinase inhibitors (TKIs. However, most patients develop an acquired resistance after a period of about 10 months. This study focuses on the therapeutic effect of NVP-BEZ235, a dual inhibitor of phosphatidylinositol- 3-kinase/mammalian target of rapamycin (PI3K/mTOR, in gefitinib-resistant non-small cell lung cancer. Methods: H1975 cell line was validated as a gefitinib-resistant cell model by the nucleotide-sequence analysis. We used the 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay to detect the growth of H1975 cell line in vitro. H1975 cells' migration was detected by the migration assay. Xenograft models were used to investigate the growth of gefitinib-resistant non-small cell lung cancer in vivo. Western blot and immunohistochemical analysis were used to investigate the level of PI3K/protein kinase B(AKT/mTOR signaling pathway proteins. Results: We show that NVP-BEZ235 effectively inhibited the growth of H1975 cells in vivo as well as in vitro. Similarly, H1975 cell migration was reduced by NVP-BEZ235. Further experiments revealed that NVP-BEZ235 attenuated the phosphorylation of PI3K/AKT/mTOR signaling pathway proteins. Conclusion: Taken together, we suggest that NVP-BEZ235 inhibits gefitinib-resistant tumor growth by downregulating PI3K

  12. A single point mutation in Tomato spotted wilt virus NSs protein is sufficient to overcome Tsw-gene-mediated resistance in pepper.

    Science.gov (United States)

    Almási, Asztéria; Nemes, Katalin; Csömör, Zsófia; Tóbiás, István; Palkovics, László; Salánki, Katalin

    2017-06-01

    The nonstructural protein (NSs) of Tomato spotted wilt virus (TSWV) was previously identified as an avirulence determinant for Tsw-based resistance on pepper. The NSs of wild-type (WT) and resistance-breaking (RB) TSWV strains isolated in Hungary had only two amino acid substitutions (104, 461). We have analysed the ability of the NSs and their point mutant variants to trigger Tsw-mediated hypersensitive responses and RNA silencing suppressor (RSS) activity in patch assays. We identified a single amino acid change at position 104 (T-A) that was responsible for the necrosis induction or loss, while a significant difference was not detected in the RSS activity of the two parental strains. We have successfully complemented the infection of the WT strain on resistant pepper cultivar with the infectious S RNA transcript of the RB strain and the WT-T104A point mutant. Our work provides direct evidence that a single amino acid change can induce an RB phenotype.

  13. Dual Drug Targeting of Mutant Bcr-Abl Induces Inactive Conformation: New Strategy for the Treatment of Chronic Myeloid Leukemia and Overcoming Monotherapy Resistance.

    Science.gov (United States)

    El Rashedy, Ahmed A; Olotu, Fisayo A; Soliman, Mahmoud E S

    2018-03-01

    Bcr-Abl is an oncogenic fusion protein which expression enhances tumorigenesis, and has been highly associated with chronic myeloid leukemia (CML). Acquired drug resistance in mutant Bcr-Abl has enhanced pathogenesis with the use of single therapy agents such as nilotinib. Moreover, allosteric targeting has been identified to consequentially inhibit Bcr-Abl activity, which led to the recent development of ABL-001 (asciminib) that selectively binds the myristoyl pocket. Experimental studies have revealed that the combination of nilotinib and ABL-001 induced a 'bent' conformation in the C-terminal helix of Bcr-Abl; a benchmark of inhibition, thereby exhibiting a greater potency in the treatment of CML, surmounting the setbacks of drug resistance, disease regression and relapse. Therefore, we report the first account of the dynamics and conformational analysis of oncogenic T334I Bcr-Abl by dual targeting. Our findings revealed that unlike in the Bcr-Abl-Nilotinib complex, dual targeting by both inhibitors induced the bent conformation in the C-terminal helix that varied with time. This was coupled with significant alteration in Bcr-Abl stability, flexibility, and compactness and an overall structural re-orientation inwards towards the hydrophobic core, which reduced the solvent-exposed residues indicative of protein folding. This study will facilitate allosteric targeting and the design of more potent allosteric inhibitors for resistive target proteins in cancer. © 2018 Wiley-VHCA AG, Zurich, Switzerland.

  14. Overcoming drug resistance of MCF-7/ADR cells by altering intracellular distribution of doxorubicin via MVP knockdown with a novel siRNA polyamidoamine-hyaluronic acid complex.

    Science.gov (United States)

    Han, Min; Lv, Qing; Tang, Xin-Jiang; Hu, Yu-Lan; Xu, Dong-Hang; Li, Fan-Zhu; Liang, Wen-Quan; Gao, Jian-Qing

    2012-10-28

    Drug resistance is one of the critical reasons leading to failure in chemotherapy. Enormous studies have been focused on increasing intracellular drug accumulation through inhibiting P-glycoprotein (Pgp). Meanwhile, we found that major vault protein (MVP) may be also involved in drug resistance of human breast cancer MCF-7/ADR cells by transporting doxorubicin (DOX) from the action target (i.e. nucleus) to cytoplasma. Herein polyamidoamine (PAMAM) dendrimers was functionalized by a polysaccharide hyaluronic acid (HA) to effectively deliver DOX as well as MVP targeted small-interfering RNA (MVP-siRNA) to down regulate MVP expression and improve DOX chemotherapy in MCF-7/ADR cells. In comparison with DOX solution (IC50=48.5 μM), an enhanced cytotoxicity could be observed for DOX PAMAM-HA (IC50=11.3 μM) as well as enhanced tumor target, higher intracellular accumulation, increased blood circulating time and less in vivo toxicity. Furthermore, codelivery of siRNA and DOX by PAMAM-HA exhibited satisfactory gene silencing effect as well as enhanced stability and efficient intracellular delivery of siRNA, which allowed DOX access to nucleus and induced subsequent much more cytotoxicity than siRNA absent case as a result of MVP knockdown. This observation highlights a promising application of novel nanocarrier PAMAM-HA, which could co-deliver anticancer drug and siRNA, in reversing drug resistance by altering intracellular drug distribution. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Overcoming multidrug resistance via simultaneous delivery of cytostatic drug and P-glycoprotein inhibitor to cancer cells by HPMA copolymer conjugate

    Czech Academy of Sciences Publication Activity Database

    Sivák, Ladislav; Šubr, Vladimír; Tomala, Jakub; Říhová, Blanka; Strohalm, Jiří; Etrych, Tomáš; Kovář, Marek

    2017-01-01

    Roč. 115, JAN 2017 (2017), s. 65-80 ISSN 0142-9612 R&D Projects: GA ČR(CZ) GAP301/12/1254; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61388971 ; RVO:61389013 Keywords : Multidrug resistance * P-glycoprotein * Doxorubicin Subject RIV: EE - Microbiology, Virology; CD - Macromolecular Chemistry (UMCH-V) OBOR OECD: Microbiology; Polymer sci ence (UMCH-V) Impact factor: 8.402, year: 2016

  16. Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation.

    Science.gov (United States)

    Geng, Kaijun; Xia, Zongjun; Ji, Yinchun; Zhang, Ruisi Ruthy; Sun, Deqiao; Ai, Jing; Song, Zilan; Geng, Meiyu; Zhang, Ao

    2018-01-20

    To address drug resistance caused by ALK kinase mutations, especially the most refractory and predominant mutation G1202R for the second-generation ALK inhibitor, a series of new diarylaminopyrimidine analogues were designed by incorporating a resorcinol moiety (A-ring) to interact the ALK kinase domain where the G1202R is located. Compound 12d turns out as the most potent with IC 50 values of 1.7, 3.5, and 1.8 nM against ALK wild type, gatekeeper mutant L1196M, and the G1202R mutant, respectively. More importantly, compound 12d has excellent inhibitory effects against the proliferation of BaF3 cells specifically expressing ALK wild type, gatekeeper L1196M, and the most challenging mutant G1202R, with IC 50 values all less than 1.5 nM. Collectively, compound 12d is worthy of further investigation as a new more potent third-generation ALK inhibitor to circumvent drug resistance of both the first-generation and the second-generation inhibitors. Copyright © 2017. Published by Elsevier Masson SAS.

  17. [Cetuximab in combination with icotinib overcomes the acquired resistance caused by EGFR T790M mutation in non-small cell lung cancer].

    Science.gov (United States)

    Wang, Meng; Zhang, Lianmin; Zhao, Xiaoliang; Liu, Jun; Chen, Yulong; Wang, Changli

    2014-09-01

    The aim of this study was to investigate the effects of combination of icotinib and cetuximab on the acquired drug resistance caused by T790M mutation of EGFR in NSCLC, and provide experimental evidence for rational treatment of NSCLC. The effects of these two agents on cell proliferation, apoptosis, and EGFR-dependent signaling were evaluated using 3-(4, 5-dimethylthiazol-2-yl)- 5-diphenyltetrazolium bromide (MTT) assay, annexin V staining, and Western blotting. The expression of molecular markers of tumor proliferation PCNA and Ki-67 protein was further examined by immunohistochemistry, and the expression of EGFR-signaling-related proteins in tissue sections taken from H1975 tumor xenografts was assessed by Western blot assay. Sensitivity to EGFR inhibitors was detected in human H1975 tumor xenograft in nude mice. The in vitro experiment showed that the proliferative ability of H1975 cells was inhibited in a dose-dependent manner, along with the increasing doses of cetuximab and icotinib, and the combination of cetuximab with icotinib resulted in a more pronounced growth inhibition of the H1975 cells. The apoptosis rate of H1975 cells after treatment with 0.5 µmol/L icotinib and 1 µg/ml cetuximab was (22.03 ± 2.41)% and that after treatment with 5 µmol/L icotinib and 10 µg/ml cetuximab was (42.75 ± 2.49)%, both were significantly higher than that after treatment with the same dose of icotinib or cetuximab alone (P icotinib treatment, but (30.8 ± 2.0) mm(3) in the cetuximab treatment group and 0 mm(3) in the cetuximab combined with icotinib group. There was a significantly decreased expression of Ki-67 and PCNA proteins and down-regulation of phosphorylation of EGFR signaling-related proteins in the cetuximab combined with icotinib group. The combination of icotinib with cetuximab can exert synergistic inhibitory effect on the acquired drug resistance caused by T790M mutation of EGFR in NSCLC H1975 cells, interrupts the EGFR-downstream signaling pathway

  18. Dual HER2\\PIK3CA targeting overcomes single-agent acquired resistance in HER2 amplified uterine serous carcinoma cell lines in vitro and in vivo

    Science.gov (United States)

    Lopez, Salvatore; Cocco, Emiliano; Black, Jonathan; Bellone, Stefania; Bonazzoli, Elena; Predolini, Federica; Ferrari, Francesca; Schwab, Carlton L.; English, Diana P.; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E.; Terranova, Corrado; Angioli, Roberto; Santin, Alessandro D.

    2015-01-01

    HER2/neu gene amplification and PIK3CA driver mutations are common in uterine serous carcinoma (USC), and may represent ideal therapeutic targets against this aggressive variant of endometrial cancer. We examined the sensitivity to neratinib, taselisib and the combination of the two compounds in in vitro and in vivo experiments using PIK3CA mutated and PIK3CA-wild type HER2/neu amplified USC cell lines. Cell viability and cell cycle distribution were assessed using flow-cytometry assays. Downstream signaling was assessed by immunoblotting. Preclinical efficacy of single versus dual inhibition was evaluated in vivo using two USC-xenografts. We found both single agent neratinib and taselisib to be active but only transiently effective in controlling the in vivo growth of USC xenografts harboring HER2/neu gene amplification with or without oncogenic PIK3CA mutations. In contrast, the combination of the two inhibitors caused a stronger and long lasting growth inhibition in both USC xenografts when compared to single agent therapy. Combined targeting of HER2 and PIK3CA was associated with a significant and dose-dependent increase in the percentage of cells in the G0/G1 phase of the cell cycle and a dose-dependent decline in the phosphorylation of S6. Importantly, dual inhibition therapy initiated after tumor progression in single agent-treated mice was still remarkably effective at inducing tumor regression in both large PIK3CA or pan-ErbB inhibitor-resistant USC xenografts. Dual HER2/PIK3CA blockade may represent a novel therapeutic option for USC patients harboring tumors with HER2/neu gene amplification and mutated or wild type PIK3CA resistant to chemotherapy. PMID:26333383

  19. Dual HER2/PIK3CA Targeting Overcomes Single-Agent Acquired Resistance in HER2-Amplified Uterine Serous Carcinoma Cell Lines In Vitro and In Vivo.

    Science.gov (United States)

    Lopez, Salvatore; Cocco, Emiliano; Black, Jonathan; Bellone, Stefania; Bonazzoli, Elena; Predolini, Federica; Ferrari, Francesca; Schwab, Carlton L; English, Diana P; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E; Terranova, Corrado; Angioli, Roberto; Santin, Alessandro D

    2015-11-01

    HER2/neu gene amplification and PIK3CA driver mutations are common in uterine serous carcinoma (USC) and may represent ideal therapeutic targets against this aggressive variant of endometrial cancer. We examined the sensitivity to neratinib, taselisib, and the combination of the two compounds in in vitro and in vivo experiments using PIK3CA-mutated and PIK3CA wild-type HER2/neu-amplified USC cell lines. Cell viability and cell-cycle distribution were assessed using flow-cytometry assays. Downstream signaling was assessed by immunoblotting. Preclinical efficacy of single versus dual inhibition was evaluated in vivo using two USC xenografts. We found both single-agent neratinib and taselisib to be active but only transiently effective in controlling the in vivo growth of USC xenografts harboring HER2/neu gene amplification with or without oncogenic PIK3CA mutations. In contrast, the combination of the two inhibitors caused a stronger and long-lasting growth inhibition in both USC xenografts when compared with single-agent therapy. Combined targeting of HER2 and PIK3CA was associated with a significant and dose-dependent increase in the percentage of cells in the G0-G1 phase of the cell cycle and a dose-dependent decline in the phosphorylation of S6. Importantly, dual inhibition therapy initiated after tumor progression in single-agent-treated mice was still remarkably effective at inducing tumor regression in both large PIK3CA and pan-ErbB inhibitor-resistant USC xenografts. Dual HER2/PIK3CA blockade may represent a novel therapeutic option for USC patients harboring tumors with HER2/neu gene amplification and mutated or wild-type PIK3CA resistant to chemotherapy. ©2015 American Association for Cancer Research.

  20. 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 ...

  1. Cationic PEGylated liposomes incorporating an antimicrobial peptide tilapia hepcidin 2–3: an adjuvant of epirubicin to overcome multidrug resistance in cervical cancer cells

    Directory of Open Access Journals (Sweden)

    Juang V

    2016-11-01

    Full Text Available Vivian Juang,1 Hsin-Pin Lee,2 Anya Maan-Yuh Lin,1,3 Yu-Li Lo1 1Department and Institute of Pharmacology, National Yang-Ming University, 2Department of Biological Sciences and Technology, National University of Tainan, 3Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China Abstract: Antimicrobial peptides (AMPs have been recently evaluated as a new generation of adjuvants in cancer chemotherapy. In this study, we designed PEGylated liposomes encapsulating epirubicin as an antineoplastic agent and tilapia hepcidin 2–3, an AMP, as a multidrug resistance (MDR transporter suppressor and an apoptosis/autophagy modulator in human cervical cancer HeLa cells. Cotreatment of HeLa cells with PEGylated liposomal formulation of epirubicin and hepcidin 2–3 significantly increased the cytotoxicity of epirubicin. The liposomal formulations of epirubicin and/or hepcidin 2–3 were found to noticeably escalate the intracellular H2O2 and O2- levels of cancer cells. Furthermore, these treatments considerably reduced the mRNA expressions of MDR protein 1, MDR-associated protein (MRP 1, and MRP2. The addition of hepcidin 2–3 in liposomes was shown to markedly enhance the intracellular epirubicin uptake and mainly localized into the nucleus. Moreover, this formulation was also found to trigger apoptosis and autophagy in HeLa cells, as validated by significant increases in the expressions of cleaved poly ADP ribose polymerase, caspase-3, caspase-9, and light chain 3 (LC3-II, as well as a decrease in mitochondrial membrane potential. The apoptosis induction was also confirmed by the rise in sub-G1 phase of cell cycle assay and apoptosis percentage of annexin V/propidium iodide assay. We found that liposomal epirubicin and hepcidin 2–3 augmented the accumulation of GFP-LC3 puncta as amplified by chloroquine, implying the involvement of autophagy. Interestingly, the partial inhibition of necroptosis and the epithelial

  2. Scopadulciol, Isolated from Scoparia dulcis, Induces β-Catenin Degradation and Overcomes Tumor Necrosis Factor-Related Apoptosis Ligand Resistance in AGS Human Gastric Adenocarcinoma Cells.

    Science.gov (United States)

    Fuentes, Rolly G; Toume, Kazufumi; Arai, Midori A; Sadhu, Samir K; Ahmed, Firoj; Ishibashi, Masami

    2015-04-24

    Scopadulciol (1), a scopadulan-type diterpenoid, was isolated from Scoparia dulcis along with three other compounds (2-4) by an activity-guided approach using the TCF reporter (TOP) luciferase-based assay system. A fluorometric microculture cytotoxicity assay (FMCA) revealed that compound 1 was cytotoxic to AGS human gastric adenocarcinoma cells. The treatment of AGS cells with 1 decreased β-catenin levels and also inhibited its nuclear localization. The pretreatment of AGS cells with a proteasome inhibitor, either MG132 or epoxomicin, protected against the degradation of β-catenin induced by 1. The 1-induced degradation of β-catenin was also abrogated in the presence of pifithrin-α, an inhibitor of p53 transcriptional activity. Compound 1 inhibited TOP activity in AGS cells and downregulated the protein levels of cyclin D1, c-myc, and survivin. Compound 1 also sensitized AGS cells to tumor necrosis factor-related apoptosis ligand (TRAIL)-induced apoptosis by increasing the levels of the death receptors, DR4 and DR5, and decreasing the level of the antiapoptotic protein Bcl-2. Collectively, our results demonstrated that 1 induced the p53- and proteasome-dependent degradation of β-catenin, which resulted in the inhibition of TCF/β-catenin transcription in AGS cells. Furthermore, 1 enhanced apoptosis in TRAIL-resistant AGS when combined with TRAIL.

  3. Monensin, a polyether ionophore antibiotic, overcomes TRAIL resistance in glioma cells via endoplasmic reticulum stress, DR5 upregulation and c-FLIP downregulation.

    Science.gov (United States)

    Yoon, Mi Jin; Kang, You Jung; Kim, In Young; Kim, Eun Hee; Lee, Ju Ahn; Lim, Jun Hee; Kwon, Taeg Kyu; Choi, Kyeong Sook

    2013-08-01

    Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is preferentially cytotoxic to cancer cells over normal cells. However, many cancer cells, including malignant glioma cells, tend to be resistant to TRAIL. Monensin (a polyether ionophore antibiotic that is widely used in veterinary medicine) and salinomycin (a compound that is structurally related to monensin and shows cancer stem cell-inhibiting activity) are currently recognized as anticancer drug candidates. In this study, we show that monensin effectively sensitizes various glioma cells, but not normal astrocytes, to TRAIL-mediated apoptosis; this occurs at least partly via monensin-induced endoplasmic reticulum (ER) stress, CHOP-mediated DR5 upregulation and proteasome-mediated downregulation of c-FLIP. Interestingly, other polyether antibiotics, such as salinomycin, nigericin, narasin and lasalocid A, also stimulated TRAIL-mediated apoptosis in glioma cells via ER stress, CHOP-mediated DR5 upregulation and c-FLIP downregulation. Taken together, these results suggest that combined treatment of glioma cells with TRAIL and polyether ionophore antibiotics may offer an effective therapeutic strategy.

