Sample records for cd2019 overcomes inhibition

  1. A retinoic acid receptor beta agonist (CD2019) overcomes inhibition of axonal outgrowth via phosphoinositide 3-kinase signalling in the injured adult spinal cord. (United States)

    Agudo, Marta; Yip, Ping; Davies, Meirion; Bradbury, Elizabeth; Doherty, Patrick; McMahon, Stephen; Maden, Malcolm; Corcoran, Jonathan P T


    After spinal cord injury in the adult mammal, axons do not normally regrow and this commonly leads to paralysis. Retinoic acid (RA) can stimulate neurite outgrowth in vitro of both the embryonic central and peripheral nervous system, via activation of the retinoic acid receptor (RAR) beta2. We show here that regions of the adult CNS, including the cerebellum and cerebral cortex, express RARbeta2. We show that when cerebellar neurons are grown in the presence of myelin-associated glycoprotein (MAG) which inhibits neurite outgrowth, RARbeta can be activated in a dose dependent manner by a RARbeta agonist (CD2019) and neurite outgrowth can occur via phosphoinositide 3-kinase (PI3K) signalling. In a model of spinal cord injury CD2019 also acts through PI3K signalling to induce axonal outgrowth of descending corticospinal fibres and promote functional recovery. Our data suggest that RARbeta agonists may be of therapeutic potential for human spinal cord injuries.

  2. Inhibition of autophagy overcomes glucocorticoid resistance in lymphoid malignant cells. (United States)

    Jiang, Lei; Xu, Lingzhi; Xie, Jiajun; Li, Sisi; Guan, Yanchun; Zhang, Yan; Hou, Zhijie; Guo, Tao; Shu, Xin; Wang, Chang; Fan, Wenjun; Si, Yang; Yang, Ya; Kang, Zhijie; Fang, Meiyun; Liu, Quentin


    Glucocorticoid (GC) resistance remains a major obstacle to successful treatment of lymphoid malignancies. Till now, the precise mechanism of GC resistance remains unclear. In the present study, dexamethasone (Dex) inhibited cell proliferation, arrested cell cycle in G0/G1-phase, and induced apoptosis in Dex-sensitive acute lymphoblastic leukemia cells. However, Dex failed to cause cell death in Dex-resistant lymphoid malignant cells. Intriguingly, we found that autophagy was induced by Dex in resistant cells, as indicated by autophagosomes formation, LC3-I to LC3-II conversion, p62 degradation, and formation of acidic autophagic vacuoles. Moreover, the results showed that Dex reduced the activity of mTOR pathway, as determined by decreased phosphorylation levels of mTOR, Akt, P70S6K and 4E-BP1 in resistant cells. Inhibition of autophagy by either chloroquine (CQ) or 3-methyladenine (3-MA) overcame Dex-resistance in lymphoid malignant cells by increasing apoptotic cell death in vitro. Consistently, inhibition of autophagy by stably knockdown of Beclin1 sensitized Dex-resistant lymphoid malignant cells to induction of apoptosis in vivo. Thus, inhibition of autophagy has the potential to improve lymphoid malignancy treatment by overcoming GC resistance.

  3. Overcoming inhibition in real-time diagnostic PCR. (United States)

    Hedman, Johannes; Rådström, Peter


    PCR is an important and powerful tool in several fields, including clinical diagnostics, food analysis, and forensic analysis. In theory, PCR enables the detection of one single cell or DNA molecule. However, the presence of PCR inhibitors in the sample affects the amplification efficiency of PCR, thus lowering the detection limit, as well as the precision of sequence-specific nucleic acid quantification in real-time PCR. In order to overcome the problems caused by PCR inhibitors, all the steps leading up to DNA amplification must be optimized for the sample type in question. Sampling and sample treatment are key steps, but most of the methods currently in use were developed for conventional diagnostic methods and not for PCR. Therefore, there is a need for fast, simple, and robust sample preparation methods that take advantage of the accuracy of PCR. In addition, the thermostable DNA polymerases and buffer systems used in PCR are affected differently by inhibitors. During recent years, real-time PCR has developed considerably and is now widely used as a diagnostic tool. This technique has greatly improved the degree of automation and reduced the analysis time, but has also introduced a new set of PCR inhibitors, namely those affecting the fluorescence signal. The purpose of this chapter is to view the complexity of PCR inhibition from different angles, presenting both molecular explanations and practical ways of dealing with the problem. Although diagnostic PCR brings together scientists from different diagnostic fields, end-users have not fully exploited the potential of learning from each other. Here, we have collected knowledge from archeological analysis, clinical diagnostics, environmental analysis, food analysis, and forensic analysis. The concept of integrating sampling, sample treatment, and the chemistry of PCR, i.e., pre-PCR processing, will be addressed as a general approach to overcoming real-time PCR inhibition and producing samples optimal for PCR