  4. Hypoxia imaging with [F-18] FMISO-PET in head and neck cancer: Potential for guiding intensity modulated radiation therapy in overcoming hypoxia-induced treatment resistance

    International Nuclear Information System (INIS)

    Hendrickson, Kristi; Phillips, Mark; Smith, Wade; Peterson, Lanell; Krohn, Kenneth; Rajendran, Joseph

    2011-01-01

    Background and purpose: Positron emission tomography (PET) imaging with [F-18] fluoromisonidazole (FMISO) has been validated as a hypoxic tracer . Head and neck cancer exhibits hypoxia, inducing aggressive biologic traits that impart resistance to treatment. Delivery of modestly higher radiation doses to tumors with stable areas of chronic hypoxia can improve tumor control . Advanced radiation treatment planning (RTP) and delivery techniques such as intensity modulated radiation therapy (IMRT) can deliver higher doses to a small volume without increasing morbidity. We investigated the utility of co-registered FMISO-PET and CT images to develop clinically feasible RTPs with higher tumor control probabilities (TCP). Materials and methods: FMISO-PET images were used to determine hypoxic sub-volumes for boost planning. Example plans were generated for 10 of the patients in the study who exhibited significant hypoxia. We created an IMRT plan for each patient with a simultaneous integrated boost (SIB) to the hypoxic sub-volumes. We also varied the boost for two patients. Result: A significant (mean 17%, median 15%) improvement in TCP is predicted when the modest additional boost dose to the hypoxic sub-volume is included. Conclusion: Combined FMISO-PET imaging and IMRT planning permit delivery of higher doses to hypoxic regions, increasing the predicted TCP (mean 17%) without increasing expected complications.

  5. Tailored antiplatelet therapy can overcome clopidogrel and aspirin resistance - The BOchum CLopidogrel and Aspirin Plan (BOCLA-Plan to improve antiplatelet therapy

    Directory of Open Access Journals (Sweden)

    Pepinghege Fenena

    2011-01-01

    Full Text Available Abstract Background Dual antiplatelet therapy using acetylsalicylic acid (ASA, aspirin and clopidogrel is of great importance following coronary stenting. However, the variable platelet inhibitory effectiveness compromises the antithrombotic advantages provided by dual antiplatelet therapy. The aim of this single-center prospective study was to reduce the low response incidence of dual antiplatelet therapy with ASA and clopidogrel according to a prespecified therapy algorithm. Methods Platelet function testing using whole blood aggregometry (Chronolog 590 was performed 48 hours following coronary stenting (for either acute coronary syndromes or stable coronary artery disease on 504 patients. The antiplatelet therapy included a loading dose of 600 mg clopidogrel and 500 mg ASA, followed by 75 mg clopidogrel and 100 mg ASA once daily. Clopidogrel low responders (CLR: >5 ohm; adenosine diphosphate (ADP 5 μM and/or ASA low responders (ALR: >0 ohm; arachidonic acid 10 μM were treated according to a structured therapy plan: in the case of CLR, the maintenance + dose was doubled (repeated loading dose followed by 150 mg daily, and when still ineffective ticlopidine or prasugrel, if available and not contraindicated, were used. ALR was treated by increasing the dose to 300 mg in a first step or to 500 mg ASA when the first modification did not take effect sufficiently. In addition, ADP receptor antagonist 2-methylthioadenosine 5'-monophosphate triethylammonium salt (MeSAMP testing and ASA incubation were performed to rule out either a platelet ADP-receptor defect or an ASA pharmacokinetic resistance. Results Of the total cohort of 504 patients, we detected 30.8% clopidogrel low-responders and 19.4% aspirin low-responders. For ALR, with a dose adjustment of 300 mg ASA daily, 94.6% of ALR were effectively treated and the residual 5.4% by administration of daily dosages of 500 mg ASA. This means that after modification of the ASA maintenance dose, all

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

    Science.gov (United States)

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

    2016-09-01

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

  7. Overcoming imatinib resistance using Src inhibitor CGP76030, Abl inhibitor nilotinib and Abl/Lyn inhibitor INNO-406 in newly established K562 variants with BCR-ABL gene amplification.

    Science.gov (United States)

    Morinaga, Koji; Yamauchi, Takahiro; Kimura, Shinya; Maekawa, Taira; Ueda, Takanori

    2008-06-01

    Because imatinib (IM) resistance in chronic myeloid leukemia is primarily caused by the re-establishment of Abl kinase, new inhibitors may be efficacious. We evaluated 3 new agents against 2 new K562 variants, IM-R1 and IM-R2 cells, which were developed having 7- and 27-fold greater IM resistance, respectively, than the parental K562 cells. Both variants possessed BCR-ABL gene amplification along with elevated levels of its transcript and protein. Greater BCR-ABL gene amplification was observed in IM-R2 cells than in IM-R1 cells, which was consistent with the higher mRNA and protein levels of Bcr-Abl, and ultimately correlated with the greater IM resistance in IM-R2 cells. No mutation in the Abl kinase domain was detected in either variant. Despite the absence of Lyn overexpression, the Src kinase inhibitor CGP76030 showed positive cooperability with IM in inhibiting cell growth of not only K562 cells but also these 2 variants. This might be because of the augmented inhibition of Erk1/2 phosphorylation. The new Abl kinase inhibitor nilotinib was 10-fold more potent than IM in inhibiting the growth of K562 cells. Nilotinib inhibited the growth of IM-R1 and IM-R2 cells as potently as K562 cells. The combination of nilotinib with CGP76030 showed little additivity, because the potency of nilotinib masked the efficacy of CGP76030. The new dual Abl/Lyn inhibitor INNO-406 (formerly NS-187) was slightly more potent than nilotinib in inhibiting the growth of all 3 cell lines. Because BCR-ABL gene amplification occurs in blast crisis, these inhibitors might overcome IM resistance in such patients' leukemia. (c) 2008 Wiley-Liss, Inc.

  8. Cationic PEGylated liposomes incorporating an antimicrobial peptide tilapia hepcidin 2-3: an adjuvant of epirubicin to overcome multidrug resistance in cervical cancer cells.

    Science.gov (United States)

    Juang, Vivian; Lee, Hsin-Pin; Lin, Anya Maan-Yuh; Lo, Yu-Li

    Antimicrobial peptides (AMPs) have been recently evaluated as a new generation of adjuvants in cancer chemotherapy. In this study, we designed PEGylated liposomes encapsulating epirubicin as an antineoplastic agent and tilapia hepcidin 2-3, an AMP, as a multidrug resistance (MDR) transporter suppressor and an apoptosis/autophagy modulator in human cervical cancer HeLa cells. Cotreatment of HeLa cells with PEGylated liposomal formulation of epirubicin and hepcidin 2-3 significantly increased the cytotoxicity of epirubicin. The liposomal formulations of epirubicin and/or hepcidin 2-3 were found to noticeably escalate the intracellular H 2 O 2 and O 2 - levels of cancer cells. Furthermore, these treatments considerably reduced the mRNA expressions of MDR protein 1, MDR-associated protein (MRP) 1, and MRP2. The addition of hepcidin 2-3 in liposomes was shown to markedly enhance the intracellular epirubicin uptake and mainly localized into the nucleus. Moreover, this formulation was also found to trigger apoptosis and autophagy in HeLa cells, as validated by significant increases in the expressions of cleaved poly ADP ribose polymerase, caspase-3, caspase-9, and light chain 3 (LC3)-II, as well as a decrease in mitochondrial membrane potential. The apoptosis induction was also confirmed by the rise in sub-G1 phase of cell cycle assay and apoptosis percentage of annexin V/propidium iodide assay. We found that liposomal epirubicin and hepcidin 2-3 augmented the accumulation of GFP-LC3 puncta as amplified by chloroquine, implying the involvement of autophagy. Interestingly, the partial inhibition of necroptosis and the epithelial-mesenchymal transition by this combination was also verified. Altogether, our results provide evidence that coincubation with PEGylated liposomes of hepcidin 2-3 and epirubicin caused programmed cell death in cervical cancer cells through modulation of multiple signaling pathways, including MDR transporters, apoptosis, autophagy, and/or necroptosis

  9. Sustainability transition dynamics: Towards overcoming policy resistance

    NARCIS (Netherlands)

    Gooyert, V. de; Rouwette, E.A.J.A.; Kranenburg, H.L. van; Freeman, R.E.; Breen, H.J. van

    2016-01-01

    Sustainability transitions receive major scholarly attention, often explicitly with the intention to develop policy recommendations aimed towards progressing such transitions. Despite these efforts, many implemented transition policies have not been able to meet expectations. This tendency of

  10. Polymer nanotherapeutics to overcome multidrug resistance

    Czech Academy of Sciences Publication Activity Database

    Braunová, Alena; Kostka, Libor; Sivák, Ladislav; Filippov, Sergey K.; Pechar, Michal; Janoušková, Olga; Šírová, Milada; Etrych, Tomáš

    2017-01-01

    Roč. 6, 4 (Suppl) (2017), s. 92 ISSN 2325-9604. [International Conference and Exhibition on Nanomedicine and Drug Delivery. 29.05.2017-31.05.2017, Osaka] R&D Projects: GA ČR(CZ) GA16-17207S; GA MZd(CZ) NV16-28600A Institutional support: RVO:61389013 ; RVO:61388971 Keywords : polymer- drug carrier * micelle * controlled drug release Subject RIV: CD - Macromolecular Chemistry

  11. Overcoming reprogramming resistance of Fanconi anemia cells

    Science.gov (United States)

    Müller, Lars U. W.; Milsom, Michael D.; Harris, Chad E.; Vyas, Rutesh; Brumme, Kristina M.; Parmar, Kalindi; Moreau, Lisa A.; Schambach, Axel; Park, In-Hyun; London, Wendy B.; Strait, Kelly; Schlaeger, Thorsten; DeVine, Alexander L.; Grassman, Elke; D'Andrea, Alan; Daley, George Q.

    2012-01-01

    Fanconi anemia (FA) is a recessive syndrome characterized by progressive fatal BM failure and chromosomal instability. FA cells have inactivating mutations in a signaling pathway that is critical for maintaining genomic integrity and protecting cells from the DNA damage caused by cross-linking agents. Transgenic expression of the implicated genes corrects the phenotype of hematopoietic cells, but previous attempts at gene therapy have failed largely because of inadequate numbers of hematopoietic stem cells available for gene correction. Induced pluripotent stem cells (iPSCs) constitute an alternate source of autologous cells that are amenable to ex vivo expansion, genetic correction, and molecular characterization. In the present study, we demonstrate that reprogramming leads to activation of the FA pathway, increased DNA double-strand breaks, and senescence. We also demonstrate that defects in the FA DNA-repair pathway decrease the reprogramming efficiency of murine and human primary cells. FA pathway complementation reduces senescence and restores the reprogramming efficiency of somatic FA cells to normal levels. Disease-specific iPSCs derived in this fashion maintain a normal karyotype and are capable of hematopoietic differentiation. These data define the role of the FA pathway in reprogramming and provide a strategy for future translational applications of patient-specific FA iPSCs. PMID:22371882

  12. Radiogenetic therapy: strategies to overcome tumor resistance.

    Science.gov (United States)

    Marples, B; Greco, O; Joiner, M C; Scott, S D

    2003-01-01

    The aim of cancer gene therapy is to selectively kill malignant cells at the tumor site, by exploiting traits specific to cancer cells and/or solid tumors. Strategies that take advantage of biological features common to different tumor types are particularly promising, since they have wide clinical applicability. Much attention has focused on genetic methods that complement radiotherapy, the principal treatment modality, or that exploit hypoxia, the most ubiquitous characteristic of most solid cancers. The goal of this review is to highlight two promising gene therapy methods developed specifically to target the tumor volume that can be readily used in combination with radiotherapy. The first approach uses radiation-responsive gene promoters to control the selective expression of a suicide gene (e.g., herpes simplex virus thymidine kinase) to irradiated tissue only, leading to targeted cell killing in the presence of a prodrug (e.g., ganciclovir). The second method utilizes oxygen-dependent promoters to produce selective therapeutic gene expression and prodrug activation in hypoxic cells, which are refractive to conventional radiotherapy. Further refining of tumor targeting can be achieved by combining radiation and hypoxia responsive elements in chimeric promoters activated by either and dual stimuli. The in vitro and in vivo studies described in this review suggest that the combination of gene therapy and radiotherapy protocols has potential for use in cancer care, particularly in cases currently refractory to treatment as a result of inherent or hypoxia-mediated radioresistance.

  13. Utility of a Novel Three-Dimensional and Dynamic (3DD Cell Culture System for PK/PD Studies: Evaluation of a Triple Combination Therapy at Overcoming Anti-HER2 Treatment Resistance in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Anusha Ande

    2018-05-01

    Full Text Available Background: Emergence of Human epidermal growth factor receptor 2 (HER2 therapy resistance in HER2-positive (HER2+ breast cancer (BC poses a major clinical challenge. Mechanisms of resistance include the over-activation of the PI3K/mTOR and Src pathways. This work aims to investigate a novel combination therapy that employs paclitaxel (PAC, a mitotic inhibitor, with everolimus (EVE, an mTOR inhibitor, and dasatinib (DAS, an Src kinase inhibitor, as a modality to overcome resistance.Methods: Static (two dimensional, 2D and three-dimensional dynamic (3DD cell culture studies were conducted using JIMT-1 cells, a HER2+ BC cell line refractory to HER2 therapies. Cell viability and caspase-3 expression were examined after JIMT-1 cell exposure to agents as monotherapy or in combination using a 2D setting. A pharmacokinetic/pharmacodynamic (PK/PD combination study with PAC+DAS+EVE was conducted over 3 weeks in a 3DD setting. PAC was administered into the system via a 3 h infusion followed by the addition of a continuous infusion of EVE+DAS 24 h post-PAC dosing. Cell counts and caspase-3 expression were quantified every 2 days. A semi-mechanistic PK/PD model was developed using the 2D data and scaled up to capture the 3DD data. The final model integrated active caspase-3 as a biomarker to bridge between drug exposures and cancer cell dynamics. Model fittings were performed using Monolix software.Results: The triple combination significantly induced caspase-3 activity in the 2D cell culture setting. In the 3DD cell culture setting, sequential dosing of PAC then EVE+DAS showed a 5-fold increase in caspase-3 activity and 8.5-fold decrease in the total cell number compared to the control. The semi-mechanistic PK/PD models fit the data well, capturing the time-course profiles of drug concentrations, caspase-3 expression, and cell counts in the 2D and 3DD settings.Conclusion: A novel, sequential triple combination therapeutic regimen was successfully evaluated

  14. Synthesis of poly[N-(2-hydroxypropyl)methacrylamide] conjugates of inhibitors of the ABC transporter that overcome multidrug resistance in doxorubicin-resistant P388 cells in vitro

    Czech Academy of Sciences Publication Activity Database

    Šubr, Vladimír; Sivák, Ladislav; Koziolová, Eva; Braunová, Alena; Pechar, Michal; Strohalm, Jiří; Kabešová, Martina; Říhová, Blanka; Ulbrich, Karel; Kovář, Marek

    2014-01-01

    Roč. 15, č. 8 (2014), s. 3030-3043 ISSN 1525-7797 R&D Projects: GA ČR GAP301/12/1254; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : N-(2-hydroxypropyl)methacrylamide copolymers * multidrug resistance * P-glycoprotein inhibitors Subject RIV: CD - Macromolecular Chemistry; FD - Oncology ; Hematology (MBU-M) Impact factor: 5.750, year: 2014

  15. EFFECT OF PHOSPHOLIPASE-A2 ON SYK-MEDIATED PHOSPHORYLATION OF HUMAN ERYTHROCYTE MEMBRANE

    Directory of Open Access Journals (Sweden)

    Lucian Bordin

    2006-08-01

    , lacking in p36 isoform, are responsible of the lower ability of kinase of catalysing band 3 Tyr-phosphorylation, probably due either to steric bulk, or to particular sequestering of the holoenzyme into membrane compartment.

  16. Drug resistance to inhibitors of the human double minute-2 E3 ligase is mediated by point mutations of p53, but can be overcome with the p53 targeting agent RITA.

    Science.gov (United States)

    Jones, Richard J; Bjorklund, Chad C; Baladandayuthapani, Veerabhadran; Kuhn, Deborah J; Orlowski, Robert Z

    2012-10-01

    The human double minute (HDM)-2 E3 ubiquitin ligase plays a key role in p53 turnover and has been validated preclinically as a target in multiple myeloma (MM) and mantle cell lymphoma (MCL). HDM-2 inhibitors are entering clinical trials, and we therefore sought to understand potential mechanisms of resistance in lymphoid models. Wild-type p53 H929 MM and Granta-519 MCL cells resistant to MI-63 or Nutlin were generated by exposing them to increasing drug concentrations. MI-63-resistant H929 and Granta-519 cells were resistant to Nutlin, whereas Nutlin-resistant cells displayed cross-resistance to MI-63. These cells also showed cross-resistance to bortezomib, doxorubicin, cisplatin, and melphalan, but remained sensitive to the small molecule inhibitor RITA (reactivation of p53 and induction of tumor cell apoptosis). HDM-2 inhibitor-resistant cells harbored increased p53 levels, but neither genotoxic nor nongenotoxic approaches to activate p53 induced HDM-2 or p21. Resequencing revealed wild-type HDM-2, but mutations were found in the p53 DNA binding and dimerization domains. In resistant cells, RITA induced a G(2)-M arrest, upregulation of p53 targets HDM-2, PUMA, and NOXA, and PARP cleavage. Combination regimens with RITA and MI-63 resulted in enhanced cell death compared with RITA alone. These findings support the possibility that p53 mutation could be a primary mechanism of acquired resistance to HDM-2 inhibitors in MCL and MM. Furthermore, they suggest that simultaneous restoration of p53 function and HDM-2 inhibition is a rational strategy for clinical translation.

  17. Rocaglamide overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance in hepatocellular carcinoma cells by attenuating the inhibition of caspase-8 through cellular FLICE-like-inhibitory protein downregulation.

    Science.gov (United States)

    Luan, Zhou; He, Ying; He, Fan; Chen, Zhishui

    2015-01-01

    The enhancement of apoptosis is a therapeutic strategy used in the treatment of cancer. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent. However, hepatocellular carcinoma (HCC) cells exhibit marked resistance to the induction of cell death by TRAIL. The present study investigated whether rocaglamide, a naturally occurring product isolated from the genus Aglaia, is able to sensitize resistant HCC cells to TRAIL-mediated apoptosis. Two HCC cell lines, HepG2 and Huh-7, were treated with rocaglamide and/or TRAIL and the induction of apoptosis and effects on the TRAIL signaling pathway were investigated. The in vivo efficacy of rocaglamide was determined in TRAIL-resistant Huh-7-derived tumor xenografts. Rocaglamide significantly sensitized the TRAIL-resistant HCC cells to apoptosis by TRAIL, which resulted from the rocaglamide-mediated downregulation of cellular FLICE-like inhibitory protein and subsequent caspase-8 activation. Furthermore, rocaglamide markedly inhibited tumor growth from Huh-7 cells propagated in severe combined immunodeficient mice, suggesting that chemosentization also occurred in vivo. These data suggest that rocaglamide acted synergistically with TRAIL against the TRAIL-resistant HCC cells. Thus, it is concluded that rocaglamide as an adjuvant to TRAIL-based therapy may present a promising therapeutic approach for the treatment of HCC.

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

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

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

  19. 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.

  20. A mechanism for overcoming P-glycoprotein-mediated drug resistance: novel combination therapy that releases stored doxorubicin from lysosomes via lysosomal permeabilization using Dp44mT or DpC.

    Science.gov (United States)

    Seebacher, Nicole A; Richardson, Des R; Jansson, Patric J

    2016-12-01

    The intracellular distribution of a drug can cause significant variability in both activity and selectivity. Herein, we investigate the mechanism by which the anti-cancer agents, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and the clinically trialed, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), re-instate the efficacy of doxorubicin (DOX), in drug-resistant P-glycoprotein (Pgp)-expressing cells. Both Dp44mT and DpC potently target and kill Pgp-expressing tumors, while DOX effectively kills non-Pgp-expressing cancers. Thus, the combination of these agents should be considered as an effective rationalized therapy for potently treating advanced and resistant tumors that are often heterogeneous in terms of Pgp-expression. These studies demonstrate that both Dp44mT and DpC are transported into lysosomes via Pgp transport activity, where they induce lysosomal-membrane permeabilization to release DOX trapped within lysosomes. This novel strategy of loading lysosomes with DOX, followed by permeabilization with Dp44mT or DpC, results in the relocalization of stored DOX from its lysosomal 'safe house' to its nuclear targets, markedly enhancing cellular toxicity against resistant tumor cells. Notably, the combination of Dp44mT or DpC with DOX showed a very high level of synergism in multiple Pgp-expressing cell types, for example, cervical, breast and colorectal cancer cells. These studies revealed that the level of drug synergy was proportional to Pgp activity. Interestingly, synergism was ablated by inhibiting Pgp using the pharmacological inhibitor, Elacridar, or by inhibiting Pgp-expression using Pgp-silencing, demonstrating the importance of Pgp in the synergistic interaction. Furthermore, lysosomal-membrane stabilization inhibited the relocalization of DOX from lysosomes to the nucleus upon combination with Dp44mT or DpC, preventing synergism. This latter observation demonstrated the importance of lysosomal

  1. Tretinoin-loaded lipid-core nanocapsules overcome the triple-negative breast cancer cell resistance to tretinoin and show synergistic effect on cytotoxicity induced by doxorubicin and 5-fluororacil.