  4. Aerobic Linear Allylic C-H Amination: Overcoming Benzoquinone Inhibition. (United States)

    Pattillo, Christopher C; Strambeanu, Iulia I; Calleja, Pilar; Vermeulen, Nicolaas A; Mizuno, Tomokazu; White, M Christina


    An efficient aerobic linear allylic C-H amination reaction is reported under palladium(II)/bis-sulfoxide/Brønsted base catalysis. The reaction operates under preparative, operationally simple conditions (1 equiv of olefin, 1 atm O2 or air) with reduced Pd(II)/bis-sulfoxide catalyst loadings while providing higher turnovers and product yields than systems employing stoichiometric benzoquinone (BQ) as the terminal oxidant. Pd(II)/BQ π-acidic interactions have been invoked in various catalytic processes and are often considered beneficial in promoting reductive functionalizations. When such electrophilic activation for functionalization is not needed, however, BQ at high concentrations may compete with crucial ligand (bis-sulfoxide) binding and inhibit catalysis. Kinetic studies reveal an inverse relationship between the reaction rate and the concentration of BQ, suggesting that BQ is acting as a ligand for Pd(II) which results in an inhibitory effect on catalysis.

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

    Hartley, Carolyn Copps


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

  6. A Chemical Screen Identifies Novel Compounds That Overcome Glial-Mediated Inhibition Of Neuronal Regeneration (United States)

    Usher, Lynn C.; Johnstone, Andrea; Ertürk, Ali; Hu, Ying; Strikis, Dinara; Wanner, Ina B.; Moorman, Sanne; Lee, Jae-Wook; Min, Jaeki; Ha, Hyung-Ho; Duan, Yuanli; Hoffman, Stanley; Goldberg, Jeffrey L.; Bradke, Frank; Chang, Young-Tae; Lemmon, Vance P.; Bixby, John L.


    A major barrier to regeneration of central nervous system (CNS) axons is the presence of growth-inhibitory proteins associated with myelin and the glial scar. To identify chemical compounds with the ability to overcome the inhibition of regeneration, we screened a novel triazine library, based on the ability of compounds to increase neurite outgrowth from cerebellar neurons on inhibitory myelin substrates. The screen produced 4 “hit compounds”, which act with nM potency on several different neuronal types, and on several distinct substrates relevant to glial inhibition. Moreover, the compounds selectively overcome inhibition rather than promote growth in general. The compounds do not affect neuronal cAMP levels, PKC activity, or EGFR activation. Interestingly, one of the compounds alters microtubule dynamics and increases microtubule density in both fibroblasts and neurons. This same compound promotes regeneration of dorsal column axons after acute lesions, and potentiates regeneration of optic nerve axons after nerve crush in vivo. These compounds should provide insight into the mechanisms through which glial-derived inhibitors of regeneration act, and could lead to the development of novel therapies for CNS injury. PMID:20357120

  7. WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance (United States)

    Zheng, Hongping; Shao, Fangyuan; Martin, Scots; Xu, Xiaoling; Deng, Chu-Xia


    Cisplatin is one of the most commonly used therapeutic drugs for cancer therapy, yet prolonged cisplatin treatment frequently results in drug resistance. To enhance therapeutic effect of cisplatin, we conducted a high throughput screening using a kinase library containing 704 kinases against triple negative breast cancer (TNBC) cells. We demonstrated that cisplatin activates ATR, CHK1 and WEE1, which shut down DNA replication and attenuate cisplatin induced-lethality. WEE1 inhibition sensitizes TNBCs and cisplatin resistant cancer cells to cisplatin-induced lethality, because it not only impairs DNA replication checkpoint more profoundly than inhibition of ATR or CHK1, but also defects G2-M cell cycle checkpoint. Finally, we demonstrated that combined cisplatin treatment and WEE1 inhibition synergistically inhibits xenograft cancer growth accompanied by markedly reduced expression of TNBC signature genes. Thus targeting DNA replication and G2-M cell cycle checkpoint simultaneously by cisplatin and WEE1 inhibition is promising for TNBCs treatment, and for overcoming their cisplatin resistance. PMID:28262781

  8. WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance. (United States)

    Zheng, Hongping; Shao, Fangyuan; Martin, Scots; Xu, Xiaoling; Deng, Chu-Xia


    Cisplatin is one of the most commonly used therapeutic drugs for cancer therapy, yet prolonged cisplatin treatment frequently results in drug resistance. To enhance therapeutic effect of cisplatin, we conducted a high throughput screening using a kinase library containing 704 kinases against triple negative breast cancer (TNBC) cells. We demonstrated that cisplatin activates ATR, CHK1 and WEE1, which shut down DNA replication and attenuate cisplatin induced-lethality. WEE1 inhibition sensitizes TNBCs and cisplatin resistant cancer cells to cisplatin-induced lethality, because it not only impairs DNA replication checkpoint more profoundly than inhibition of ATR or CHK1, but also defects G2-M cell cycle checkpoint. Finally, we demonstrated that combined cisplatin treatment and WEE1 inhibition synergistically inhibits xenograft cancer growth accompanied by markedly reduced expression of TNBC signature genes. Thus targeting DNA replication and G2-M cell cycle checkpoint simultaneously by cisplatin and WEE1 inhibition is promising for TNBCs treatment, and for overcoming their cisplatin resistance.

  9. Sorafenib overcomes irinotecan resistance in colorectal cancer by inhibiting the ABCG2 drug-efflux pump. (United States)

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


    Despite recent advances in the treatment of colorectal cancer (CRC), tumor resistance is a frequent cause of chemotherapy failure. Therefore, new treatment options are needed to improve survival of patients with irinotecan-refractory CRCs, particularly those bearing KRAS mutations that preclude the use of anti-EGFR therapies. In this study, we investigated whether sorafenib could reverse irinotecan resistance, thereby enhancing the therapeutic efficacy of routinely used irinotecan-based chemotherapy. We used both in vitro (the HCT116, SW48, SW620, and HT29 colon adenocarcinoma cell lines and four SN-38-resistant HCT-116 and SW48 clones) and in vivo models (nude mice xenografted with SN-38-resistant HCT116 cells) to test the efficacy of sorafenib alone or in combination with irinotecan or its active metabolite, SN-38. We have shown that sorafenib improved the antitumoral activity of irinotecan in vitro, in both parental and SN-38-resistant colon adenocarcinoma cell lines independently of their KRAS status, as well as in vivo, in xenografted mice. By inhibiting the drug-efflux pump ABCG2, sorafenib favors irinotecan intracellular accumulation and enhances its toxicity. Moreover, we found that sorafenib improved the efficacy of irinotecan by inhibiting the irinotecan-mediated p38 and ERK activation. In conclusion, our results show that sorafenib can suppress resistance to irinotecan and suggest that sorafenib could be used to overcome resistance to irinotecan-based chemotherapies in CRC, particularly in KRAS-mutated tumors.

  10. Arsenite-loaded nanoparticles inhibit PARP-1 to overcome multidrug resistance in hepatocellular carcinoma cells (United States)

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


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

  11. Histone deacetylase inhibition overcomes drug resistance through a miRNA-dependent mechanism. (United States)

    Murray-Stewart, Tracy; Hanigan, Christin L; Woster, Patrick M; Marton, Laurence J; Casero, Robert A


    The treatment of specific tumor cell lines with poly- and oligoamine analogs results in a superinduction of polyamine catabolism that is associated with cytotoxicity; however, other tumor cells show resistance to analog treatment. Recent data indicate that some of these analogs also have direct epigenetic effects. We, therefore, sought to determine the effects of combining specific analogs with an epigenetic targeting agent in phenotypically resistant human lung cancer cell lines. We show that the histone deacetylase inhibitor MS-275, when combined with (N(1), N(11))-bisethylnorspermine (BENSpm) or (N(1), N(12))-bis(ethyl)-cis-6,7-dehydrospermine tetrahydrochloride (PG-11047), synergistically induces the polyamine catabolic enzyme spermidine/spermine N(1)-acetyltransferase (SSAT), a major determinant of sensitivity to the antitumor analogs. Evidence indicates that the mechanism of this synergy includes reactivation of miR-200a, which targets and destabilizes kelch-like ECH-associated protein 1 (KEAP1) mRNA, resulting in the translocation and binding of nuclear factor (erythroid-derived 2)-like 2 (NRF2) to the polyamine-responsive element of the SSAT promoter. This transcriptional stimulation, combined with positive regulation of SSAT mRNA and protein by the analogs, results in decreased intracellular concentrations of natural polyamines and growth inhibition. The finding that an epigenetic targeting agent is capable of inducing a rate-limiting step in polyamine catabolism to overcome resistance to the antitumor analogs represents a completely novel chemotherapeutic approach. In addition, this is the first demonstration of miRNA-mediated regulation of the polyamine catabolic pathway. Furthermore, the individual agents used in this study have been investigated clinically; therefore, translation of these combinations into the clinical setting holds promise.