    Science.gov (United States)

    Schultze, Eduarda; Buss, Julieti; Coradini, Karine; Begnini, Karine Rech; Guterres, Silvia S; Collares, Tiago; Beck, Ruy Carlos Ruver; Pohlmann, Adriana R; Seixas, Fabiana Kömmling

    2017-12-01

    Nanostructured drug delivery systems have been extensively studied, mainly for applications in cancer therapy. The advantages of these materials include protection against drug degradation and improvement in both the relative solubility of poorly water soluble drugs as in targeting of therapy, due to the enhanced permeability and retention effect on tumor sites. In this work, we evaluate the antitumor activity of tretinoin-loaded lipid core nanocapsules (TT-LNC) in a tretinoin-resistant breast cancer cell-line, MDA-MB- 231, as well as the synergistic effect of combination of this treatment with 5-FU or DOXO. The inhibition of cell growth was assayed by MTT reduction. Live/Dead assay and DAPI staining evaluated cytotoxicity. Apoptosis was evaluated by Annexin V-PE/7AAD and the effect of chronic exposure was evaluated by colony formation assay. TT-LNC reduced the cell viability even at lower concentrations (1μM) and displayed synergistic effect with 5-FU or DOXO on cytotoxicity and colony formation inhibition. Our work shows a possibility of using nanocapsules to improve the antitumoral activity of TT for its use either alone or in combination with other chemotherapeutic drugs, especially considering the chronic effect. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  2. Reversal of methylation silencing of Apo2L/TRAIL receptor 1 (DR4) expression overcomes resistance of SK-MEL-3 and SK-MEL-28 melanoma cells to interferons (IFNs) or Apo2L/TRAIL.

    Science.gov (United States)

    Bae, S I; Cheriyath, V; Jacobs, B S; Reu, F J; Borden, E C

    2008-01-17

    Human melanoma cell lines, SK-MEL-3 and SK-MEL-28, despite induction of the proapoptotic cytokine, Apo2L/TRAIL, did not undergo apoptosis in response to interferons (IFN-alpha2b or IFN-beta). Postulating that genes important for apoptosis induction by IFNs might be silenced by methylation, the DNA demethylating agent 5-aza-2'-deoxycytidine (5-AZAdC) was assessed. DR4 (TRAIL-R1) was identified as one of the genes reactivated by 5-AZAdC with a >3-fold increase in 8 of 10 melanoma cell lines. Pretreatment with 5-AZAdC sensitized SK-MEL-3 and SK-MEL-28 cells to apoptosis induced by IFN-alpha2b and IFN-beta; methylation-specific PCR and bisulfite sequencing confirmed demethylation of 5'CpG islands of DR4 and flow cytometry showed an increase in DR4 protein on the cell surface. In cells with reactivated DR4, neutralizing mAB to TRAIL reduced apoptosis in response to IFN-beta or Apo2L/TRAIL. To further confirm the role of DR4, it was expressed by retroviral vector in SK-MEL-3 and SK-MEL-28 cells with reversal of resistance to IFN-beta and Apo2L/TRAIL. Thus, reexpressing DR4 by 5-AZAdC or retroviral transfection in melanoma cell in which promoter methylation had suppressed its expression, potentiated apoptosis by IFN-alpha2b, IFN-beta and Apo2L/TRAIL. Reactivation of silenced proapoptotic genes by inhibitors of DNA methylation may enhance clinical response to IFNs or Apo2L/TRAIL.

  3. Seismic signals hard clipping overcoming

    Science.gov (United States)

    Olszowa, Paula; Sokolowski, Jakub

    2018-01-01

    In signal processing the clipping is understand as the phenomenon of limiting the signal beyond certain threshold. It is often related to overloading of a sensor. Two particular types of clipping are being recognized: soft and hard. Beyond the limiting value soft clipping reduces the signal real gain while the hard clipping stiffly sets the signal values at the limit. In both cases certain amount of signal information is lost. Obviously if one possess the model which describes the considered signal and the threshold value (which might be slightly more difficult to obtain in the soft clipping case), the attempt of restoring the signal can be made. Commonly it is assumed that the seismic signals take form of an impulse response of some specific system. This may lead to belief that the sine wave may be the most appropriate to fit in the clipping period. However, this should be tested. In this paper the possibility of overcoming the hard clipping in seismic signals originating from a geoseismic station belonging to an underground mine is considered. A set of raw signals will be hard-clipped manually and then couple different functions will be fitted and compared in terms of least squares. The results will be then analysed.

  4. Heating plant overcomes coal crisis

    International Nuclear Information System (INIS)

    Sobinkovic, B.

    2006-01-01

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

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

    Science.gov (United States)

    2015-10-01

    et al., Skp2 regulates androgen receptor through ubiquitin-mediated degradation independent of Akt /mTOR pathways in prostate cancer. Prostate, 2014...I remained fairly steady with only marginal production of LC-3 II, so did the p- Akt . Because of the relative stable AR expression and yet...show ubiquitination of AR via co- immunoprecipitation of AR and ubiquitin. LNCaP C4-2B cells were treated with metformin alone or in combinations

  6. The University Immune System: Overcoming Resistance to Change

    Science.gov (United States)

    Gilley, Ann; Godek, Marisha; Gilley, Jerry W.

    2009-01-01

    A university, similar to any other organization, has an immune system that erects a powerful barrier against change. This article discusses the university immune system and what can be done to counteract its negative effects and thereby allow change to occur.

  7. Mandatory Use of Electronic Health Records: Overcoming Physician Resistance

    Science.gov (United States)

    Brown, Viseeta K.

    2012-01-01

    Literature supports the idea that electronic health records hold tremendous value for the healthcare system in that it increases patient safety, improves the quality of care and provides greater efficiency. The move toward mandatory implementation of electronic health records is a growing concern in the United States health care industry. The…

  8. Intervention: Help a Loved One Overcome Addiction

    Science.gov (United States)

    Intervention: Help a loved one overcome addiction An intervention can motivate someone to seek help for alcohol or drug misuse, compulsive eating, or ... successful. By Mayo Clinic Staff It's challenging to help a loved one struggling with any type of ...

  9. Learning communities and overcoming poverty in Brazil

    Directory of Open Access Journals (Sweden)

    Tatiana Santos Pitanga

    2015-09-01

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

  10. Overcoming Learned Helplessness in Community College Students.

    Science.gov (United States)

    Roueche, John E.; Mink, Oscar G.

    1982-01-01

    Reviews research on the effects of repeated experiences of helplessness and on locus of control. Identifies conditions necessary for overcoming learned helplessness; i.e., the potential for learning to occur; consistent reinforcement; relevant, valued reinforcers; and favorable psychological situation. Recommends eight ways for teachers to…

  11. 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…

  12. Overcoming Barriers in Working with Families

    Science.gov (United States)

    Heru, Alison M.; Drury, Laura

    2006-01-01

    Objective: The Accreditation Council for Graduate Medical Education and the Residency Review Committee for psychiatry outline the expected competencies for residents. These competencies include working with families. This article describes barriers that residents face when working with families, and offers ways to overcome these barriers. Method:…

  13. Successful Writing: Five Roadblocks to Overcome

    Science.gov (United States)

    King, Kathleen P.

    2013-01-01

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

  14. 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)

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

    Directory of Open Access Journals (Sweden)

    Daiha Shin

    2017-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Tang Y

    2017-01-01

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

  17. Resistance to Linezolid

    DEFF Research Database (Denmark)

    Vester, Birte; Ntokou, Eleni

    2017-01-01

    Linezolid is an antimicrobial agent that binds to the bacterial ribosome and thereby inhibits protein synthesis. Soon after its release as a clinical drug, it became clear that bacteria could become resistant to linezolid. The resistance mechanisms are mainly causing alteration of the drug target...... site, but probably efflux might also play a role. The resistance is still rare in surveillance studies, but outbreaks of resistant clones from hospitals have been observed. So far the main mechanisms of resistance are occurrence of mutations in ribosomal genes or obtaining plasmids with a gene coding...... for a methyltransferase providing resistance. The most obvious way to avoid resistance may be development of derivatives of linezolid overcoming the known resistance mechanisms....

  18. Overcoming challenges to secure a renewable future

    Energy Technology Data Exchange (ETDEWEB)

    McGrath, Rob; Philpott, Angie; Bown, Charles W.; Thompson, Robert; Dunderdale, Kathy

    2010-09-15

    Newfoundland and Labrador is on the brink of two extraordinary energy achievements: 1) becoming one of the world's only jurisdictions thermal generation almost entirely; and 2) making a huge contribution of renewable energy to North America. These achievements require the development of the 3,000 MW Lower Churchill Hydroelectric Project; however, the Project will not be developed without a business case to support it. This paper will highlight how the province, through its Energy Plan, has set the path forward for the future development of its renewable resources, including how it plans to overcome some of the challenges ahead.

  19. Overcoming barriers to membrane protein structure determination.

    Science.gov (United States)

    Bill, Roslyn M; Henderson, Peter J F; Iwata, So; Kunji, Edmund R S; Michel, Hartmut; Neutze, Richard; Newstead, Simon; Poolman, Bert; Tate, Christopher G; Vogel, Horst

    2011-04-01

    After decades of slow progress, the pace of research on membrane protein structures is beginning to quicken thanks to various improvements in technology, including protein engineering and microfocus X-ray diffraction. Here we review these developments and, where possible, highlight generic new approaches to solving membrane protein structures based on recent technological advances. Rational approaches to overcoming the bottlenecks in the field are urgently required as membrane proteins, which typically comprise ~30% of the proteomes of organisms, are dramatically under-represented in the structural database of the Protein Data Bank.

  20. 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...

  1. Overcome IMF crisis with idea and invention

    International Nuclear Information System (INIS)

    Wang, Yeon Jung

    1998-01-01

    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.

  2. 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.

  3. Reshaping transport operations to overcome new challenges

    Energy Technology Data Exchange (ETDEWEB)

    Harari, F.; Blachet, L. [COGEMA Logistics, (AREVA Group) (France)

    2004-07-01

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

  4. Reshaping transport operations to overcome new challenges

    International Nuclear Information System (INIS)

    Harari, F.; Blachet, L.

    2004-01-01

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

  5. Disposition of overcoming students for critical reading

    Directory of Open Access Journals (Sweden)

    Rosangela Miola Galvão

    2018-03-01

    Full Text Available This article aims to present the possibilities of an educational practice that focuses on the formation of Basic Education students in critical readers. For this, understand the concepts of alienation and language from the point of view of Historical and Dialectical Materialism and Historical-Cultural Theory was essential to understand how the students of the 7th year are able to overcome this paradigm that contributes to the naive reading of texts worked in the classroom. It was a qualitative study of bibliographic revision in union with the dialectical practice with students in a public school located in the north of the State of Paraná. As methodology, was developed twelve classes with diversified material in which the teacher's mediation sought to contemplate form and content in the way that occurred the deconstruction of the fictitious hero concept represented at the end by the art of the haicai poem. The use of the cell phone instrument and Whatsapp were important for the development of the poetic sense. It seeks, therefore, to demonstrate the contributions of historical and dialectical materialism to teaching practice and human development. The theorists considerations allow us to note that language contributes to the development of higher psychic functions in man and the alienation of subjects in today's society considerably affects the students interpretation and, consequently, formation for critical reading, which can be overcome with the use of a conscious theoretical current.

  6. Overcoming Obstacles to Drug Repositioning in Japan

    Directory of Open Access Journals (Sweden)

    Yuhei Nishimura

    2017-10-01

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

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

    African Journals Online (AJOL)

    Towards overcoming poor readership and building reading culture of in schools. ... of this paper is to find strategies that can overcome poor readership in schools. ... Keywords: English First Additional Language, Writing Skills, Spelling Errors, ...

  8. Synthesis of Nanodiamond-Daunorubicin Conjugates to Overcome Multidrug Chemoresistance in Leukemia

    Science.gov (United States)

    Man, Han B.; Kim, Hansung; Kim, Ho-Joong; Robinson, Erik; Liu, Wing Kam; Chow, Edward Kai-Hua; Ho, Dean

    2013-01-01

    Nanodiamonds (NDs) are promising candidates in nanomedicine, demonstrating significant potential as gene/drug delivery platforms for cancer therapy. We have synthesized ND vectors capable of chemotherapeutic loading and delivery with applications towards chemoresistant leukemia. The loading of Daunorubicin (DNR) onto NDs was optimized by adjusting reaction parameters such as acidity and concentration. The resulting conjugate, a novel therapeutic payload for NDs, was characterized extensively for size, surface charge, and loading efficiency. A K562 human myelogenous leukemia cell line, with multidrug resistance conferred by incremental DNR exposure, was used to demonstrate the efficacy enhancement resulting from ND-based delivery. While resistant K562 cells were able to overcome treatment from DNR alone, as compared with non-resistant K562 cells, NDs were able to improve DNR delivery into resistant K562 cells. By overcoming efflux mechanisms present in this resistant leukemia line, ND-enabled therapeutics have demonstrated the potential to improve cancer treatment efficacy, especially towards resistant strains. PMID:23916889

  9. Overcoming the current deadlock in antibiotic research.

    Science.gov (United States)

    Schäberle, Till F; Hack, Ingrid M

    2014-04-01

    Antibiotic-resistant bacteria are on the rise, making it harder to treat bacterial infections. The situation is aggravated by the shrinking of the antibiotic development pipeline. To finance urgently needed incentives for antibiotic research, creative financing solutions are needed. Public-private partnerships (PPPs) are a successful model for moving forward. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Overcoming obstacles to interspecies hybridization of ash

    Science.gov (United States)

    Jennifer L. Koch; David W. Carey; Mary E. Mason; M. Nurul. Islam-Faridi

    2010-01-01

    Tree species that share a long co-evolutionary history with insects and pathogens are likely to have developed mechanisms of resistance that allow them to coexist. When insects and pathogens are introduced to different parts of the world, high levels of susceptibility can be observed, presumably in part due to the lack of co-evolutionary history between the insect (or...

  11. 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.

  12. Cooperative networks overcoming defectors by social influence

    Science.gov (United States)

    Gomez Portillo, Ignacio

    2014-01-01

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

  13. Overcoming soil compaction in surface mine reclamation

    Energy Technology Data Exchange (ETDEWEB)

    Sweigard, R.J. (University of Kentucky, Lexington, KY (USA). Dept. of Mining Engineering)

    1991-01-01

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

  14. Overcoming soil compaction in surface mine reclamation

    International Nuclear Information System (INIS)

    Sweigard, R.J.

    1991-01-01

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

  15. Overponderabilia: Overcoming Overthinking When Studying "Ourselves"

    Directory of Open Access Journals (Sweden)

    Kasper Tang Vangkilde

    2016-05-01

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

  16. Developing an intervention to overcome procrastination.

    Science.gov (United States)

    Otermin-Cristeta, Solange; Hautzinger, Martin

    2018-01-01

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

  17. 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.

  18. 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.

  19. Overcoming the Challenges of Co-creation

    Science.gov (United States)

    Pandya, R.; Udu-gama, N.; Goodwin, M.; Otellini, P.

    2016-12-01

    There is growing interest in co-creation, especially for community-related issues like climate change, resilience, pollution, and environmental justice. Nevertheless, co-creation is still not mainstream practice in either geosciences or the world of decision-makers. This presents many challenges. On the science side, challenges include a paucity of training opportunities, lack of funding for co-creation, difficulty publishing or otherwise getting credit for the effort, and a perceived lack of prestige compared to theoretical research. On the community side, parallel challenges include a lack of experience working with scientists or thinking about geoscience's relevance to community issues, tight budgets and competing priorities, the need for outputs beyond publications, and the difficulty including science among a range of factors. Additionally, scientists and community leaders often work across public and private sectors and must navigate different approaches to data, privacy, and accountability. We'll use this session to explore opportunities to overcome the challenges of co-creation. Systems thinking suggests a range of approaches: enabling individuals, reducing specific challenges, changing the relationship between the elements of the systems, and changing the goals or mindsets of the systems - each more powerful than the last. For example, mentoring and coaching enables individuals, and pro-bono work eases the challenge of getting professional credit. New modes of output, like plain language abstracts, change the relationship between publications and other outputs. We can work on changing mindsets by publicizing and celebrating individual successes. With more effort and impact, we can build collaborations in the collective impact model, where we bring scientific and community organizations together around a common agenda and shared measurement. Building on these examples, we will use this session to collect strategies and opportunities from all participants.

  20. A SYSTEMIC VISION OF BIOLOGY: OVERCOMING LINEARITY

    Directory of Open Access Journals (Sweden)

    M. Mayer

    2005-07-01

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

  1. Why Mondragon? Analyzing What Works in Overcoming Inequalities

    Science.gov (United States)

    Redondo, Gisela; Santa Cruz, Ignacio; Rotger, Josep Maria

    2011-01-01

    Research using the critical communicative methodology (CCM) aims to identify the elements that help overcome inequalities. Drawing on research on the Basque Mondragon Corporation (MC), the authors focus on two major elements such as, selecting research cases that have been shown to succeed in overcoming inequalities, and communicative data…

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

    Science.gov (United States)

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

  3. Assistive technologies to overcome sarcopenia in ageing.

    Science.gov (United States)

    Scott, Rachel A; Callisaya, Michele L; Duque, Gustavo; Ebeling, Peter R; Scott, David

    2018-06-01

    Sarcopenia is an age-related decline in skeletal muscle mass and function that results in disability and loss of independence. It affects up to 30% of older adults. Exercise (particularly progressive resistance training) and nutrition are key strategies in preventing and reversing declines in muscle mass, strength and power during ageing, but many sarcopenic older adults fail to meet recommended levels of both physical activity and dietary nutrient intake. Assistive technology (AT) describes devices or systems used to maintain or improve physical functioning. These may help sarcopenic older adults to maintain independence, and also to achieve adequate physical activity and nutrition. There is a paucity of research exploring the use of AT in sarcopenic patients, but there is evidence that AT, including walking aids, may reduce functional decline in other populations with disability. Newer technologies, such as interactive and virtual reality games, as well as wearable devices and smartphone applications, smart homes, 3D printed foods, exoskeletons and robotics, and neuromuscular electrical stimulation also hold promise for improving engagement in physical activity and nutrition behaviours to prevent further functional declines. While AT may be beneficial for sarcopenic patients, clinicians should be aware of its potential limitations. In particular, there are high rates of patient abandonment of AT, which may be minimised by appropriate training and monitoring of use. Clinicians should preferentially prescribe AT devices which promote physical activity. Further research is required in sarcopenic populations to identify strategies for effective use of current and emerging AT devices. Copyright © 2018 Elsevier B.V. All rights reserved.

  4. Overcoming weak intrinsic depolarizing resonances with energy-jump

    International Nuclear Information System (INIS)

    Huang, H.; Ahrens, L.; Alessi, J.G.

    1997-01-01

    In the recent polarized proton runs in the AGS, a 5% partial snake was used successfully to overcome the imperfection depolarizing resonances. Polarized proton beam was accelerated up to the required RHIC injection energy of 25 GeV. However, significant amount of polarization was lost at 0+ν y , 12+ν y and 36+ν y , which is believed to be partially due to the coupling resonances. To overcome the coupling resonance, an energy-jump was generated by rapidly changing the beam circumference using the powerful AGS rf system. It clearly demonstrates that the novel energy-jump method can successfully overcome coupling resonances and weak intrinsic resonances

  5. Resistance to Barley Leaf Stripe

    DEFF Research Database (Denmark)

    Nørgaard Knudsen, J. C.

    1986-01-01

    in well adapted Northwest European spring cultivars. Virulence matching two hitherto not overcome resistances was demonstrated. Differences in apparent race nonspecific or partial resistance were also present, changing the percentage of infected plants of susceptible genotypes from about 20 to 44 per cent.......Ten barley [Hordeum vulgare] genotypes were inoculated with twelve isolates of Pyrenophora graminea of diverse European and North African origin. Race specific resistance occurred. Four, possibly five, genetically different sources of race-specific resistance were found, three of them occurring...