  12. Salmonella overcomes tumor immune tolerance by inhibition of tumor indoleamine 2, 3-dioxygenase 1 expression. (United States)

    Kuan, Yu-Diao; Lee, Che-Hsin


    Over the past decades, Salmonella has been proven capable of inhibiting tumor growth. It can specifically target tumors and due to its facultative anaerobic property, can be more penetrative than other drug therapies. However, the molecular mechanism by which Salmonella inhibits tumor growth is still incompletely known. The antitumor therapeutic effect mediated by Salmonella is associated with an inflammatory immune response at the tumor site and a T cell-dependent immune response. Many tumors have been proven to have a high expression of indoleamine 2, 3-dioxygenase 1 (IDO), which is a rate-limiting enzyme that catalyzes tryptophan to kynurenine, thus causing immune tolerance within the tumor microenvironment. With decreased expression of IDO, increased immune response can be observed, which might be helpful when developing cancer immunotherapy. The expression of IDO was decreased after tumor cells were infected with Salmonella. In addition, Western blot analysis showed that the expression levels of phospho-protein kinase B (P-AKT), phospho-mammalian targets of rapamycin (P-mTOR), and phospho-p70 ribosomal s6 kinase (P-p70s6K) in tumor cells were decreased after Salmonella infection. In conclusion, our results indicate that Salmonella inhibits IDO expression and plays a crucial role in anti-tumor therapy, which might be a promising strategy combined with other cancer treatments.

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

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    Xiaocong Yu


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

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


    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. PMID:28134290

  15. Overcoming paclitaxel resistance in lung cancer cells via dual inhibition of stathmin and Bcl-2. (United States)

    Han, Zheng-Xiang; Wang, Hong-Mei; Jiang, Guan; Du, Xiu-Ping; Gao, Xiang-Yang; Pei, Dong-Sheng


    Lung cancer is the leading cause of death from malignancy in people and over 85% of these patients eventually die from disseminated disease. Paclitaxel (TAX) is widely used as an antimicrotubule agent for the treatment of lung cancer. Unfortunately, the resistance to this antimicrotubule agent occurs frequently. Stathmin (STMN1) is a ubiquitous microtubule destabilizing protein linked to cancer and cell health and its expression level often correlates with cancer stage progression and prognosis for survival. Overexpression of the antiapoptotic protein Bcl-2 has been shown to prolong drug-induced growth arrest, potentially inducing resistance. In this study, we used a short hairpin RNA (shRNA) approach to evaluate the effect of STMN1 and Bcl-2 downregulation in the sensitivity to TAX in lung cancer cells. We achieved significant downregulation of STMN1 and Bcl-2 mRNA and protein expression by a combination of double shRNA treatment strategy. Our experimental data showed that inhibition of STMN1 and Bcl-2 expression with RNA interference can sensitize lung cancer cells to TAX. These findings suggest a novel approach to improve the efficacy of certain antimicrotubule agents against lung cancer by regulating the function of STMN1 and Bcl-2.

  16. 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.

  17. Overcoming resistance of targeted EGFR monotherapy by inhibition of STAT3 escape pathway in soft tissue sarcoma (United States)

    Wang, Xiaochun; Goldstein, David; Crowe, Philip J.; Yang, Mark; Garrett, Kerryn; Zeps, Nikolajs; Yang, Jia-Lin


    Although epidermal growth factor receptor (EGFR) is often over-expressed in soft tissue sarcoma (STS), a phase II trial using an EGFR inhibitor gefitinib showed a low response rate. This study identified a new secondary resistance mechanism of gefitinib in STS, and developed new strategies to improve the effectiveness of EGFR inhibition particularly by blocking the STAT3 pathway. We demonstrated that seven STS cell lines of diverse histological origin showed resistance to gefitinib despite blockade of phosphorylated EGFR (pEGFR) and downstream signal transducers (pAKT and pERK) in PI3K/AKT and RAS/ERK pathways. Gefitinib exposure was not associated with decrease in the ratio of pSTAT3/pSTAT1. The relative STAT3 abundance and activation may be responsible for the drug resistance. We therefore hypothesized that the addition of a STAT3 inhibitor could overcome the STAT3 escape pathway. We found that the addition of STAT3 inhibitor S3I-201 to gefitinib achieved synergistic anti-proliferative and pro-apoptotic effects in all three STS cell lines examined. This was confirmed in a fibrosarcoma xenografted mouse model, where the tumours from the combination group (418mm3) were significantly smaller than those from untreated (1032mm3) or single drug (912 and 798mm3) groups. Our findings may have clinical implications for optimising EGFR-targeted therapy in STS. PMID:26909593

  18. Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism-Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer. (United States)

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


    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; 1-11. ©2016 AACR.

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

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    Balart Luis A


    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.

  20. Combined therapy with RAD001 e BEZ235 overcomes resistance of PET immortalized cell lines to mTOR inhibition. (United States)

    Passacantilli, Ilaria; Capurso, Gabriele; Archibugi, Livia; Calabretta, Sara; Caldarola, Sara; Loreni, Fabrizio; Delle Fave, Gianfranco; Sette, Claudio


    Pancreatic endocrine tumors (PETs) are characterised by an indolent behaviour in terms of tumor growth. However, most patients display metastasis at diagnosis and no cure is currently available. Since the PI3K/AKT/mTOR axis is deregulated in PETs, the mTOR inhibitor RAD001 represents the first line treatment. Nevertheless, some patients do not respond to treatments and most acquire resistance. Inhibition of mTOR leads to feedback re-activation of PI3K activity, which may promote resistance to RAD001. Thus, PI3K represents a novel potential target for PETs. We tested the impact of three novel PI3K inhibitors (BEZ235, BKM120 and BYL719) on proliferation of PET cells that are responsive (BON-1) or unresponsive (QGP-1) to RAD001. BEZ235 was the most efficient in inhibiting proliferation in PET cells. Furthermore, combined treatment with BEZ235 and RAD001 exhibited synergic effects and was also effective in BON-1 that acquired resistance to RAD001 (BON-1 RR). Analysis of PI3K/AKT/mTOR pathway showed that RAD001 and BEZ235 only partially inhibited mTOR-dependent phosphorylation of 4EBP1. By contrast, combined therapy with the two inhibitors strongly inhibited phosphorylation of 4EBP1, assembly of the translational initiation complex and protein synthesis. Thus, combined treatment with BEZ235 may represent suitable therapy to counteract primary and acquired resistance to RAD001 in PETs.

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

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    Minyong Kang


    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

  2. Combined therapy with RAD001 e BEZ235 overcomes resistance of PET immortalized cell lines to mTOR inhibition



    Pancreatic endocrine tumors (PETs) are characterised by an indolent behaviour in terms of tumor growth. However, most patients display metastasis at diagnosis and no cure is currently available. Since the PI3K/AKT/mTOR axis is deregulated in PETs, the mTOR inhibitor RAD001 represents the first line treatment. Nevertheless, some patients do not respond to treatments and most acquire resistance. Inhibition of mTOR leads to feedback re-activation of PI3K activity, which may promote resistance to...

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

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    Nadia Bakkour


    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.

  4. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells. (United States)

    Kwok, Marwan; Davies, Nicholas; Agathanggelou, Angelo; Smith, Edward; Oldreive, Ceri; Petermann, Eva; Stewart, Grant; Brown, Jeff; Lau, Alan; Pratt, Guy; Parry, Helen; Taylor, Malcolm; Moss, Paul; Hillmen, Peter; Stankovic, Tatjana


    TP53 and ataxia telangiectasia mutated (ATM) defects are associated with genomic instability, clonal evolution, and chemoresistance in chronic lymphocytic leukemia (CLL). Currently, therapies capable of providing durable remissions in relapsed/refractory TP53- or ATM-defective CLL are lacking. Ataxia telangiectasia and Rad3-related (ATR) mediates response to replication stress, the absence of which leads to collapse of stalled replication forks into chromatid fragments that require resolution through the ATM/p53 pathway. Here, using AZD6738, a novel ATR kinase inhibitor, we investigated ATR inhibition as a synthetically lethal strategy to target CLL cells with TP53 or ATM defects. Irrespective of TP53 or ATM status, induction of CLL cell proliferation upregulated ATR protein, which then became activated in response to replication stress. In TP53- or ATM-defective CLL cells, inhibition of ATR signaling by AZD6738 led to an accumulation of unrepaired DNA damage, which was carried through into mitosis because of defective cell cycle checkpoints, resulting in cell death by mitotic catastrophe. Consequently, AZD6738 was selectively cytotoxic to both TP53- and ATM-defective CLL cell lines and primary cells. This was confirmed in vivo using primary xenograft models of TP53- or ATM-defective CLL, where treatment with AZD6738 resulted in decreased tumor load and reduction in the proportion of CLL cells with such defects. Moreover, AZD6738 sensitized TP53- or ATM-defective primary CLL cells to chemotherapy and ibrutinib. Our findings suggest that ATR is a promising therapeutic target for TP53- or ATM-defective CLL that warrants clinical investigation.