  6. Regicide and Resistance

    DEFF Research Database (Denmark)

    Flohr, Mikkel

    2016-01-01

    This article examines the role of resistance in Michel Foucault’s political thought. The article recovers this otherwise obscured aspect of Foucault’s thought through a systematic analysis of his theoretical regicide and consequent reconceptualization of power, agency and resistance. It is argued...... that Foucault developed a highly original account of resistance, which was, and should continue to be considered, central to his thought and its critical potential. It is shown how Foucault’s concept of resistance overcomes the limitation of voluntarism and determinism, which continue to mare contemporary...... political theory, providing a passage from the critique of contemporary configurations of power to the irrepressible possibility that they may be contested and changed....

  7. 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....

  8. Overcoming Family Planning Challenges in Africa: Toward Meeting ...

    African Journals Online (AJOL)

    USER

    Overcoming Family Planning Challenges in Africa: Toward Meeting. Unmet Need ... The challenges posed are greater in ... Gaps in meeting women's needs persist especially ..... WHO. Everybody's business: Strengthening health systems to.

  9. Overcoming barriers to high performance seismic design using lessons learned from the green building industry

    Science.gov (United States)

    Glezil, Dorothy

    NEHRP's Provisions today currently governing conventional seismic resistant design. These provisions, though they ensure the life-safety of building occupants, extensive damage and economic losses may still occur in the structures. This minimum performance can be enhanced using the Performance-Based Earthquake Engineering methodology and passive control systems like base isolation and energy dissipation systems. Even though these technologies and the PBEE methodology are effective reducing economic losses and fatalities during earthquakes, getting them implemented into seismic resistant design has been challenging. One of the many barriers to their implementation has been their upfront costs. The green building community has faced some of the same challenges that the high performance seismic design community currently faces. The goal of this thesis is to draw on the success of the green building industry to provide recommendations that may be used overcome the barriers that high performance seismic design (HPSD) is currently facing.

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

    Science.gov (United States)

    Shin, Daiha; Kim, Eun Hye; Lee, Jaewang; Roh, Jong-Lyel

    2017-10-01

    Reactivation of p53 and induction of tumor cell apoptosis (RITA) is a small molecule that blocks p53-MDM2 interaction, thereby reactivating p53 in tumors. RITA can induce exclusive apoptosis in cancer cells independently of the p53 pathway; however, the resistance of cancer cells remains a major drawback. Here, we found a novel resistance mechanism of RITA treatment and an effective combined treatment to overcome RITA resistance in head and neck cancer (HNC) cells. The effects of RITA and 3-methyladenine (3-MA) were tested in different HNC cell lines, including cisplatin-resistant and acquired RITA-resistant HNC cells. The effects of each drug alone and in combination were assessed by measuring cell viability, apoptosis, cell cycle, glutathione, reactive oxygen species, protein expression, genetic inhibition of p62 and Nrf2, and a mouse xenograft model of cisplatin-resistant HNC. RITA induced apoptosis of HNC cells at different levels without significantly inhibiting normal cell viability. Following RITA treatment, RITA-resistant HNC cells exhibited a sustained expression of other autophagy-related proteins, overexpressed p62, and displayed activation of the Keap1-Nrf2 antioxidant pathway. The autophagy inhibitor 3-MA sensitized resistant HNC cells to RITA treatment via the dual inhibition of molecules related to the autophagy and antioxidant systems. Silencing of the p62 gene augmented the combined effects. The effective antitumor activity of RITA plus 3-MA was also confirmed in vivo in mouse xenograft models transplanted with resistant HNC cells, showing increased oxidative stress and DNA damage. The results indicate that RITA plus 3-MA can help overcome RITA resistance in HNC cells. This study revealed a novel RITA resistant mechanism associated with the sustained induction of autophagy, p62 overexpression, and Keap1-Nrf2 antioxidant system activation. The combined treatment of RITA with the autophagy inhibitor 3-methyladenine overcomes RITA resistance via dual

  11. Overcoming Blockages to Collective Innovation in Digital Infrastructures

    DEFF Research Database (Denmark)

    Rukanova, Boriana; Reuver, Mark; Henningsson, Stefan

    2017-01-01

    Decentralized digital technologies increasingly enable multiple organizations to co-create digital infrastructures. However, collective innovation processes often come to a stand-still because of conflicting interests and business models. While existing research suggests various factors that block...... collective innovation processes, there is still little understanding of how organizations can overcome these blockages. In this paper, we identify patterns that explain how organizations overcome blockages of collective innovation processes for digital infrastructures. We follow a processual approach...... and develop a conceptual framework based on collective action theory. We evaluate the framework through a longitudinal case study on mobile payment infrastructure development. We find various reconfiguration processes that organizations use to overcome blockages of collective innovation. Theoretically...

  12. 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 barr......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...

  13. CONSIDERATIONS CONCERNING THE MANAGEMENT OF RESISTANCE IN ORGANIZATIONS

    OpenAIRE

    Marius-Dan DALOTĂ

    2011-01-01

    The difficulty of organisational change is often exacerbated by the mismanagement of resistance derived from a simple set of assumptions that misunderstand resistance’s essential nature. It is suggested that management may greatly gain from techniques that carefully manage resistance to change by looking for ways of utilising it rather than overcoming it. Today, suggestions and prescriptions for managing resistance have left little room for utility in resistance. Traditionally, resistance has...

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

    African Journals Online (AJOL)

    SAM

    2014-09-03

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

  15. Overcoming The Problem Of English Sound System Among ...

    African Journals Online (AJOL)

    This paper tries to examine important issues in teaching phonetics. These are the interference problem that can affect one's speech during communication and how the teacher through the use of appropriate techniques and methods can assist the second language learner overcome these problems. Journal of Technology ...

  16. Objections to tubal sterilization: what reversibility can and cannot overcome.

    Science.gov (United States)

    Shain, R N

    1980-09-01

    In a study of 1074 women, 696 and 338 subjects would not seriously consider permanent and hypothetically reversible sterilization, respectively; they were asked to explain their feelings. The reason accounting for most objections to permanent sterilization (65%) was irreversibility and of the subjects who would not consider reversible sterilization or were unsure, 42.7% attributed their principal objection to unnecessary surgery, a factor at least currently intrinsic to the procedure and not readily overcome by education. Many of the remaining objections to both permanent and reversible sterilization may be amenable to change either through education or financial subsidies. In response to a question concerning female attractiveness subsequent to permanent sterilization, 3% of the sample felt attractiveness would decrease and 17.5% were unsure of the surgery's effect. Unsure responses were largely negative in character. This issue is important because of its relationship to intention to undergo sterilization. Upon consideration of reversible sterilization, negative and unsure responses significantly declined, even on the part of those women whose friends have had a poor experience with currently available procedures. Thus, whereas the option of reversibility cannot overcome objections to surgery, it does overcome those regarding permanency; moreover, the "temporary" character it bestows upon surgical sterilization appears to help certain individuals overcome their fears of losing their physical appeal as a result of such procedures.

  17. Overcoming Jealousy: An Experiential Analysis of Common Factors.

    Science.gov (United States)

    Barrell, James J.; Richards, Anne C.

    1982-01-01

    Investigated key aspects of the experience of jealousy through the recorded experiences of a study group consisting of three males and three females. Results indicated that jealousy is a complex experience which may be accompanied by a variety of negative feelings. Provides suggestions for overcoming jealousy. (RC)

  18. Dos Hermanas Chicanas: Overcoming Barriers to Professional Advancement

    Science.gov (United States)

    Prospero, Moises

    2007-01-01

    Women and ethnic minorities face steep barriers to professional advancement, and those who rise to the executive level typically use a variety of strategies to overcome obstacles in their way. This study first reviewed the literature on barriers to professional advancement for women and ethnic minorities and the strategies that they report using…

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

    Science.gov (United States)

    Chyr, Fred

    2017-01-01

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

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

    African Journals Online (AJOL)

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

  1. 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…

  2. Does SGLT2 inhibition with dapagliflozin overcome individual therapy resistance to RAAS inhibition?

    NARCIS (Netherlands)

    Petrykiv, Sergei; Laverman, Gozewijn D.; de Zeeuw, Dick; Heerspink, Hiddo J. L.

    Individual patients show a large variation in their response to renin-angiotensin-aldosteron system (RAAS) inhibition (RAASi), both in surrogates such as albuminuria and in hard renal outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2) have been shown to lower albuminuria and to confer

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

    KAUST Repository

    Manzoor, Safia; Bilal, Aishah; Khan, Sardraz; Ullah, Rahim; Iftikhar, Sunniya; Emwas, Abdul-Hamid M.; Alazmi, Meshari; Gao, Xin; Jawaid, Ali; Saleem, Rahman Shah Zaib; Faisal, Amir

    2018-01-01

    . Here we describe the discovery and characterization of SSE15206, a pyrazolinethioamide derivative [3-phenyl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide] that has potent antiproliferative activities in cancer cell lines

  4. Immunotherapeutic Vaccine as an Alternative Treatment to Overcome Drug-Resistant Ovarian Cancer

    Science.gov (United States)

    2012-07-01

    Hattan S, et al. Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol Cell Proteomics 2004;3...length human TACE and DDR1 cDNA plasmids, pCMV-XL-5-TACE and pCMV-XL-DDR1 were purchased from Origene (Rockville, MD). We used Not I and Xba I

  5. Doxorubicin potentiates TRAIL cytotoxicity and apoptosis and can overcome TRAIL-resistance in rhabdomyosarcoma cells

    NARCIS (Netherlands)

    Komdeur, R; Meijer, C; Van Zweeden, M; De Jong, S; Wesseling, J; Hoekstra, HJ; van der Graaf, WTA

    Doxorubicin (DOX) and ifosfamide (IFO) are the most active single agents in soft tissue sarcomas (STS). Tumour necrosis factor-alpha (TNF-alpha) is used for STS in the setting of isolated limb perfusions. Like TNF-alpha, TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis. In contrast to

  6. Targeting the HER Family with Pan-HER Effectively Overcomes Resistance to Cetuximab

    NARCIS (Netherlands)

    Iida, M.; Bahrar, H.; Brand, T.M.; Pearson, H.E.; Coan, J.P.; Orbuch, R.A.; Flanigan, B.G.; Swick, A.D.; Prabakaran, P.J.; Lantto, J.; Horak, I.D.; Kragh, M.; Salgia, R.; Kimple, R.J.; Wheeler, D.L.

    2016-01-01

    Cetuximab, an antibody against the EGFR, has shown efficacy in treating head and neck squamous cell carcinoma (HNSCC), metastatic colorectal cancer, and non-small cell lung cancer (NSCLC). Despite the clinical success of cetuximab, many patients do not respond to cetuximab. Furthermore, virtually

  7. Overcoming Drug Resistant Prostate Cancer with APE1/Ref 1 Blockade

    Science.gov (United States)

    2016-10-01

    from prostate specimens removed collaterally from bladder cancer patients undergoing radical cystectomy (cystoprosta- tectomy) as control human specimens...pretreatment with Bacillus Calmette-Guerin as first-line therapy because these patients had presented with muscle invasive bladder cancer . Further, the controls...Krolewski JJ. FLIP-ping out: Death receptor signaling in the prostate. Cancer Biol Ther 2008;7:1171–1179. 21. Shariat SF, Ashfaq R, Roehrborn CG, Slawin

  8. Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy

    Science.gov (United States)

    2010-09-01

    Sakamaki T, Pestell RG: Cyclin D1: normal and abnormal functions. Endocrinology 145, 5439–5447 (2004). 43 Hengstschlager M, Braun K, Soucek T...culture system. Cell Biochem Biophys 2008;52(1):37e46. [44] Fu M, Wang C, Li Z, Sakamaki T, Pestell RG. Cyclin D1: normal and abnormal functions

  9. Overcoming Endocrine Resistance by Targeting ER/FoxA1/IL 8 Axis

    Science.gov (United States)

    2016-10-01

    Nardone, Carmine De Angelis, Laura M. Heiser , Pavana Anur, Nicholas Wang, Catherine S. Grasso, Paul Spellman, Obi L. Griffith, Anna Tsimelzon...presentations Publications Fu X, Jeselsohn R, Pereira R, Hollingsworth EF, Creighton CJ, Li F, Shea M, Nardone A, Angelis CD, Heiser LM, Anur P, Wang N...performed the bioinformatics analysis of RNA-Seq and ChIP-Seq data. Name: Laura Heiser Project Role: Collaborator Nearest person month worked: 1

  10. Overcoming Endocrine Resistance by Targeting ER/FoxA1/IL-8 Axis

    Science.gov (United States)

    2015-10-01

    Creighton, Fugen Li, Martin Shea, Agostina Nardone, Tao Wang, Laura M. Heiser , Pavana Anur, Nicholas Wang, Catie Grasso, Paul Spellman, Carolina...Xiaoyong Fu, Rinath Jeselsohn, Resel Pereira, Emporia F. Hollingsworth, Chad J. Creighton, Fugen Li, Martin Shea, Agostina Nardone, Laura M. Heiser , Pavana...Rinath Jeselsohn, Emporia F. Hollingsworth, Dolores Lopez-Terrada, Chad J. Creighton, Agostina Nardone, Martin Shea, Laura M. Heiser , Pavana Anur

  11. Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy

    Science.gov (United States)

    2013-09-01

    introduced to the nanoparticle by a comicellization of TCRN and DSPE-PEG- folate to form FLPEI/DM-PCL. But the ability of the PEI to disrupt the 6...firstly synthesized via living cationic polymerization of 2- methyl -2-oxazoline (MeOz) terminated with dioctadecylamine15. The resulting DOPMeOz was

  12. Overcoming CRPC Treatment Resistance via Novel Dual AKR1C3 Targeting

    Science.gov (United States)

    2017-10-01

    Accomplishments 3 4. Impact 8 5. Changes/Problems 8 6. Products 8 7. Participants & Other Collaborating Organizations 8 8. Special Reporting Requirements...orthotopic animal model 3. ACCOMPLISHMENTS: What were the major goals of the project? Specific Aim 1 To determine the mechanisms of AKR1C3-mediated...selected for stable clones with respective antibiotics . Here we showed the characterization of the tet-inducible LNCaP/TR/AKR1C3 stale clone

  13. Chemical inhibition of host toxicity as a means of overcoming tumor resistance

    International Nuclear Information System (INIS)

    Yuhas, J.M.; Pardini, M.C.; Children's Hospital of Philadelphia, PA)

    1983-01-01

    Largely because we have accumulated so much information on WR-2721 in the past decade, we know that this drug is not a universal panacea which will solve all the problems which confront us. However, in those instances where it would appear applicable, clinical testing would appear appropriate. Thanks largely to the efforts of M.M. Kligerman, these studies have been initiated. In those instances where WR-2721 would appear inappropriate or not of sufficient activity, the information we have already accumulated should point the way to the development of qualitatively and/or quantitatively superior drugs which selectively inhibit host toxicity

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

    Science.gov (United States)

    2017-01-01

    v e V ia b il it y Figure 8. PC3-LN4 cells in normoxia or hypoxia were treated with Pim inhibitors. Left panel shows a Western blot and the...3728-36, PMID 25241892 4. Warfel, NA, Kraft, AS. Pim kinase (and Akt) biology and signaling in tumors. Pharmacol Ther. 2015 Jul; 151: 41 - 9. doi: 10.1016...Associated Fibroblast Biology in Prostate Cancer These studies will accelerate and significantly advance the rational development of targeted agents

  15. Overcoming Faculty Avoidance of Online Education: From Resistance to Support to Active Participation

    Science.gov (United States)

    Mitchell, Lorianne D.; Parlamis, Jennifer D.; Claiborne, Sarah A.

    2015-01-01

    The online delivery of higher education courses and programs continues to expand across academic disciplines at colleges and universities. This expansion of online education has been precipitated by, among other things, (a) the rise in personal computer ownership, (b) the ease of access to the Internet, (c) the availability and continuous…

  16. Past-focused temporal communication overcomes conservatives' resistance to liberal political ideas.

    Science.gov (United States)

    Lammers, Joris; Baldwin, Matt

    2018-04-01

    Nine studies and a meta-analysis test the role of past-focused temporal communication in reducing conservatives' disagreement with liberal political ideas. We propose that conservatives are more prone to warm, affectionate, and nostalgic feelings for past society. Therefore, they are more likely to support political ideas-including those expressing liberal values-that can be linked to a desirable past state (past focus), rather than a desirable future state (future focus) of society. Study 1 supports our prediction that political conservatives are more nostalgic for the past than liberals. Building on this association, we demonstrate that communicating liberal ideas with a past focus increases conservatives' support for leniency in criminal justice (Studies 2a and 2b), gun control (Study 3), immigration (Study 4), social diversity (Study 5), and social justice (Study 6). Communicating messages with a past focus reduced political disagreement (compared with a future focus) between liberals and conservatives by between 30 and 100% across studies. Studies 5 and 6 identify the mediating role of state and trait nostalgia, respectively. Study 7 shows that the temporal communication effect only occurs under peripheral (and not central) information processing. Study 8 shows that the effect is asymmetric; a future focus did not increase liberals' support for conservative ideas. A mixed-effects meta-analysis across all studies confirms that appealing to conservatives' nostalgia with a past-focused temporal focus increases support for liberal political messages (Study 9). A large portion of the political disagreement between conservatives and liberals appears to be disagreement over style, and not content of political issues. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  17. Pseudomonas sax genes overcome aliphatic isothiocyanate-mediated non-host resistance in Arabidopsis

    Science.gov (United States)

    Jun Fan; Casey Crooks; Gary Creissen; Lionel Hill; Shirley Fairhurst; Peter Doerner; Chris Lamb

    2011-01-01

    Most plant-microbe interactions do not result in disease; natural products restrict non-host pathogens. We found that sulforaphane (4-methylsulfinylbutyl isothiocyanate), a natural product derived from aliphatic glucosinolates, inhibits growth in Arabidopsis of non-host Pseudomonas bacteria in planta. Multiple sax genes (saxCAB/F/D/G) were identified in Pseudomonas...

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

    Directory of Open Access Journals (Sweden)

    Rania Abdel Galil

    2015-12-01

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

  19. Methadone, commonly used as maintenance medication for outpatient treatment of opioid dependence, kills leukemia cells and overcomes chemoresistance.

    Science.gov (United States)

    Friesen, Claudia; Roscher, Mareike; Alt, Andreas; Miltner, Erich

    2008-08-01

    The therapeutic opioid drug methadone (d,l-methadone hydrochloride) is the most commonly used maintenance medication for outpatient treatment of opioid dependence. In our study, we found that methadone is also a potent inducer of cell death in leukemia cells and we clarified the unknown mechanism of methadone-induced cell killing in leukemia cells. Methadone inhibited proliferation in leukemia cells and induced cell death through apoptosis induction and activated apoptosis pathways through the activation of caspase-9 and caspase-3, down-regulation of Bcl-x(L) and X chromosome-linked inhibitor of apoptosis, and cleavage of poly(ADP-ribose) polymerase. In addition, methadone induced cell death not only in anticancer drug-sensitive and apoptosis-sensitive leukemia cells but also in doxorubicin-resistant, multidrug-resistant, and apoptosis-resistant leukemia cells, which anticancer drugs commonly used in conventional therapies of leukemias failed to kill. Depending on caspase activation, methadone overcomes doxorubicin resistance, multidrug resistance, and apoptosis resistance in leukemia cells through activation of mitochondria. In contrast to leukemia cells, nonleukemic peripheral blood lymphocytes survived after methadone treatment. These findings show that methadone kills leukemia cells and breaks chemoresistance and apoptosis resistance. Our results suggest that methadone is a promising therapeutic approach not only for patients with opioid dependence but also for patients with leukemias and provide the foundation for new strategies using methadone as an additional anticancer drug in leukemia therapy, especially when conventional therapies are less effective.

  20. Namaste (counterbalancing) technique: Overcoming warping in costal cartilage.

    Science.gov (United States)

    Agrawal, Kapil S; Bachhav, Manoj; Shrotriya, Raghav

    2015-01-01

    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. We present the data of 51 patients of rhinoplasty done using CCG with counterbalancing technique over a period of 4 years. No evidence of warping was found in any patient up to a maximum follow-up period of 4 years. 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.