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

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


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

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    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: [Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan, 602-714 (Korea, Republic of)


    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

  7. Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line. (United States)

    Sheng, Xianfu; Zhong, Hua; Wan, Haixia; Zhong, Jihua; Chen, Fangyuan


    Combining cytarabine, aclarubicin and granulocyte colony-stimulating factor (G-CSF) has demonstrated marked efficacy in the treatment of elderly and relapsed/refractory patients with acute myeloid leukemia (AML); however, the role of G-CSF remains poorly understood. The present study aimed to investigate the ability of G-CSF to overcome stromal-mediated drug resistance and the underlying molecular mechanism. Two types of co-culture models were established in the HS-5 human bone marrow/stromal and HL-60 human promyelocytic leukemia cell lines, in order to imitate the interactions between stromal and leukemia cells in vitro, which is mediated by the stromal cell-derived factor (SDF)-1α signaling axis. In the present study, HL-60 cells were attracted and adhered to HS-5 cells using migration assay and flow cytometry, respectively; however, these interactions were inhibited by treatment with G-CSF and/or the C-X-C chemokine receptor type 4 (CXCR4) antagonist, AMD3100. Co-culture with HS-5 cells, including direct and indirect contact, protected HL-60 cells against spontaneous apoptosis or drug-induced apoptosis; however, these protective effects were disrupted by treatment with G-CSF and/or AMD3100. Notably, G-CSF and/or AMD3100 did not alter cell viability or apoptosis when HL-60 cells were cultured with medium alone. In addition, G-CSF significantly reduced the expression levels of surface CXCR4 protein, total CXCR4 protein and CXCR4 mRNA, and significantly upregulated the expression of microRNA (miR)-146a. Conversely, AMD3100 significantly reduced surface CXCR4 expression levels, but not the total CXCR4, CXCR4 mRNA or miR-146a expression levels. The results of the present study suggested that interfering with the CXCR4/SDF-1α signaling axis via G-CSF inhibited the migration and adhesion of HL-60 cells to HS-5 cells and eliminated HS5 cell-mediated protective effects. Furthermore, G-CSF administration reduced CXCR4 expression levels by upregulating the expression of

  8. Overcoming resistance to molecularly targeted anticancer therapies: Rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies. (United States)

    Tortora, Giampaolo; Bianco, Roberto; Daniele, Gennaro; Ciardiello, Fortunato; McCubrey, James A; Ricciardi, Maria Rosaria; Ciuffreda, Ludovica; Cognetti, Francesco; Tafuri, Agostino; Milella, Michele


    Accumulating evidence suggests that cancer can be envisioned as a "signaling disease", in which alterations in the cellular genome affect the expression and/or function of oncogenes and tumour suppressor genes. This ultimately disrupts the physiologic transmission of biochemical signals that normally regulate cell growth, differentiation and programmed cell death (apoptosis). From a clinical standpoint, signal transduction inhibition as a therapeutic strategy for human malignancies has recently achieved remarkable success. However, as additional drugs move forward into the clinical arena, intrinsic and acquired resistance to "targeted" agents becomes an issue for their clinical utility. One way to overcome resistance to targeted agents is to identify genetic and epigenetic aberrations underlying sensitivity/resistance, thus enabling the selection of patients that will most likely benefit from a specific therapy. Since resistance often ensues as a result of the concomitant activation of multiple, often overlapping, signaling pathways, another possibility is to interfere with multiple, cross-talking pathways involved in growth and survival control in a rational, mechanism-based, fashion. These concepts may be usefully applied, among others, to agents that target two major signal transduction pathways: the one initiated by epidermal growth factor receptor (EGFR) signaling and the one converging on mitogen-activated protein kinase (MAPK) activation. Here, we review the molecular mechanisms of sensitivity/resistance to EGFR inhibitors, as well as the rationale for combining them with other targeted agents, in an attempt to overcome resistance. In the second part of the paper, we review MAPK-targeted agents, focusing on their therapeutic potential in haematologic malignancies, and examine the prospects for combinations of MAPK inhibitors with cytotoxic agents or other signal transduction-targeted agents to obtain synergistic anti-tumour effects.

  9. The RARgamma selective agonist CD437 inhibits gastric cell growth through the mechanism of apoptosis. (United States)

    Jiang, S Y; Lin, D Y; Shyu, R Y; Reichert, U; Yeh, M Y


    Retinoids are differentiation-inducing agents that exhibit multiple functions. Their activities are mediated through interaction with nuclear retinoic acid receptors (RAR) and retinoid X receptors (RXR). We have investigated the activities of synthetic retinoids on the growth of five gastric cancer cell lines. The effects of agonists selective for RARalpha, RARbeta and RARgamma (AM580, CD2019 and CD437, respectively) on cell growth were determined, in comparison to all-trans retinoic acid, by measuring total cellular DNA. AM580 and CD2019 had little or no effect on the growth of all five cell lines. In contrast, the RARgamma agonist CD437 inhibited cell growth up to 90-99% in both retinoic acid sensitive and resistant gastric cancer cells at a concentration of 1 microM. The growth suppression caused by CD437 was accompanied by the induction of apoptosis as judged by morphological criteria and DNA ladder formation. However, the extent of CD437-induced growth suppression was not correlated with RARgamma mRNA levels, which indicates that CD437 induces apoptosis in gastric cancer cells via an RARgamma independent pathway.

  10. Synergistic effect of folate-mediated targeting and verapamil-mediated P-gp inhibition with paclitaxel -polymer micelles to overcome multi-drug resistance. (United States)

    Wang, Feihu; Zhang, Dianrui; Zhang, Qiang; Chen, Yuxuan; Zheng, Dandan; Hao, Leilei; Duan, Cunxian; Jia, Lejiao; Liu, Guangpu; Liu, Yue


    Multidrug resistance (MDR) in tumor cells is a significant obstacle for successful cancer chemotherapy. Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) is a key factor contributing to the development of tumor drug resistance. Verapamil (VRP), a P-gp inhibitor, has been reported to be able to reverse completely the resistance caused by P-gp. For optimal synergy, the drug and inhibitor combination may need to be temporally colocalized in the tumor cells. Herein, we investigated the effectiveness of simultaneous and targeted delivery of anticancer drug, paclitaxel (PTX), along with VRP, using DOMC-FA micelles to overcome tumor drug resistance. The floate-functionalized dual agent loaded micelles resulted in the similar cytotoxicity to PTX-loaded micelles/free VRP combination and co-administration of two single-agent loaded micelles, which was higher than that of PTX-loaded micelles. Enhanced therapeutic efficacy of dual agent micelles could be ascribe to increased accumulation of PTX in drug-resistant tumor cells. We suggest that the synergistic effect of folate receptor-mediated internalization and VRP-mediated overcoming MDR could be beneficial in treatment of MDR solid tumors by targeting delivery of micellar PTX into tumor cells. As a result, the difunctional micelle systems is a very promising approach to overcome tumor drug resistance.

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

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    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)


    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.

  12. SIRT1-mediated downregulation of p27Kip1 is essential for overcoming contact inhibition of Kaposi's sarcoma-associated herpesvirus transformed cells. (United States)

    He, Meilan; Yuan, Hongfeng; Tan, Brandon; Bai, Rosemary; Kim, Heon Seok; Bae, Sangsu; Che, Lu; Kim, Jin-Soo; Gao, Shou-Jiang


    Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus associated with Kaposi's sarcoma (KS), a malignancy commonly found in AIDS patients. Despite intensive studies in the last two decades, the mechanism of KSHV-induced cellular transformation and tumorigenesis remains unclear. In this study, we found that the expression of SIRT1, a metabolic sensor, was upregulated in a variety of KSHV-infected cells. In a model of KSHV-induced cellular transformation, SIRT1 knockdown with shRNAs or knockout by CRISPR/Cas9 gene editing dramatically suppressed cell proliferation and colony formation in soft agar of KSHV-transformed cells by inducing cell cycle arrest and contact inhibition. SIRT1 knockdown or knockout induced the expression of cyclin-dependent kinase inhibitor 1B (p27Kip1). Consequently, p27 knockdown rescued the inhibitory effect of SIRT1 knockdown or knockout on cell proliferation and colony formation. Furthermore, treatment of KSHV-transformed cells with a SIRT1 inhibitor, nicotinamide (NAM), had the same effect as SIRT1 knockdown and knockout. NAM significantly inhibited cell proliferation in culture and colony formation in soft agar, and induced cell cycle arrest. Significantly, NAM inhibited the progression of tumors and extended the survival of mice in a KSHV-induced tumor model. Collectively, these results demonstrate that SIRT1 suppression of p27 is required for KSHV-induced tumorigenesis and identify a potential therapeutic target for KS.