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

    Directory of Open Access Journals (Sweden)

    Kapil S Agrawal

    2015-01-01

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

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

    International Nuclear Information System (INIS)

    Wong, Sam

    2012-01-01

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

  3. 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.

  4. Comment: Kidney exchange to overcome financial barriers to kidney transplantation

    OpenAIRE

    Baines, L.S.; Jindal, R.M.

    2017-01-01

    Rees et al. have shown the feasibility of global kidney exchange (GKE) to overcome financial cost and address the current shortage of organs for transplantation. Wiseman and Gill, question their interpretation of definition of "financial incompatibility". The authors1 do not factor in the well documented cognitive and emotional aspects of kidney transplantation. Particularly, relevant to kidney transplantation is how patients calculate risk and the emotional turmoil characterised by anxiety a...

  5. Namaste (counterbalancing) technique: Overcoming warping in costal cartilage

    OpenAIRE

    Kapil S Agrawal; Manoj Bachhav; Raghav Shrotriya

    2015-01-01

    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 th...

  6. Fear of examinations and educational factors of its overcoming

    OpenAIRE

    Bagdonas, Algimantas; Merkys, Gediminas

    2005-01-01

    This article, based on the carried out scientific researches' data of late decades, tries to reveal die actuality of the phenomenon of exam fear and opportunities of solving this problem. In this article there is analyzed an actual exam fear phenomenon characteristic of different aged students from various countries and social classes. Exam fear is presented as a constituent part of the complicated phenomenon of school fear, emphasizing educational factors of its overcoming. Exam fear is also...

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

    International Nuclear Information System (INIS)

    1990-05-01

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

  8. Overcoming violence - a basic task of Christian churches

    Directory of Open Access Journals (Sweden)

    Wolfgang Huber

    2011-06-01

    Full Text Available In this article � based on the second of two keynote lectures at a conference on violence � the view is developed that the task of the church with respect to violence consists mainly in overcoming violence. In the first part of the article dealing with the basic tasks of the church it is argued that the task to overcome violence is close to the essence of the church. The point of departure is taken in Article 7 of the Augsburg Confession, which understands the church as the �communion of saints� and names the pure proclamation of the gospel and the right administration of the sacraments as the two characteristics of the church. The Christian message that the church has to proclaim the gospel entails a preferential option for nonviolence that includes the responsibility to put an end to existing violence. In the second part of the article attention is given to the implications the basic task of the church in overcoming violence holds for the practice of the church. It is argued that the starting point is that the church has to proclaim the gospel of peace and as a community of faith become a community of peace herself. Some of the most important practical consequences the proclamation of the gospel of peace has for the church as a community of action, for her work in education, for her promotion of justice and for her solidarity with those in need, are discussed.

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

    Indian Academy of Sciences (India)

    2016-02-16

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

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

    Indian Academy of Sciences (India)

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

  11. Clopidogrel Resistance: Current Issues

    Directory of Open Access Journals (Sweden)

    NS Neki

    2016-05-01

    Full Text Available Antiplatelet agents are mainly used in the prevention and management of atherothrombotic complications. Dual antiplatelet therapy, combining aspirin and clopidogrel, is the standard care for patients having acute coronary syndromes or undergoing percutaneous coronary intervention according to the current ACC/AHA and ESC guidelines. But in spite of administration of dual antiplatelet therapy, some patients develop recurrent cardiovascular ischemic events especially stent thrombosis which is a serious clinical problem. Antiplatelet response to clopidogrel varies widely among patients based on ex vivo platelet function measurements. Clopidogrel is an effective inhibitor of platelet activation and aggregation due to its selective and irreversible blockade of the P2Y12 receptor. Patients who display little attenuation of platelet reactivity with clopidogrel therapy are labeled as low or nonresponders or clopidogrel resistant. The mechanism of clopidogrel resistance remains incompletely defined but there are certain clinical, cellular and genetic factors including polymorphisms responsible for therapeutic failure. Currently there is no standardized or widely accepted definition of clopidogrel resistance. The future may soon be realised in the routine measurement of platelet activity in the same way that blood pressure, cholesterol and blood sugar are followed to help guide the therapy, thus improving the care for millions of people. This review focuses on the methods used to identify patients with clopidogrel resistance, the underlying mechanisms, metabolism, clinical significance and current therapeutic strategies to overcome clopidogrel resistance. J Enam Med Col 2016; 6(1: 38-46

  12. Antifungal resistance in mucorales.

    Science.gov (United States)

    Dannaoui, E

    2017-11-01

    The order Mucorales, which includes the agents of mucormycosis, comprises a large number of species. These fungi are characterised by high-level resistance to most currently available antifungal drugs. Standardised antifungal susceptibility testing methods are now available, allowing a better understanding of the in vitro activity of antifungal drugs against members of Mucorales. Such tests have made apparent that antifungal susceptibility within this group may be species-specific. Experimental animal models of mucormycosis have also been developed and are of great importance in bridging the gap between in vitro results and clinical trials. Amphotericin B, posaconazole and isavuconazole are currently the most active agents against Mucorales; however, their activity remains suboptimal and new therapeutic strategies are needed. Combination therapy could be a promising approach to overcome resistance, but further studies are required to confirm its benefits and safety for patients. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  13. Resisting temptation: a psychological analysis.

    Science.gov (United States)

    Hodgson, R J

    1989-03-01

    It is proposed that self control involves several related processes including vivid awareness of future consequences, overcoming learned helplessness and tunnel vision, developing commitment and accepting anxiety/frustration. Facing up to temptation and resisting the compulsive urge is considered to be a crucial therapeutic experience. Evidence is presented to support the view that cue exposure should therefore be a central component of treatments for compulsions and addictions.

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

    Directory of Open Access Journals (Sweden)

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

    2011-06-01

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

  15. Recognizing and overcoming challenges of couple interview research.

    Science.gov (United States)

    Mellor, Ruth M; Slaymaker, Emma; Cleland, John

    2013-10-01

    In this article we discuss some methodological and ethical challenges we faced when conducting a couple-based study on men's role in contraceptive switching, and how we overcame them. The challenges we discuss include recruiting couples with a range of experiences, ensuring informed consent of participants, maintaining confidentiality within interviews, and participants discussing interview content between interviews. As appropriate, we have drawn on study participants' views of these challenges. We conclude that although couple research poses challenges, they can be overcome or minimized, and that for certain research questions this methodology is well worth using.

  16. Overcoming the Law of the Hidden in Cyberinfrastructures.

    Science.gov (United States)

    Bucksch, Alexander; Das, Abhiram; Schneider, Hannah; Merchant, Nirav; Weitz, Joshua S

    2017-02-01

    Cyberinfrastructure projects (CIPs) are complex, integrated systems that require interaction and organization amongst user, developer, hardware, technical infrastructure, and funding resources. Nevertheless, CIP usability, functionality, and growth do not scale with the sum of these resources. Instead, growth and efficient usage of CIPs require access to 'hidden' resources. These include technical resources within CIPs as well as social and functional interactions among stakeholders. We identify approaches to overcome resource limitations following the conceptual basis of Liebig's Law of the Minimum. In so doing, we recommend practical steps towards efficient and scaleable resource use, taking the iPlant/CyVerse CIP as an example. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. 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.

  18. 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.

  19. Outwitting the series resistance in scanning spreading resistance microscopy

    International Nuclear Information System (INIS)

    Schulze, A.; Cao, R.; Eyben, P.; Hantschel, T.; Vandervorst, W.

    2016-01-01

    The performance of nanoelectronics devices critically depends on the distribution of active dopants inside these structures. For this reason, dopant profiling has been defined as one of the major metrology challenges by the international technology roadmap of semiconductors. Scanning spreading resistance microscopy (SSRM) has evolved as one of the most viable approaches over the last decade due to its excellent spatial resolution, sensitivity and quantification accuracy. However, in case of advanced device architectures like fins and nanowires a proper measurement of the spreading resistance is often hampered by the increasing impact of parasitic series resistances (e.g. bulk series resistance) arising from the confined nature of the aforementioned structures. In order to overcome this limitation we report in this paper the development and implementation of a novel SSRM mode (fast Fourier transform-SSRM: FFT-SSRM) which essentially decouples the spreading resistance from parasitic series resistance components. We show that this can be achieved by a force modulation (leading to a modulated spreading resistance signal) in combination with a lock-in deconvolution concept. In this paper we first introduce the principle of operation of the technique. We discuss in detail the underlying physical mechanisms as well as the technical implementation on a state-of-the-art atomic force microscope (AFM). We demonstrate the performance of FFT-SSRM and its ability to remove substantial series resistance components in practice. Eventually, the possibility of decoupling the spreading resistance from the intrinsic probe resistance will be demonstrated and discussed. - Highlights: • A novel electrical AFM mode for carrier profiling in confined volumes is presented. • Thereby the force and hence the contact area between AFM probe and sample is modulated. • Information on the spreading resistance is derived using a lock-in approach. • Bulk series resistance components are

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

    International Nuclear Information System (INIS)

    Hamada, Nobuyuki; Hara, Takamitsu; Omura-Minamisawa, Motoko; Funayama, Tomoo; Sakashita, Tetsuya; Sora, Sakura; Yokota, Yuichiro; Nakano, Takashi

    2008-01-01

    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 G 2 /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 G 2 /M arrest. Thus, heavy-ion therapy may be a promising modality for Bcl-2 overexpressing radioresistant tumors

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

    Directory of Open Access Journals (Sweden)

    Alessandro Dalpiaz

    2018-03-01

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

  2. Clinical Variants of New Delhi Metallo-β-Lactamase Are Evolving To Overcome Zinc Scarcity.

    Science.gov (United States)

    Stewart, Alesha C; Bethel, Christopher R; VanPelt, Jamie; Bergstrom, Alex; Cheng, Zishuo; Miller, Callie G; Williams, Cameron; Poth, Robert; Morris, Matthew; Lahey, Olivia; Nix, Jay C; Tierney, David L; Page, Richard C; Crowder, Michael W; Bonomo, Robert A; Fast, Walter

    2017-12-08

    Use and misuse of antibiotics have driven the evolution of serine β-lactamases to better recognize new generations of β-lactam drugs, but the selective pressures driving evolution of metallo-β-lactamases are less clear. Here, we present evidence that New Delhi metallo-β-lactamase (NDM) is evolving to overcome the selective pressure of zinc(II) scarcity. Studies of NDM-1, NDM-4 (M154L), and NDM-12 (M154L, G222D) demonstrate that the point mutant M154L, contained in 50% of clinical NDM variants, selectively enhances resistance to the penam ampicillin at low zinc(II) concentrations relevant to infection sites. Each of the clinical variants is shown to be progressively more thermostable and to bind zinc(II) more tightly than NDM-1, but a selective enhancement of penam turnover at low zinc(II) concentrations indicates that most of the improvement derives from catalysis rather than stability. X-ray crystallography of NDM-4 and NDM-12, as well as bioinorganic spectroscopy of dizinc(II), zinc(II)/cobalt(II), and dicobalt(II) metalloforms probe the mechanism of enhanced resistance and reveal perturbations of the dinuclear metal cluster that underlie improved catalysis. These studies support the proposal that zinc(II) scarcity, rather than changes in antibiotic structure, is driving the evolution of new NDM variants in clinical settings.

  3. 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. © 2015 Society for Risk Analysis.

  4. 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.

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

    Directory of Open Access Journals (Sweden)

    María Luz Fuentes-Pérez

    2016-07-01

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

  6. Novel resistance functions uncovered using functional metagenomic investigations of resistance reservoirs

    Directory of Open Access Journals (Sweden)

    Erica C. Pehrsson

    2013-06-01

    Full Text Available Rates of infection with antibiotic-resistant bacteria have increased precipitously over the past several decades, with far-reaching healthcare and societal costs. Recent evidence has established a link between antibiotic resistance genes in human pathogens and those found in non-pathogenic, commensal, and environmental organisms, prompting deeper investigation of natural and human-associated reservoirs of antibiotic resistance. Functional metagenomic selections, in which shotgun-cloned DNA fragments are selected for their ability to confer survival to an indicator host, have been increasingly applied to the characterization of many antibiotic resistance reservoirs. These experiments have demonstrated that antibiotic resistance genes are highly diverse and widely distributed, many times bearing little to no similarity to known sequences. Through unbiased selections for survival to antibiotic exposure, functional metagenomics can improve annotations by reducing the discovery of false-positive resistance and by allowing for the identification of previously unrecognizable resistance genes. In this review, we summarize the novel resistance functions uncovered using functional metagenomic investigations of natural and human-impacted resistance reservoirs. Examples of novel antibiotic resistance genes include those highly divergent from known sequences, those for which sequence is entirely unable to predict resistance function, bifunctional resistance genes, and those with unconventional, atypical resistance mechanisms. Overcoming antibiotic resistance in the clinic will require a better understanding of existing resistance reservoirs and the dissemination networks that govern horizontal gene exchange, informing best practices to limit the spread of resistance-conferring genes to human pathogens.

  7. Overcoming the Challenges of siRNA Delivery: Nanoparticle Strategies.

    Science.gov (United States)

    Shajari, Neda; Mansoori, Behzad; Davudian, Sadaf; Mohammadi, Ali; Baradaran, Behzad

    2017-01-01

    Despite therapeutics based on siRNA have an immense potential for the treatment of incurable diseases such as cancers. However, the in vivo utilization of siRNA and also the delivery of this agent to the target site is one of the most controversial challenges. The helpful assistance by nanoparticles can improve stable delivery and also enhance efficacy. More nanoparticle-based siRNA therapeutics is expected to become available in the near future. The search strategy followed the guidelines of the Centre of Reviews and Dissemination. The studies were identified from seven databases (Scopus, Web of Science, Academic Search Premiere, CINAHL, Medline Ovid, Eric and Cochrane Library). Studies was selected based on titles, abstracts and full texts. One hundred twenty nine papers were included in the review. These papers defined hurdles in RNAi delivery and also strategies to overcome these hurdles. This review discussed the existing hurdles for systemic administration of siRNA as therapeutic agents and highlights the various strategies to overcome these hurdles, including lipid-based nanoparticles and polymeric nanoparticles, and we also briefly reviewed chemical modification. Delivery of siRNA to the target site is the biggest challenge for its application in the clinic. The findings of this review confirmed by encapsulation siRNA in the nanoparticles can overcome these challenges. The rapid progress in nanotechnology has enabled the development of effective nanoparticles as the carrier for siRNA delivery. However, our data about siRNA-based therapeutics and also nanomedicine are still limited. More clinical data needs to be completely understood in the benefits and drawbacks of siRNA-based therapeutics. Prospective studies must pay attention to the in vivo safety profiles of the different delivery systems, including uninvited immune system stimulation and cytotoxicity. In essence, the development of nontoxic, biocompatible, and biodegradable delivery systems for

  8. Antimicrobial Resistance

    Science.gov (United States)

    ... least 10 countries (Australia, Austria, Canada, France, Japan, Norway, Slovenia, South Africa, Sweden and the United Kingdom ... plan Global report on surveillance Country situation analysis Policy to combat antimicrobial resistance More on antimicrobial resistance ...

  9. Antimicrobial Resistance

    Science.gov (United States)

    ... can prevent and manage antimicrobial resistance. It is collaborating with partners to strengthen the evidence base and ... on the global action plan. WHO has been leading multiple initiatives to address antimicrobial resistance: World Antibiotic ...

  10. Overcoming Barriers to Successfully Commercializing Carbon Dioxide Utilization

    Energy Technology Data Exchange (ETDEWEB)

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

    2017-09-13

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

  11. How insects overcome two-component plant chemical defence

    DEFF Research Database (Denmark)

    Pentzold, Stefan; Zagrobelny, Mika; Rook, Frederik

    2014-01-01

    Insect herbivory is often restricted by glucosylated plant chemical defence compounds that are activated by plant β-glucosidases to release toxic aglucones upon plant tissue damage. Such two-component plant defences are widespread in the plant kingdom and examples of these classes of compounds...... are alkaloid, benzoxazinoid, cyanogenic and iridoid glucosides as well as glucosinolates and salicinoids. Conversely, many insects have evolved a diversity of counteradaptations to overcome this type of constitutive chemical defence. Here we discuss that such counter-adaptations occur at different time points......, 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...

  12. 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

  13. 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

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

    Science.gov (United States)

    Markschies, C

    2007-08-01

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

  15. Overcoming Gender Stereotypes & Improving Learning through the Participation of the

    Directory of Open Access Journals (Sweden)

    Carme Garcia

    2012-02-01

    Full Text Available This article presents the results of research on how the daily participation of the "Other Women" women without an academic background or from cultural and ethnic minorities contributes to overcoming sexist stereotypes. The study demonstrates that their participation in instrumental learning activities transforms stereotypical beliefs about the skills of women without academic education, immigrant women, or those from cultural minorities. It can also be observed that their participation in decision-making spaces and in learning activities promotes student learning. In short, this study demonstrates that we need to include the "Other Women" into our diverse schools to progress towards the achievement of gender equity in education and society, and to create more positive learning experiences for all children.

  16. Overcoming Barriers to Successfully Commercializing Carbon Dioxide Utilization

    International Nuclear Information System (INIS)

    Kant, Marvin

    2017-01-01

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

  17. Overcoming barriers to public understanding of nuclear waste management

    International Nuclear Information System (INIS)

    Wilder, M.; Hall, S.

    1987-01-01

    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

  18. 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.

  19. Overcoming preexisting humoral immunity to AAV using capsid decoys.

    Science.gov (United States)

    Mingozzi, Federico; Anguela, Xavier M; Pavani, Giulia; Chen, Yifeng; Davidson, Robert J; Hui, Daniel J; Yazicioglu, Mustafa; Elkouby, Liron; Hinderer, Christian J; Faella, Armida; Howard, Carolann; Tai, Alex; Podsakoff, Gregory M; Zhou, Shangzhen; Basner-Tschakarjan, Etiena; Wright, John Fraser; High, Katherine A

    2013-07-17

    Adeno-associated virus (AAV) vectors delivered through the systemic circulation successfully transduce various target tissues in animal models. However, similar attempts in humans have been hampered by the high prevalence of neutralizing antibodies to AAV, which completely block vector transduction. We show in both mouse and nonhuman primate models that addition of empty capsid to the final vector formulation can, in a dose-dependent manner, adsorb these antibodies, even at high titers, thus overcoming their inhibitory effect. To further enhance the safety of the approach, we mutated the receptor binding site of AAV2 to generate an empty capsid mutant that can adsorb antibodies but cannot enter a target cell. Our work suggests that optimizing the ratio of full/empty capsids in the final formulation of vector, based on a patient's anti-AAV titers, will maximize the efficacy of gene transfer after systemic vector delivery.

  20. Strategies to overcome obstacles in the facilitation of critical thinking in nursing education.

    Science.gov (United States)

    Mangena, Agnes; Chabeli, Mary M

    2005-05-01

    This paper seeks to describe strategies that can be used to overcome obstacles in the facilitation of critical thinking in nursing education. A qualitative, explorative, descriptive and contextual design was used to conduct the research in which fourth year basic comprehensive students and nurse educators volunteered to take part in the study by signing an informed consent. The participants were purposively selected. Focus group interviews were used to collect data from both groups. Tesch's descriptive method of open coding described in (Creswell, J. 1994. Qualitative and quantitative approach. Sage, London.) was used to analyse data. (Democratic Nursing Organisation of South Africa, 1998. Ethical standards for nurse researchers. Denosa, Pretoria) ethical standards for research were observed to maintain the standard and quality of the research. (Lincoln, Y.S., Guba, E.G. 1985. Naturalistic inquiry. Sage, London.) framework was used to ensure trustworthiness of the study. The following obstacles were identified and recontextualised within the existing literature to be able to describe the strategies to overcome the identified obstacles to the facilitation of critical thinking of students: the educators' lack of knowledge; use of teaching and assessment methods that do not facilitate critical thinking of learners; the negative attitudes of educators and their resistance to change; inappropriate selection process and poor educational background that did not facilitate critical thinking of students; inadequate socialisation, cultural and instructional language incompetence. Findings indicated that there is a need for nurse educators to model critical thinking in all aspects of nursing education. It is recommended that there be a whole paradigm shift in nursing education from the traditional teacher-centred methods to a more learner-centred approach that will facilitate critical thinking of student nurses.

  1. Staphylococcus aureus: methicillin-susceptible S. aureus to methicillin-resistant S. aureus and vancomycin-resistant S. aureus.

    Science.gov (United States)

    Rehm, Susan J; Tice, Alan

    2010-09-15

    The evolution of methicillin-resistant and vancomycin-resistant Staphylococcus aureus has demanded serious review of antimicrobial use and development of new agents and revised approaches to prevent and overcome drug resistance. Depending on local conditions and patient risk factors, empirical therapy of suspected S. aureus infection may require coverage of drug-resistant organisms with newer agents and novel antibiotic combinations. The question of treatment with inappropriate antibiotics raises grave concerns with regard to methicillin-resistant S. aureus selection, overgrowth, and increased virulence. Several strategies to reduce the nosocomial burden of resistance are suggested, including shortened hospital stays and outpatient parenteral antimicrobial therapy of the most serious infections.

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

    Directory of Open Access Journals (Sweden)

    María Ángela Mattar Yunes

    2015-09-01

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

  3. '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

  4. 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

  5. Overcoming etch challenges related to EUV based patterning (Conference Presentation)

    Science.gov (United States)

    Metz, Andrew W.; Cottle, Hongyun; Honda, Masanobu; Morikita, Shinya; Kumar, Kaushik A.; Biolsi, Peter

    2017-04-01

    Research and development activities related to Extreme Ultra Violet [EUV] defined patterning continue to grow for cost and extreme process control challenges of Self-Aligned Quad Patterning [SAQP] with continued momentum for EUV ecosystem readiness could provide cost advantages in addition to improved intra-level overlay performance relative to multiple patterning approaches. However, Line Edge Roughness [LER] and Line Width Roughness [LWR] performance of EUV defined resist images are still far from meeting technology needs or ITRS spec performance. Furthermore, extreme resist height scaling to mitigate flop over exacerbates the plasma etch trade-offs related to traditional approaches of PR smoothing, descum implementation and maintaining 2D aspect ratios of short lines or elliptical contacts concurrent with ultra-high photo resist [PR] selectivity. In this paper we will discuss sources of LER/LWR, impact of material choice, integration, and innovative plasma process techniques and describe how TELTM VigusTM CCP Etchers can enhance PR selectivity, reduce LER/LWR, and maintain 2D aspect ratio of incoming patterns. Beyond traditional process approaches this paper will show the utility of: [1] DC Superposition in enhancing EUV resist hardening and selectivity, increasing resistance to stress induced PR line wiggle caused by CFx passivation, and mitigating organic planarizer wiggle; [2] Quasi Atomic Layer Etch [Q-ALE] for ARC open eliminating the tradeoffs between selectivity, CD, and shrink ratio control; and [3] ALD+Etch FUSION technology for feature independent CD shrink and LER reduction. Applicability of these concepts back transferred to 193i based lithography is also confirmed.

  6. Antibiotic resistance

    Directory of Open Access Journals (Sweden)

    Marianne Frieri

    2017-07-01

    Full Text Available Summary: Antimicrobial resistance in bacterial pathogens is a challenge that is associated with high morbidity and mortality. Multidrug resistance patterns in Gram-positive and -negative bacteria are difficult to treat and may even be untreatable with conventional antibiotics. There is currently a shortage of effective therapies, lack of successful prevention measures, and only a few new antibiotics, which require development of novel treatment options and alternative antimicrobial therapies. Biofilms are involved in multidrug resistance and can present challenges for infection control. Virulence, Staphylococcus aureus, Clostridium difficile infection, vancomycin-resistant enterococci, and control in the Emergency Department are also discussed. Keywords: Antibiotic resistance, Biofilms, Infections, Public health, Emergency Department

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

    Directory of Open Access Journals (Sweden)

    T. V. Danylova

    2014-12-01

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

  8. 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

  9. 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

  10. Patterns of Force, Sequences of Resistance

    DEFF Research Database (Denmark)

    Lindegaard, Marie Rosenkrantz; Daniël De Vries, Thomas; Bernasco, Wim

    2018-01-01

    Robberies are improvised encounters involving offender threat, sometimes force, and often victim resistance. While the association between threat, force, and resistance in robberies is well-established, sequential patterns are disputed due to biases of retrospective studies. To overcome these bia...... the likelihood of victim resistance despite having no effect on offender vio- lence. By providing more reliable and detailed accounts of real-life behavior during robberies, our analysis illustrates the potential of a newly emergent field of studies of crimes caught on camera....

  11. Strategies for dealing with resistance to recommendations from accident investigations

    OpenAIRE

    Lundberg, Jonas; Rollenhagen, Carl; Hollnagel, Erik; Rankin, Amy

    2012-01-01

    Accident investigation reports usually lead to a set of recommendations for change. These recommendations are, however, sometimes resisted for reasons such as various aspects of ethics and power. When accident investigators are aware of this, they use several strategies to overcome the resistance. This paper describes strategies for dealing with four different types of resistance to change. The strategies were derived from qualitative analysis of 25 interviews with Swedish accident investigat...

  12. 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. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

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

    Directory of Open Access Journals (Sweden)

    Bañuls Mari Carmen

    2017-01-01

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

  14. Overcoming multicollinearity in multiple regression using correlation coefficient

    Science.gov (United States)

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

    2013-09-01

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

  15. Overcoming complexities: Damage detection using dictionary learning framework

    Science.gov (United States)

    Alguri, K. Supreet; Melville, Joseph; Deemer, Chris; Harley, Joel B.

    2018-04-01

    For in situ damage detection, guided wave structural health monitoring systems have been widely researched due to their ability to evaluate large areas and their ability detect many types of damage. These systems often evaluate structural health by recording initial baseline measurements from a pristine (i.e., undamaged) test structure and then comparing later measurements with that baseline. Yet, it is not always feasible to have a pristine baseline. As an alternative, substituting the baseline with data from a surrogate (nearly identical and pristine) structure is a logical option. While effective in some circumstance, surrogate data is often still a poor substitute for pristine baseline measurements due to minor differences between the structures. To overcome this challenge, we present a dictionary learning framework to adapt surrogate baseline data to better represent an undamaged test structure. We compare the performance of our framework with two other surrogate-based damage detection strategies: (1) using raw surrogate data for comparison and (2) using sparse wavenumber analysis, a precursor to our framework for improving the surrogate data. We apply our framework to guided wave data from two 108 mm by 108 mm aluminum plates. With 20 measurements, we show that our dictionary learning framework achieves a 98% accuracy, raw surrogate data achieves a 92% accuracy, and sparse wavenumber analysis achieves a 57% accuracy.

  16. The telephone effect: Overcoming initiation deficits in two settings.

    Science.gov (United States)

    Vickers, Kayci L; Keesler, Michael E; Williams, Kelli S; Charles, Jeremy Y; Hamilton, Roy H

    2018-04-19

    Disorders of motivation substantially impair an individual's ability to communicate with their families, therapists, and doctors. One method of overcoming initiation deficits is by utilizing the telephone effect, which is the ability for individuals with severe motivation deficits to communicate more readily when speaking on a telephone. However, little is available in the extant literature on how this effect works or how best to integrate this into patient care. This article aims to provide the first report of a proposed mechanism underlying the telephone effect and the first published procedures for eliciting this effect. This is largely a review article that also contains descriptions of clinical procedures for eliciting the telephone effect with 2 patient populations: acute inpatients following brain injury and dementia residents. A case vignette is also provided. We propose that the telephone effect is the result of an interaction between the patient and environment, and occurs because of Gibson's (1979) law of affordances. The use of this theory provides an explanation of the behaviors often observed when attempting to elicit this effect (i.e., disruption of the effect when using a cellular phone). Moreover, we argue that this can, and does, apply to social interactions as well. The telephone effect is an understudied phenomenon that provides a means of improving care for individuals with disorders of motivation. Future directions include systematic research into the telephone effect and further investigation of the mechanism underlying this effect. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  17. 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.

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

    Science.gov (United States)

    Hoffmann, Sandra

    2011-09-01

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

  19. Methods for overcoming dormancy in Stryphnodendron pulcherrimum seeds

    Directory of Open Access Journals (Sweden)

    Adriano Gonçalves Pereira

    2016-09-01

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

  20. 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.

  1. Dormancy overcome and seedling quality of pecan in nursery

    Directory of Open Access Journals (Sweden)

    Tales Poletto

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

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

    Science.gov (United States)

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

    2016-12-01

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

  3. Overcoming recruitment challenges in palliative care clinical trials.

    Science.gov (United States)

    LeBlanc, Thomas W; Lodato, Jordan E; Currow, David C; Abernethy, Amy P

    2013-11-01

    Palliative care is increasingly viewed as a necessary component of cancer care, especially for patients with advanced disease. Rigorous clinical trials are thus needed to build the palliative care evidence base, but clinical research-especially participant recruitment-is difficult. Major barriers include (1) patient factors, (2) "gatekeeping," and (3) ethical concerns. Here we discuss an approach to overcoming these barriers, using the Palliative Care Trial (PCT) as a case study. The PCT was a 2 × 2 × 2 factorial randomized controlled trial (RCT) of different service delivery models to improve pain control in the palliative setting. It used a recruitment protocol that fused evidence-based strategies with principles of "social marketing," an approach involving the systematic application of marketing techniques. Main components included (1) an inclusive triage algorithm, (2) information booklets targeting particular stakeholders, (3) a specialized recruitment nurse, and (4) standardization of wording across all study communications. From an eligible pool of 607 patients, the PCT enrolled 461 patients over 26 months. Twenty percent of patients referred to the palliative care service were enrolled (76% of those eligible after screening). Several common barriers were minimized; among those who declined participation, family disinterest was uncommon (5%), as was the perception of burden imposed (4%). Challenges to clinical trial recruitment in palliative care are significant but not insurmountable. A carefully crafted recruitment and retention protocol can be effective. Our experience with designing and deploying a social-marketing-based protocol shows the benefits of such an approach.

  4. Biodiesel Production From Algae to Overcome the Energy Crisis

    Directory of Open Access Journals (Sweden)

    Suliman Khan

    2017-10-01

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

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

    Science.gov (United States)

    Tavormina, Romina; Tavormina, Maurilio Giuseppe Maria

    2017-09-01

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

  6. Rapid parallel evolution overcomes global honey bee parasite.

    Science.gov (United States)

    Oddie, Melissa; Büchler, Ralph; Dahle, Bjørn; Kovacic, Marin; Le Conte, Yves; Locke, Barbara; de Miranda, Joachim R; Mondet, Fanny; Neumann, Peter

    2018-05-16

    In eusocial insect colonies nestmates cooperate to combat parasites, a trait called social immunity. However, social immunity failed for Western honey bees (Apis mellifera) when the ectoparasitic mite Varroa destructor switched hosts from Eastern honey bees (Apis cerana). This mite has since become the most severe threat to A. mellifera world-wide. Despite this, some isolated A. mellifera populations are known to survive infestations by means of natural selection, largely by supressing mite reproduction, but the underlying mechanisms of this are poorly understood. Here, we show that a cost-effective social immunity mechanism has evolved rapidly and independently in four naturally V. destructor-surviving A. mellifera populations. Worker bees of all four 'surviving' populations uncapped/recapped worker brood cells more frequently and targeted mite-infested cells more effectively than workers in local susceptible colonies. Direct experiments confirmed the ability of uncapping/recapping to reduce mite reproductive success without sacrificing nestmates. Our results provide striking evidence that honey bees can overcome exotic parasites with simple qualitative and quantitative adaptive shifts in behaviour. Due to rapid, parallel evolution in four host populations this appears to be a key mechanism explaining survival of mite infested colonies.

  7. Overcoming the Confucian psychological barrier in government cyberspace.

    Science.gov (United States)

    Lee, Ook; Gong, Sung Jin

    2004-02-01

    The Confucian tradition still dictates the behavior of many people in East Asian countries such as South Korea. Even in e-mail communication, people try their best to show signs of respect which is required by the Confucian tradition. This psychological barrier can be detrimental to the development of democracy as people are educated not to challenge opinions of elders or bosses. After a long military dictatorship, South Korea has emerged as a newly democratized nation where the Confucian tradition is less emphasized. However, this tradition dies hard, and citizens are still afraid of offending government officials who have the power to affect lives of citizens. In light of creating a more democratic society, the e-government project has been implemented, and one of the features of cyber-government is to give citizens a place in cyberspace to express their concerns. Even though citizens have to use their real names, it is found that those who wrote messages in the bulletin board of the city of Seoul government's web pages tend not to use terms that are often used in e-mails for the purpose of expressing respect. A survey was conducted, and results show that people were able to overcome the Confucian psychological barrier in government cyberspace. Self-efficacy is proposed to explain this phenomenon.

  8. 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.

  9. Overcoming Barriers to Successfully Commercializing Carbon Dioxide Utilization

    Directory of Open Access Journals (Sweden)

    Marvin Kant

    2017-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Carlos Kosera Neto

    2015-12-01

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

  11. Challenges confronting female surgical leaders: overcoming the barriers.

    Science.gov (United States)

    Kass, Rena B; Souba, Wiley W; Thorndyke, Luanne E

    2006-05-15

    The number of women reaching top ranks in academic surgery is remarkably low. The purpose of this study was to identify: 1) barriers to becoming a female surgical leader; 2) key attributes that enable advancement and success; and 3) current leadership challenges faced as senior leaders. Semi-structured interviews of ten female surgical leaders queried the following dimensions: attributes for success, lessons learned, mistakes, key career steps, the role of mentoring, gender advantages/disadvantages, and challenges. Perseverance (60%) and drive (50%) were identified as critical success factors, as were good communication skills, a passion for scholarship, a stable home life and a positive outlook. Eighty percent identified discrimination or gender prejudice as a major obstacle in their careers. While 90% percent had mentors, 50% acknowledged that they had not been effectively mentored. Career advice included: develop broad career goals (50%); select a conducive environment (30%); find a mentor (60%); take personal responsibility (40%); organize time and achieve balance (40%); network (30%); create a niche (30%); pursue research (30%); publish (50%); speak in public (30%); and enjoy the process (30%). Being in a minority, being highly visible and being collaborative were identified as advantages. Obtaining buy-in and achieving consensus was the greatest leadership challenge reported. Female academic surgeons face challenges to career advancement. While these barriers are real, they can be overcome by resolve, commitment, and developing strong communication skills. These elements should be taken into consideration in designing career development programs for junior female surgical faculty.

  12. Mapping, isolation and characterization of genes responsible for late blight resistance in potato

    NARCIS (Netherlands)

    Pel, M.

    2010-01-01

    Late blight (LB), caused by the oomycete Phytophthora infestans, is one of the most
    devastating diseases on potato. Resistance (R) genes from the wild species Solanum demissum
    have been used by breeders to generate late blight resistant cultivars, but resistance was soon
    overcome

  13. Induced resistance in plants and the role of pathogenesis-related proteins

    NARCIS (Netherlands)

    Loon, L.C. van

    1997-01-01

    The nature of induced resistance Resistance, according to Agrios (1988) is the ability of an organism to exclude or overcome, completely or in some degree, the effect of a pathogen or other damaging factor. Disease resistance in plants is manifested by limited symptoms, reflecting the

  14. Perfluoropolyether-Impregnated Mesoporous Alumina Composites Overcome the Dewetting-Tribological Properties Trade-Off.

    Science.gov (United States)

    Rowthu, Sriharitha; Hoffmann, Patrik

    2018-03-28

    Conventional omniphobic surfaces suffer from wear-sensitivity due to soft apolar coatings or substrates and protruding surface features that are eroded even for mild abrasion treatments, leading to the loss of dewetting properties after wear. Evidently, there was a trade-off between dewetting and tribological properties. Here, we show the establishment of self-healing slippery properties post severe abrasion by utilizing perfluoropolyether-impregnated mesoporous Al 2 O 3 (MPA) composites. The hard polar alumina matrix provides the optimal tribological properties, and the liquid lubricant in the porous network contributes to both tribological and self-healing dewetting properties. These composites sustained normal pressures up to 350 MPa during reciprocating sliding contacts. The severely abraded surfaces are capable of self-replenishing in ambient environment, driven by capillarity and surface diffusion processes, and regained their slippery properties toward water and hexadecane after 15 h of self-healing. Eventually, a dewetting-tribology diagram has been introduced to show different regimes, namely-optimal slippery properties, optimal tribological properties, and a mixed regime). We found out that the microstructural expression [Formula: see text] is a robust guiding tool to predict the regime of interest. This dewetting-tribological diagram may be marked as an inception to designing abrasion-resistant slippery liquid impregnated composites for overcoming the dewetting tribological properties trade-off. Such surfaces may potentially find applications in paint industries and as anti-icing surfaces.

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

    Directory of Open Access Journals (Sweden)

    J. Stastny

    2014-04-01

    Full Text Available 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 present an algorithm for EEG-based identification designed to be resistant to variations in EEG recordings between sessions, which is also demonstrated by an experiment with an EEG database containing two sessions recorded one year apart. Further, our algorithm is designed to be compatible with our movement-related BCI device and the evaluation of the algorithm performance took place under conditions of a standard BCI experiment. Estimation of the mu rhythm fundamental frequency using the Frequency Zooming AR modeling is used for EEG feature extraction followed by a classifier based on the regularized Mahalanobis distance. An average subject identification score of 96 % is achieved.

  16. Negotiation genius how to overcome obstacles and achieve brilliant results at the bargaining table and beyond

    CERN Document Server

    Malhotra, Deepak

    2008-01-01

    From two leaders in executive education at Harvard Business School, here are the mental habits and proven strategies you need to achieve outstanding results in any negotiation. Whether you’ve “seen it all” or are just starting out, Negotiation Genius will dramatically improve your negotiating skills and confidence. Drawing on decades of behavioral research plus the experience of thousands of business clients, the authors take the mystery out of preparing for and executing negotiations—whether they involve multimillion-dollar deals or improving your next salary offer. What sets negotiation geniuses apart? They are the men and women who know how to: •Identify negotiation opportunities where others see no room for discussion •Discover the truth even when the other side wants to conceal it •Negotiate successfully from a position of weakness •Defuse threats, ultimatums, lies, and other hardball tactics •Overcome resistance and “sell” proposals using proven influence tactics •Negotia...

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

    Science.gov (United States)

    Jones, Daniel L; Baxter, Bonnie K

    2017-01-01

    Halophilic archaea push the limits of life at several extremes. In particular, they are noted for their biochemical strategies in dealing with osmotic stress, low water activity and cycles of desiccation in their hypersaline environments. Another feature common to their habitats is intense ultraviolet (UV) radiation, which is a challenge that microorganisms must overcome. The consequences of high UV exposure include DNA lesions arising directly from bond rearrangement of adjacent bipyrimidines, or indirectly from oxidative damage, which may ultimately result in mutation and cell death. As such, these microorganisms have evolved a number of strategies to navigate the threat of DNA damage, which we differentiate into two categories: DNA repair and photoprotection. Photoprotection encompasses damage avoidance strategies that serve as a "first line of defense," and in halophilic archaea include pigmentation by carotenoids, mechanisms of oxidative damage avoidance, polyploidy, and genomic signatures that make DNA less susceptible to photodamage. Photolesions that do arise are addressed by a number of DNA repair mechanisms that halophilic archaea efficiently utilize, which include photoreactivation, nucleotide excision repair, base excision repair, and homologous recombination. This review seeks to place DNA damage, repair, and photoprotection in the context of halophilic archaea and the solar radiation of their hypersaline environments. We also provide new insight into the breadth of strategies and how they may work together to produce remarkable UV-resistance for these microorganisms.

  18. A Viral Receptor Complementation Strategy to Overcome CAV-2 Tropism for Efficient Retrograde Targeting of Neurons.

    Science.gov (United States)

    Li, Shu-Jing; Vaughan, Alexander; Sturgill, James Fitzhugh; Kepecs, Adam

    2018-06-06

    Retrogradely transported neurotropic viruses enable genetic access to neurons based on their long-range projections and have become indispensable tools for linking neural connectivity with function. A major limitation of viral techniques is that they rely on cell-type-specific molecules for uptake and transport. Consequently, viruses fail to infect variable subsets of neurons depending on the complement of surface receptors expressed (viral tropism). We report a receptor complementation strategy to overcome this by potentiating neurons for the infection of the virus of interest-in this case, canine adenovirus type-2 (CAV-2). We designed AAV vectors for expressing the coxsackievirus and adenovirus receptor (CAR) throughout candidate projection neurons. CAR expression greatly increased retrograde-labeling rates, which we demonstrate for several long-range projections, including some resistant to other retrograde-labeling techniques. Our results demonstrate a receptor complementation strategy to abrogate endogenous viral tropism and thereby facilitate efficient retrograde targeting for functional analysis of neural circuits. Copyright © 2018 Elsevier Inc. All rights reserved.

  19. A generic concept to overcome bandgap limitations for designing highly efficient multi-junction photovoltaic cells.

    Science.gov (United States)

    Guo, Fei; Li, Ning; Fecher, Frank W; Gasparini, Nicola; Ramirez Quiroz, Cesar Omar; Bronnbauer, Carina; Hou, Yi; Radmilović, Vuk V; Radmilović, Velimir R; Spiecker, Erdmann; Forberich, Karen; Brabec, Christoph J

    2015-07-16

    The multi-junction concept is the most relevant approach to overcome the Shockley-Queisser limit for single-junction photovoltaic cells. The record efficiencies of several types of solar technologies are held by series-connected tandem configurations. However, the stringent current-matching criterion presents primarily a material challenge and permanently requires developing and processing novel semiconductors with desired bandgaps and thicknesses. Here we report a generic concept to alleviate this limitation. By integrating series- and parallel-interconnections into a triple-junction configuration, we find significantly relaxed material selection and current-matching constraints. To illustrate the versatile applicability of the proposed triple-junction concept, organic and organic-inorganic hybrid triple-junction solar cells are constructed by printing methods. High fill factors up to 68% without resistive losses are achieved for both organic and hybrid triple-junction devices. Series/parallel triple-junction cells with organic, as well as perovskite-based subcells may become a key technology to further advance the efficiency roadmap of the existing photovoltaic technologies.

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

    Directory of Open Access Journals (Sweden)

    Daniel L. Jones

    2017-09-01

    Full Text Available Halophilic archaea push the limits of life at several extremes. In particular, they are noted for their biochemical strategies in dealing with osmotic stress, low water activity and cycles of desiccation in their hypersaline environments. Another feature common to their habitats is intense ultraviolet (UV radiation, which is a challenge that microorganisms must overcome. The consequences of high UV exposure include DNA lesions arising directly from bond rearrangement of adjacent bipyrimidines, or indirectly from oxidative damage, which may ultimately result in mutation and cell death. As such, these microorganisms have evolved a number of strategies to navigate the threat of DNA damage, which we differentiate into two categories: DNA repair and photoprotection. Photoprotection encompasses damage avoidance strategies that serve as a “first line of defense,” and in halophilic archaea include pigmentation by carotenoids, mechanisms of oxidative damage avoidance, polyploidy, and genomic signatures that make DNA less susceptible to photodamage. Photolesions that do arise are addressed by a number of DNA repair mechanisms that halophilic archaea efficiently utilize, which include photoreactivation, nucleotide excision repair, base excision repair, and homologous recombination. This review seeks to place DNA damage, repair, and photoprotection in the context of halophilic archaea and the solar radiation of their hypersaline environments. We also provide new insight into the breadth of strategies and how they may work together to produce remarkable UV-resistance for these microorganisms.

  1. Strategies for improving rust resistance in oats

    International Nuclear Information System (INIS)

    Harder, D.E.; McKenzie, R.I.H.; Martens, J.W.; Brown, P.D.

    1977-01-01

    During the history of breeding oats for rust resistance in Canada the known sources of resistance proved inadequate to counter the virulence potential of both stem rust (Puccinia graminis avenae) and crown rust (P. coronata avenae). A major programme to overcome the rust problem was undertaken at Winnipeg, involving four alternate approaches: (1) A search for new resistance in wild oat species, particularly Avena sterilis, has provided a wealth of good resistance to crown rust, but less to stem rust. Much of the A. sterilis-derived crown rust resistance is now being used world-wide; (2) Efforts at synthesizing new resistance by mutation breeding methods have not been successful. Of about seven million plants examined, only one showed significant new resistance, but this was associated with poor plant type; (3) Resistance with low levels of expression but which appears broadly effective has been observed against both stem and crown rusts. It appears that numbers of these low-level genes exist, and that they can be accumulated to provide increasingly effective resistance. Problems in using this type of resistance in a practical way are discussed; (4) Excellent rust resistance has been found in lower ploidy species such as A. barbata, but it was not previously possible to stabilize this resistance in hexaploid species. By using mutagenic treatments attempts have been made to translocate smaller portions of the A. barbata chromosome carrying the resistance to the hexaploid cultivar Rodney. In conclusion, mutation breeding methods at present appear to have limited application in synthesizing new rust-resistant genotypes in oats. The search for already existing genetic resistance and its synthesis into multi-genic resistant lines appears to be the most effective way at present of resolving the rust problem in oats. (author)

  2. The return to keynesianism in overcoming cyclical fluctuations?

    Directory of Open Access Journals (Sweden)

    Praščević Aleksandra

    2008-01-01

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

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

    Science.gov (United States)

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

    2018-01-01

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

  4. Overcoming the Photovoltage Plateau in Large Bandgap Perovskite Photovoltaics.

    Science.gov (United States)

    Rajagopal, Adharsh; Stoddard, Ryan J; Jo, Sae Byeok; Hillhouse, Hugh W; Jen, Alex K-Y

    2018-05-09

    Development of large bandgap (1.80-1.85 eV E g ) perovskite is crucial for perovskite-perovskite tandem solar cells. However, the performance of 1.80-1.85 eV E g perovskite solar cells (PVKSCs) are significantly lagging their counterparts in the 1.60-1.75 eV E g range. This is because the photovoltage ( V oc ) does not proportionally increase with E g due to lower optoelectronic quality of conventional (MA,FA,Cs)Pb(I,Br) 3 and results in a photovoltage plateau ( V oc limited to 80% of the theoretical limit for ∼1.8 eV E g ). Here, we incorporate phenylethylammonium (PEA) in a mixed-halide perovskite composition to solve the inherent material-level challenges in 1.80-1.85 eV E g perovskites. The amount of PEA incorporation governs the topography and optoelectronic properties of resultant films. Detailed structural and spectroscopic characterization reveal the characteristic trends in crystalline size, orientation, and charge carrier recombination dynamics and rationalize the origin of improved material quality with higher luminescence. With careful interface optimization, the improved material characteristics were translated to devices and V oc values of 1.30-1.35 V were achieved, which correspond to 85-87% of the theoretical limit. Using an optimal amount of PEA incorporation to balance the increase in V oc and the decrease in charge collection, a highest power conversion efficiency of 12.2% was realized. Our results clearly overcome the photovoltage plateau in the 1.80-1.85 eV E g range and represent the highest V oc achieved for mixed-halide PVKSCs. This study provides widely translatable insights, an important breakthrough, and a promising platform for next-generation perovskite tandems.

  5. Resistant Hypertension.

    Science.gov (United States)

    Doroszko, Adrian; Janus, Agnieszka; Szahidewicz-Krupska, Ewa; Mazur, Grzegorz; Derkacz, Arkadiusz

    2016-01-01

    Resistant hypertension is a severe medical condition which is estimated to appear in 9-18% of hypertensive patients. Due to higher cardiovascular risk, this disorder requires special diagnosis and treatment. The heterogeneous etiology, risk factors and comorbidities of resistant hypertension stand in need of sophisticated evaluation to confirm the diagnosis and select the best therapeutic options, which should consider lifestyle modifications as well as pharmacological and interventional treatment. After having excluded pseudohypertension, inappropriate blood pressure measurement and control as well as the white coat effect, suspicion of resistant hypertension requires an analysis of drugs which the hypertensive patient is treated with. According to one definition - ineffective treatment with 3 or more antihypertensive drugs including diuretics makes it possible to diagnose resistant hypertension. A multidrug therapy including angiotensin - converting enzyme inhibitors, angiotensin II receptor blockers, beta blockers, diuretics, long-acting calcium channel blockers and mineralocorticoid receptor antagonists has been demonstrated to be effective in resistant hypertension treatment. Nevertheless, optional, innovative therapies, e.g. a renal denervation or baroreflex activation, may create a novel pathway of blood pressure lowering procedures. The right diagnosis of this disease needs to eliminate the secondary causes of resistant hypertension e.g. obstructive sleep apnea, atherosclerosis and renal or hormonal disorders. This paper briefly summarizes the identification of the causes of resistant hypertension and therapeutic strategies, which may contribute to the proper diagnosis and an improvement of the long term management of resistant hypertension.

  6. Camptothecin resistance

    DEFF Research Database (Denmark)

    Brangi, M; Litman, Thomas; Ciotti, M

    1999-01-01

    . Glucuronides were found at equal levels in both parental and resistant colon cancer cell lines for epirubicin and to a lesser extent for SN-38 and mitoxantrone. Low levels of glucuronidation could also be detected in the resistant breast cancer cells. These results were confirmed by analysis of the UGT1A...

  7. Antibiotic Resistance

    DEFF Research Database (Denmark)

    Munck, Christian

    morbidity and mortality as well as an increase in the cost of treatment. Understanding how bacteria respond to antibiotic exposure gives the foundations for a rational approach to counteract antimicrobial resistance. In the work presented in this thesis, I explore the two fundamental sources...... of antimicrobial resistance: (1) adaptive mutations and (2) horizontal acquisition of resistance genes from antibiotic gene reservoirs. By studying the geno- and phenotypic changes of E. coli in response to single and drug-pair exposures, I uncover the evolutionary trajectories leading to adaptive resistance. I...... to rationally design drug combinations that limit the evolution of antibiotic resistance due to counteracting evolutionary trajectories. My results highlight that an in-depth knowledge about the genetic responses to the individual antimicrobial compounds enables the prediction of responses to drug combinations...

  8. Drug-resistant tuberculosis in Sindh

    International Nuclear Information System (INIS)

    Almani, S.A.; Memon, N.M.; Qureshi, A.F.

    2002-01-01

    Objective: To assess the prevalence of primary and secondary drug resistance amongst the clinical isolates of M.tuberculosis, to identify risk factors and how to overcome this problem. Design: A case series of 50 indoor patients with sputum smear-positive pulmonary tuberculosis. Place and duration of Study: Department of Medicine, Liaquat University of Medical and Health Sciences Jamshoro, Sindh, (Pakistan) from January 1999 to December 2000. Patients and methods: Four first line anti-tuberculous drugs rifampicine, ethambutol and streptomycin were tested for sensitivity pattern. Results: Twelve (26.66%) were sensitive to all four drugs, 12(26.66%) were resistant to one drug, 14 (31.11%) were resistant to two drugs, 2 (4.44%) were resistant to three drugs, and 5(11.11%) were resistant to all four drugs. Resistance to isoniazid was the most common in 27 cases (60%) with primary resistance in 6(13.33%) and secondary resistance in 21(46.66%), followed by resistance to streptomycin in 17 cases (37.77%) with primary resistance in 5(11.11%) and secondary resistance in 12 (26.66%). Resistance to ethambutol in 10 cases (22.22%) and rifampicine in 11 (24.44%) and all cases were secondary. Similarly multi-drugs resistance (MRD) TB was found in 11(24.44%) isolates. Conclusion: This study showed high prevalence of drug resistance among clinical isolates of M. tuberculosis. Their is a need to establish centers at number of places with adequate facilities for susceptibility testing so that the resistant pattern could be ascertained and treatment regimens tailored accordingly. (author)

  9. 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

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

    Science.gov (United States)

    McCurdy, K. M.

    2015-12-01

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

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

    Science.gov (United States)

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

    2017-08-15

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

  12. The Evaluation of Techniques for Overcoming with the Stress in a Physician Group

    OpenAIRE

    Humman Sen; Mehmet Toygar; Turker Turker; Nurhan Ince; Harun Tugcu; Halit Keskin

    2012-01-01

    Objective: This study was made in order to determine the methods of overcoming with stress of the specialist physicians. Material-Method: Our study is a descriptive study. In the study, the scale of overcoming with stress was applied to the 100 specialist physicians who working in 5 different health care institutions in and around the Istanbul in 2009. Results: The scores that the participants takes from sub-categories of scales of overcoming with stress types were measured respectively as; 2...

  13. 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.

  14. Drug-resistant spinal tuberculosis

    Directory of Open Access Journals (Sweden)

    Anil K Jain

    2018-01-01

    Full Text Available Drug-resistant spinal tuberculosis (TB is an emerging health problem in both developing and developed countries. In this review article, we aim to define management protocols for suspicion, diagnosis, and treatment of such patients. Spinal TB is a deep-seated paucibacillary lesion, and the demonstration of acid-fast bacilli on Ziehl-Neelsen staining is possible only in 10%–30% of cases. Drug resistance is suspected in patients showing the failure of clinicoradiological improvement or appearance of a fresh lesion of osteoarticular TB while on anti tubercular therapy (ATT for a minimum period of 5 months. The conventional culture of Mycobacterium tuberculosis remains the gold standard for both bacteriological diagnosis and drug sensitivity testing (DST; however, the high turn around time of 2–6 weeks for detection with added 3 weeks for DST is a major limitation. To overcome this problem, rapid culture methods and molecular methods have been introduced. From a public health perspective, reducing the period between diagnosis and treatment initiation has direct benefits for both the patient and the community. For all patients of drug-resistant spinal TB, a complete Drug-O-Gram should be prepared which includes details of all drugs, their doses, and duration. Patients with confirmed multidrug-resistant TB strains should receive a regimen with at least five effective drugs, including pyrazinamide and one injectable. Patients with resistance to additional antitubercular drugs should receive individualized ATT as per their DST results.

  15. Antimicrobial Resistance

    Science.gov (United States)

    ... past two decades due to the increase in immunocompromised and elderly patients, increasing use of invasive indwelling ... aureus developing resistance to vancomycin, a very powerful antibiotic prescribed for the most intractable bacterial infections. In ...

  16. Drug Resistance

    Science.gov (United States)

    ... Drug-resistance testing is also recommended for all pregnant women with HIV before starting HIV medicines and also in some pregnant women already taking HIV medicines. Pregnant women will work with their health ...

  17. Overcoming Barriers in the Implementation of Environmental Remediation Projects

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2013-06-15

    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.

  18. Overcoming Barriers in the Implementation of Environmental Remediation Projects

    International Nuclear Information System (INIS)

    2013-01-01

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

  19. Antimicrobial resistance

    DEFF Research Database (Denmark)

    Llor, Carl; Bjerrum, Lars

    2014-01-01

    Antimicrobial resistance is a global public health challenge, which has accelerated by the overuse of antibiotics worldwide. Increased antimicrobial resistance is the cause of severe infections, complications, longer hospital stays and increased mortality. Overprescribing of antibiotics......-the-counter sale of antibiotics, the use of antimicrobial stewardship programmes, the active participation of clinicians in audits, the utilization of valid rapid point-of-care tests, the promotion of delayed antibiotic prescribing strategies, the enhancement of communication skills with patients with the aid...

  20. Statistical Method to Overcome Overfitting Issue in Rational Function Models

    Science.gov (United States)

    Alizadeh Moghaddam, S. H.; Mokhtarzade, M.; Alizadeh Naeini, A.; Alizadeh Moghaddam, S. A.

    2017-09-01

    Rational function models (RFMs) are known as one of the most appealing models which are extensively applied in geometric correction of satellite images and map production. Overfitting is a common issue, in the case of terrain dependent RFMs, that degrades the accuracy of RFMs-derived geospatial products. This issue, resulting from the high number of RFMs' parameters, leads to ill-posedness of the RFMs. To tackle this problem, in this study, a fast and robust statistical approach is proposed and compared to Tikhonov regularization (TR) method, as a frequently-used solution to RFMs' overfitting. In the proposed method, a statistical test, namely, significance test is applied to search for the RFMs' parameters that are resistant against overfitting issue. The performance of the proposed method was evaluated for two real data sets of Cartosat-1 satellite images. The obtained results demonstrate the efficiency of the proposed method in term of the achievable level of accuracy. This technique, indeed, shows an improvement of 50-80% over the TR.

  1. Proliferation resistance modeling

    International Nuclear Information System (INIS)

    Bari, R.; Peterson, P.; Roglans, J.; Mladineo, S.; Nuclear Engineering Division; BNL; Univ. of California at Berkely; PNNL

    2004-01-01

    The National Nuclear Security Administration is developing methods for nonproliferation assessments. A working group on Nonproliferation Assessment Methodology (NPAM) assembled a toolbox of methods for various applications in the nonproliferation arena. One application of this methodology is to the evaluation of the proliferation resistance of Generation IV nuclear energy systems. This paper first summarizes the key results of the NPAM program and then provides results obtained thus far in the ongoing application, which is co-sponsored by the DOE Office of Nuclear Energy Science and Technology. In NPAM, a top-level measure of proliferation resistance for a fuel cycle system is developed from a hierarchy of metrics. The problem is decomposed into: metrics to be computed, barriers to proliferation, and a finite set of threats. The analyst models the process undertaken by the proliferant to overcome barriers to proliferation and evaluates the outcomes. In addition to proliferation resistance (PR) evaluation, the application also addresses physical protection (PP) evaluation against sabotage and theft. The Generation IV goal for future nuclear energy systems is to assure that they are very unattractive and the least desirable route for diversion or theft of weapons-usable materials, and provide increased physical protection against terrorism. An Expert Group, addressing this application, has identified six high-level measures for the PR goals (six measures have also been identified for the PP goals). Combined together, the complete set of measures provides information for program policy makers and system designers to compare specific system design features and integral system characteristics and to make choices among alternative options. The Group has developed a framework for a phased evaluation approach to analyzing PR and PP of system characteristics and to quantifying metrics and measures. This approach allows evaluations to become more detailed and representative

  2. Diagnosing resistance to change in the change management process

    Directory of Open Access Journals (Sweden)

    Tetiana Kuzhda

    2016-12-01

    Full Text Available This article explains the change management process and resistance to organizational change through examining causes of resistance to change, diagnosing them, and finding the ways to deal with resistance to change. In business environment, the one thing any company can be assured of is change. If an organization experiences change it may also need to implement new business strategies, which can create resistance among employees. Managers need to know in which phase they have to expect unusual situations, problems, and resistance to change. Most successful organizations are those that are able to adjust themselves to new conditions quickly. Preparing for change, managing change through resistance management plan and reinforcing change have been identified in the article as the main phrases of change management process that lead to improve the organization performance. Managing resistance to change is important part for success of any change effort in each company. Dealing with resistance in large part will depend on timely recognition of the real causes of resistance to change and finding the ways to reduce, overcome or eliminate the resistance to change. Developing efficient ways to introduce and implement change can ease the stress the staff feels when change is introduced. Different resistance states, causes of change resistance and forms of change resistance have been emphasized in the change management process. The proposed diagnosing model has been used to identify significant and weighty causes of resistance to change by using the expert survey and ranking causes of resistance to change. The ways to reduce and overcome resistance to change have been explained.

  3. Strategies of Overcoming Acculturation Stress in Students from Different Parts of the World

    Directory of Open Access Journals (Sweden)

    E Ju Chebotareva

    2012-03-01

    Full Text Available This article describes the results of the study of strategies of acculturation stress overcoming in the students from different regions, as well as the correlations of preferring certain strategies with successful cross-cultural adaptation. It was found out that, in general, the constructive coping strategies contribute to successful adaptation, help to overcome adaptation problems and negative emotional states.

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

    Science.gov (United States)

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

    2012-01-01

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

  5. Disciplinary maintenance of process of overcoming of deformations of professional-pedagogical authentication of future teachers

    Directory of Open Access Journals (Sweden)

    Zhanna P. Pavlova

    2011-04-01

    Full Text Available In the article examined disciplinary maintenance of process of overcoming of deformations of professional-pedagogical authentication of future teachers and maintenance of process of overcoming of deformations, which is built on module principle on the basis of disciplinary connections.

  6. 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.

  7. Resistant hypertension.

    Science.gov (United States)

    Wei, Fang-Fei; Zhang, Zhen-Yu; Huang, Qi-Fang; Yang, Wen-Yi; Staessen, Jan A

    2018-06-15

    The publication of the first non-randomised proof-of-concept trial of renal denervation as a treatment modality in treatment-resistant hypertension set the stage for a search for novel devices with the expectation that technology would reduce the burden of hypertension by reducing or eliminating the costly and lifelong use of blood pressure lowering medications. As we demonstrate in this review, this idea so attractive to manufacturers and invasive cardiologists and radiologists overlooked decades of careful pathophysiological research in a disease, which still remains enigmatic but remains the major cause of cardiovascular mortality worldwide. To make our point, we first reviewed the prevalence and risks associated with treatment-resistant hypertension. Next, we highlighted the key points required for the diagnosis of treatment-resistant hypertension, including the recording of the ambulatory blood pressure and the assessment of adherence to medication. Finally, we summarised new insights in the management of treatment-resistant hypertension by medication and devices and in the future research. Throughout our review, we focused on new evidence became available since 2013. Our conclusion is that optimising medical treatment based on simple algorithms remains the state of the art in treatment-resistant hypertension.

  8. Anticoagulant Resistance

    DEFF Research Database (Denmark)

    Heiberg, Ann-Charlotte

    Although sewer rat control is carried out in more than 80 % of all Danish municipalities, with usage of large amounts of anticoagulant rodenticides, knowledge on anticoagulant resistance among rats living in the sewers is limited. As rat problems in urban areas are believed to be related to sewer...... problems (70-90 % in UK and DK) unawareness of resistance amongst these populations of Brown rats may constitute a future control problem and knowledge on this issue has become crucial. Rats were captured in sewers from seven different locations in the suburban area of Copenhagen. Locations was chosen...... to represent different sewer rat management strategies i) no anticoagulants for approx. 20 years ii) no anticoagulants for the last 5 years and iii) continuous control for many years. Animals were tested for resistance to bromadiolone by Blood-Clotting Response test, as bromadiolone is the most frequently used...

  9. Reducing Resistance

    DEFF Research Database (Denmark)

    Lindell, Johanna

    care may influence decisions on antibiotic use. Based on video-and audio recordings of physician-patient consultations it is investigated how treatment recommendations are presented, can be changed, are forecast and explained, and finally, how they seemingly meet resistance and how this resistance......Antibiotic resistance is a growing public health problem both nationally and internationally, and efficient strategies are needed to reduce unnecessary use. This dissertation presents four research studies, which examine how communication between general practitioners and patients in Danish primary...... is responded to.The first study in the dissertation suggests that treatment recommendations on antibiotics are often done in a way that encourages patient acceptance. In extension of this, the second study of the dissertation examines a case, where acceptance of such a recommendation is changed into a shared...

  10. Nanostructured coatings for controlling bacterial biofilms and antibiotic resistance

    OpenAIRE

    Ivanova, Kristina Dimitrova

    2017-01-01

    The accelerated emergence of drug resistant bacteria is one of the most serious problems in healthcare and the difficulties in finding new antibiotics make it even more challenging. To overcome the action of antibiotics bacteria develop effective resistance mechanisms including the formation of biofilms. Biofilms are bacterial communities of cells embedded in a self-produced polymeric matrix commonly found on medical devices such as indwelling catheters. When pathogens adopt this mode of grow...

  11. Drug resistance

    NARCIS (Netherlands)

    Gorter, J.A.; Potschka, H.; Noebels, J.L.; Avoli, M.; Rogawski, M.A.; Olsen, R.W.; Delgado-Escueta, A.V.

    2012-01-01

    Drug resistance remains to be one of the major challenges in epilepsy therapy. Identification of factors that contribute to therapeutic failure is crucial for future development of novel therapeutic strategies for difficult-to-treat epilepsies. Several clinical studies have shown that high seizure

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

    Directory of Open Access Journals (Sweden)

    Al-Din Salar Salah Muhy

    2017-01-01

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

  13. Enhanced Peroxide Resistance of In Vitro Mutagenized Fluorideresistant Klebsiella pneumoniae Ureases for Catalytic Buffering of Agent Decontamination Reactions

    National Research Council Canada - National Science Library

    Fry, Ilona J; DeFrank, Joseph J

    2004-01-01

    .... Fluoride-resistant (FR) ureases developed previously in our laboratory were >95% inhibited by 1% hydrogen peroxide. To overcome this problem, the FR mutant urease structural genes of Klebsiella pneumoniae were mutagenized in vitro in an E...

  14. Novel mutations detected in avirulence genes overcoming tomato Cf resistance genes in isolates of a Japanese population of Cladosporium fulvum

    NARCIS (Netherlands)

    Iida, Y.; Hof, van 't P.M.J.; Beenen, H.G.; Mesarich, C.H.; Kubota, M.; Stergiopoulos, I.; Mehrabi, A.; Notsu, A.; Fujiwara, K.; Bahkali, A.; Abd-Elsalam, K.; Collemare, J.; Wit, de P.J.G.M.

    2015-01-01

    Leaf mold of tomato is caused by the biotrophic fungus Cladosporium fulvum which complies with the gene-for-gene system. The disease was first reported in Japan in the 1920s and has since been frequently observed. Initially only race 0 isolates were reported, but since the consecutive introduction

  15. Application of interferon modulators to overcome partial resistance of human ovarian cancers to VSV-GP oncolytic viral therapy

    Directory of Open Access Journals (Sweden)

    Catherine Dold

    2016-01-01

    Full Text Available Previously, we described an oncolytic vesicular stomatitis virus variant pseudotyped with the nonneurotropic glycoprotein of the lymphocytic choriomeningitis virus, VSV-GP, which was highly effective in glioblastoma. Here, we tested its potency for the treatment of ovarian cancer, a leading cause of death from gynecological malignancies. Effective oncolytic activity of VSV-GP could be demonstrated in ovarian cancer cell lines and xenografts in mice; however, remission was temporary in most mice. Analysis of the innate immune response revealed that ovarian cancer cell lines were able to respond to and produce type I interferon, inducing an antiviral state upon virus infection. This is in stark contrast to published data for other cancer cell lines, which were mostly found to be interferon incompetent. We showed that in vitro this antiviral state could be reverted by combining VSV-GP with the JAK1/2-inhibitor ruxolitinib. In addition, for the first time, we report the in vivo enhancement of oncolytic virus treatment by ruxolitinib, both in subcutaneous as well as in orthotopic xenograft mouse models, without causing significant additional toxicity. In conclusion, VSV-GP has the potential to be a potent and safe oncolytic virus to treat ovarian cancer, especially when combined with an inhibitor of the interferon response.

  16. Selective BRAFV600E inhibitor PLX4720, requires TRAIL assistance to overcome oncogenic PIK3CA resistance

    Czech Academy of Sciences Publication Activity Database

    Oikonomou, E.; Koc, Michal; Šourková, Vladimíra; Anděra, Ladislav; Pintzas, A.

    2011-01-01

    Roč. 6, č. 6 (2011), e21632 E-ISSN 1932-6203 Grant - others:EK(XE) LSHC-CT-2006-037278 Institutional research plan: CEZ:AV0Z50520514 Keywords : 17- AAG * apoptosis * colorectal cancer Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.092, year: 2011

  17. Selective BRAFV600E inhibitor PLX4720, requires TRAIL assistance to overcome oncogenic PIK3CA resistance

    Czech Academy of Sciences Publication Activity Database

    Oikonomou, E.; Koc, Michal; Šourková, Vladimíra; Anděra, Ladislav; Pintzas, A.

    2011-01-01

    Roč. 6, č. 6 (2011), e21632 E-ISSN 1932-6203 Grant - others:EK(XE) LSHC-CT-2006-037278 Institutional research plan: CEZ:AV0Z50520514 Keywords : 17-AAG * apoptosis * colorectal cancer Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.092, year: 2011

  18. Overcoming multidrug resistance using folate receptor-targeted and pH-responsive polymeric nanogels containing covalently entrapped doxorubicin

    Czech Academy of Sciences Publication Activity Database

    Chen, Y.; Tezcan, O.; Li, D.; Beztsinna, N.; Lou, B.; Etrych, Tomáš; Ulbrich, Karel; Metselaar, J. M.; Lammers, T.; Hennink, W. E.

    2017-01-01

    Roč. 9, č. 29 (2017), s. 10404-10419 ISSN 2040-3364 R&D Projects: GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : drug delivery * doxorubicin * pH controlled release Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 7.367, year: 2016

  19. Can innovative business models overcome resistance to electric vehicles? Better Place and battery electric cars in Denmark

    International Nuclear Information System (INIS)

    Budde Christensen, Thomas; Wells, Peter; Cipcigan, Liana

    2012-01-01

    This paper explores the geographical and policy context for an emergent business model from Better Place to deliver battery electric car mobility in Denmark. It argues that the combination of radically different technologies and a highly complex multi-agency operating environment theoretically provide the conditions and requirements for such an emergent business model. While focused on battery electric cars, renewable energy generation and smart grids, the paper has wider applicability to an understanding of the interplay between place, innovation and sustainability which suggests that diverse solutions are likely to be the characteristic solution rather than ubiquity and standardization. The paper argues, however, that the innovative business model, the deployment of electric vehicles, and the use of renewable energy systems, in this case largely based on wind power, while mutually supportive and contributing to wider policy aims with respect to the reduction of carbon emissions, may still fail in the face of entrenched practices. At the theoretical level it is concluded that theorization of business models needs a broader perspective beyond the typical ‘value creation, value capture’ rubric to better understand the wider role such models have in meeting societal goals, and to understand the structural impediments to organizational and technical innovation. - Highlights: ► We explore the context for an innovative emergent business model to deliver battery electric car mobility in Denmark. ► We explore the interplay between battery electric cars, renewable energy generation and smart grids. ► We discuss the integration of electric cars in energy systems based on renewable energy sources. ► We discuss the likely success of the Better Place business model.

  20. Improved tumor-specific drug accumulation by polymer therapeutics with pH-sensitive drug release overcomes chemotherapy resistance

    Czech Academy of Sciences Publication Activity Database

    Heinrich, A. K.; Lucas, H.; Schindler, Lucie; Chytil, Petr; Etrych, Tomáš; Mäder, K.; Mueller, T.

    2016-01-01

    Roč. 15, č. 5 (2016), s. 998-1007 ISSN 1535-7163 R&D Projects: GA MŠk(CZ) ED1.1.00/02.0109; GA ČR(CZ) GA15-02986S; GA ČR(CZ) GCP207/12/J030; GA ČR(CZ) GA14-12742S Institutional support: RVO:61389013 Keywords : HPMA copolymers * doxorubicin * pH-sensitivity Subject RIV: CD - Macromolecular Chemistry Impact factor: 5.764, year: 2016

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

    Science.gov (United States)

    Kang, Minyong; Lee, Kyoung-Hwa; Lee, Hye Sun; Jeong, Chang Wook; Kwak, Cheol; Kim, Hyeon Hoe; Ku, Ja Hyeon

    2017-02-04

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

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

    Directory of Open Access Journals (Sweden)

    Minyong Kang

    2017-02-01

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

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

    Science.gov (United States)

    2004-06-01

    Prahalad , C. K. (1981). Headquarters influence and strategic control in MNCs. Sloan Management Review, 23(1), 15-29. Gagne, M., Koestner, R...p. 124). Rousseau, et al. (1998) defined trust as “a psychological state comprising the intention to accept vulnerability based on the positive...expectations of the intentions or behavior of another” (p. 395). McAllister (1995) defined trust as “the extent to which a person is confident in and

  4. Overcoming resistance to bisphosphonates through the administration of alfacalcidol: results of a 1-year, open follow-up study.

    Science.gov (United States)

    Gaál, János; Bender, Tamás; Varga, József; Horváth, Irén; Kiss, Judit; Somogyi, Péter; Surányi, Péter

    2009-11-01

    This study intended to determine whether the replacement of vitamin D3 with alfacalcidol results in any bone mineral density (BMD) increase in 76 patients unresponsive to the combination of alendronate and conventional vitamin D3 treatment. In these patients the conventional vitamin D3 had been replaced with alfacalcidol (0.5 μg/day), and then the patients were followed up for a year. After treatment for 1 year, Wilcoxon test revealed a small but statistically significant (P d-pyr/creatinine ratio decreased significantly (P < 0.001). As suggested by our results, combination therapy with alendronate and alfacalcidol increases bone density and improves the biochemical markers of bone turnover, without any substantial increase in the incidence of adverse effects.

  5. Cytoplasmic Overexpression of CD95L in Esophageal Adenocarcinoma Cells Overcomes Resistance to CD95-Mediated Apoptosis

    Directory of Open Access Journals (Sweden)

    Gregory A. Watson

    2011-03-01

    Full Text Available Introduction: The CD95/CD95L pathway plays a critical role in tissue homeostasis and immune system regulation; however, the function of this pathway in malignancy remains poorly understood. We hypothesized that CD95L expression in esophageal adenocarcinoma confers advantages to the neoplasm other than immune privilege. Methods: CD95L expression was characterized in immortalized squamous esophagus (HET-1A and Barrett esophagus (BAR-T cells; adenocarcinoma cell lines FLO-1, SEG-1, and BIC-1, and MDA468 (- control; and KFL cells (+ control. Analyses included reverse transcription-polymerase chain reaction, immunoblots of whole cell and secretory vesicle lysates, FACScan analysis, laser scanning confocal microscopy of native proteins and fluorescent constructs, and assessment of apoptosis and ERK1/2 pathways. Results: Cleaved, soluble CD95L is expressed at both the RNA and protein levels in these cell lines derived from esophageal adenocarcinoma and other human tissues. CD95L was neither trafficked to the cell membrane nor secreted into the media or within vesicles, rather the protein seems to be sequestered in the cytoplasm. CD95 and CD95L colocalize by immunofluorescence, but an interaction was not proven by immunoprecipitation. Overexpression of CD95L in the adenocarcinoma cell lines induced robust apoptosis and, under conditions of pan-caspase inhibition, resulted in activation of ERK signaling. Conclusions: CD95L localization in EA cells is inconsistent with the conference of immune privilege and is more consistent with a function that promotes tumor growth through alternative CD95 signaling. Reduced cell surface expression of CD95 affects cell sensitivity to extracellular apoptotic signals more significantly than alterations in downstream modulators of apoptosis.

  6. TRAIL-coated lipid-nanoparticles overcome resistance to soluble recombinant TRAIL in non-small cell lung cancer cells

    International Nuclear Information System (INIS)

    De Miguel, Diego; Gallego-Lleyda, Ana; Erviti-Ardanaz, Sandra; Anel, Alberto; Martinez-Lostao, Luis; Ayuso, José María; Fernández, Luis José; Ochoa, Ignacio; Pazo-Cid, Roberto; Del Agua, Celia

    2016-01-01

    Purpose. Non-small cell lung cancer (NSCLC) is one the types of cancer with higher prevalence and mortality. Apo2-Ligand/TRAIL is a TNF family member able to induce apoptosis in tumor cells but not in normal cells. It has been tested in clinical trials against different types of human cancer including NSCLC. However, results of clinical trials have shown a limited efficacy of TRAIL-based therapies. Recently we have demonstrated that artificial lipid nanoparticles coated with bioactive Apo2L/TRAIL (LUV-TRAIL) greatly improved TRAIL cytotoxic ability being capable of killing chemoresistant hematological cancer cells. In the present work we have extended the study to NSCLC. Methods/patients. LUV-TRAIL-induced cytotoxicity was assessed on different NSCLC cell lines with different sensitivity to soluble TRAIL and on primary human tumor cells from three patients suffering from NSCLC cancer. We also tested LUV-TRAIL-cytotoxic ability in combination with several anti-tumor agents. Results. LUV-TRAIL exhibited a greater cytotoxic effect compared to soluble TRAIL both in A549 cells and primary human NSCLC cells. LUV-TRAIL-induced cell death was dependent on caspase-8 and caspase-3 activation. Moreover, combination of LUV-TRAIL with other anti-tumor agents such as flavopiridol, and SNS-032 clearly enhanced LUV-TRAIL-induced cytotoxicity against NSCLC cancer cells. Conclusion. The novel formulation of TRAIL based on displaying it on the surface of lipid nanoparticles greatly increases its anti-tumor activity and has clinical potential in cancer treatment. (paper)

  7. Following the genes that make resistant plants: shared tools for breeding and pathology

    Science.gov (United States)

    Although plant pathology and breeding are distinct disciplines with unique perspectives, they frequently share a common goal: that of identifying and understanding durable resistance, the kind of resistance that will not be overcome quickly and will remain effective against a wide array of isolates....

  8. Genomic dissection of nonhost resistance to wheat stem rust in Brachypodium distachyon

    Science.gov (United States)

    Wheat stem rust caused by the fungus Puccinia graminis f.sp. tritici (Pgt) is a devastating disease that has largely been controlled for decades by the deployment of resistance genes. However, new races of this pathogen have emerged that overcome many important wheat stem rust resistance genes used ...

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

    Science.gov (United States)

    1995-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Amanda Badenhorst

    2016-09-01

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

  11. Identifying and Overcoming Barriers to Diabetes Management in the Elderly: An Intervention Study

    National Research Council Canada - National Science Library

    Munshi, Medha

    2008-01-01

    .... The interventions are now being implemented with help of a geriatric life specialist (GLS). Intervention by GDT includes focused strategies to overcome barriers in the areas of clinical care, education, social environment, and finances...

  12. A rapid seedling resistance assay identifies wild tomato lines that are resistant to Psuedomonas syringe pv. tomato race 1

    Science.gov (United States)

    Bacterial speck caused by Pseudomonas syringae has historically been controlled by the Pto/Prf gene cluster. Emerging strains like P. syringae pv. tomato race 1 overcome resistance conferred by Pto/Prf, and can cause serious crop loss under appropriate environmental conditions. We developed a rapid ...

  13. Animation of Antimicrobial Resistance

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  14. A Structural View on Medicinal Chemistry Strategies against Drug Resistance.

    Science.gov (United States)

    Agnello, Stefano; Brand, Michael; Chellat, Mathieu F; Gazzola, Silvia; Riedl, Rainer

    2018-05-30

    The natural phenomenon of drug resistance represents a generic impairment that hampers the benefits of drugs in all major clinical indications. Antibacterials and antifungals are affected as well as compounds for the treatment of cancer, viral infections or parasitic diseases. Despite the very diverse set of biological targets and organisms involved in the development of drug resistance, underlying molecular processes have been identified to understand the emergence of resistance and to overcome this detrimental mechanism. Detailed structural information of the root causes for drug resistance is nowadays frequently available to design next generation drugs anticipated to suffer less from resistance. This knowledge-based approach is a prerequisite in the fight against the inevitable occurrence of drug resistance to secure the achievements of medicinal chemistry in the future. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Animation of Antimicrobial Resistance

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  16. Insulin Resistance

    DEFF Research Database (Denmark)

    Jensen, Benjamin Anderschou Holbech

    Insulin resistance (IR) is escalating with alarming pace and is no longer restricted to westernized countries. As a forerunner for some of the most serious threats to human health including metabolic syndrome, cardiovascular diseases, and type 2-diabetes, the need for new treatment modalities...... interventions. We further show that improving the inflammatory toning, using fish oil as fat source, protects mice against diet induced obesity and -inflammation while preserving insulin sensitivity, even in the absence of free fatty acid receptor 4. Conversely, HFD-induced intestinal dysbiosis is associated...

  17. Development of virulence to Meloidogyne incognita on resistant pepper rootstocks

    Energy Technology Data Exchange (ETDEWEB)

    Ros-Ibanez, C.; Robertson, L.; Martinez-Lluch, M. C.; Cano-Garcia, A.; Lacasa-Plasencia, A.

    2014-06-01

    The root-knot nematode (RKN) Meloidogyne incognita is a major soil parasite of pepper crops in greenhouses in Southeast Spain. Due to the limitations of the use of soil fumigants, grafting plants on resistant rootstocks (R-rootstocks) has become an important alternative to chemical nematicides. The repeated use of R-rootstocks can bring about the selection of virulent populations capable of overcoming resistance. We carried out a six-year investigation on resistant rootstocks in a naturally M. incognita infested greenhouse, and found that two successive years of growing plants grafted on R-rootstocks Atlante (ATL) were sufficient to overcome resistance (galling index 1.5 and 5.6 in the first and second years respectively). A large variability was observed between several R-rootstocks. Two R-rootstocks (C19 and Snooker) behaved like ATL while two others (Terrano and DRO 8801) were not infected by RKN. Laboratory studies with the same R-rootstocks, inoculated with two nematode isolates (avirulent and virulent against ATL) confirmed the greenhouse results, indicating that some rootstocks may be infested by virulent populations and others may not. It suggests that different R-genes, which are differentially overcome by RKN, have been introgressed into the rootstocks. This may have consequences for the management of resistant rootstocks in the field. (Author)

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