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

    Directory of Open Access Journals (Sweden)

    Michiro Susa

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

  14. Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways. (United States)

    Gunda, V; Bucur, O; Varnau, J; Vanden Borre, P; Bernasconi, M J; Khosravi-Far, R; Parangi, S


    Current treatment for recurrent and aggressive/anaplastic thyroid cancers is ineffective. Novel targeted therapies aimed at the inhibition of the mutated oncoprotein BRAF(V600E) have shown promise in vivo and in vitro but do not result in cellular apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner by activating the extrinsic apoptotic pathway. Here, we show that a TRAIL-R2 agonist antibody, lexatumumab, induces apoptosis effectively in some thyroid cancer cell lines (HTh-7, TPC-1 and BCPAP), while more aggressive anaplastic cell lines (8505c and SW1736) show resistance. Treatment of the most resistant cell line, 8505c, using lexatumumab in combination with the BRAF(V600E) inhibitor, PLX4720, and the PI3K inhibitor, LY294002, (triple-drug combination) sensitizes the cells by triggering both the extrinsic and intrinsic apoptotic pathways in vitro as well as 8505c orthotopic thyroid tumors in vivo. A decrease in anti-apoptotic proteins, pAkt, Bcl-xL, Mcl-1 and c-FLIP, coupled with an increase in the activator proteins, Bax and Bim, results in an increase in the Bax to Bcl-xL ratio that appears to be critical for sensitization and subsequent apoptosis of these resistant cells. Our results suggest that targeting the death receptor pathway in thyroid cancer can be a promising strategy for inducing apoptosis in thyroid cancer cells, although combination with other kinase inhibitors may be needed in some of the more aggressive tumors initially resistant to apoptosis.

  15. Hypochlorous Acid as a Potential Wound Care Agent: Part II. Stabilized Hypochlorous Acid: Its Role in Decreasing Tissue Bacterial Bioburden and Overcoming the Inhibition of Infection on Wound Healing. (United States)

    Robson, Martin C; Payne, Wyatt G; Ko, Francis; Mentis, Marni; Donati, Guillermo; Shafii, Susan M; Culverhouse, Susan; Wang, Lu; Khosrovi, Behzad; Najafi, Ramin; Cooper, Diane M; Bassiri, Mansour


    Background: A topical antimicrobial that can decrease the bacterial bioburden of chronic wounds without impairing the wound's ability to heal is a therapeutic imperative. A stabilized form of hypochlorous acid (NVC-101) has been demonstrated in vitro and in standard toxicity testing to possess properties that could fulfill these criteria. Materials and Methods: Using a standard rodent model of a chronically infected granulating wound, various preparations of NVC-101 and multiple treatment regimens were investigated to evaluate the role of NVC-101 in decreasing tissue bacterial bioburden and overcoming the inhibition of infection on wound healing. Quantitative bacteriology of tissue biopsies and wound healing trajectories were used to compare the various NVC-101 preparations and regimens to saline-treated negative controls and silver sulfadiazine-treated positive controls. Results: NVC-101 at 0.01% hypochlorous acid with a pH of 3.5 to 4.0 proved to be an effective topical antimicrobial. It was most effective when used for a brief period (15-30 minutes), and followed with another application. Possibly this was due to its rapid neutralization in the wound bed environment. Although not as effective at decreasing the tissue bacterial bioburden as silver sulfadiazine, NVC-101 was associated with improved wound closure. Conclusions: This stabilized form of hypochlorous acid (NVC-101) could have potential application as an antimicrobial wound irrigation and treatment solution if its effective pH range can be maintained in the clinical situation. NVC-101 solution was equally effective at pH 3.5 or 4.0 and more efficient soon after its application. As opposed to other antimicrobials investigated in this animal model, NVC-101 controls the tissue bacterial bioburden without inhibiting the wound healing process.

  16. Overcoming the Polyester Image. (United States)

    Regan, Dorothy


    Urges community colleges to overcome their image problem by documenting the colleges' impact on their communities. Suggests ways to determine what data should be collected, how to collect the information, and how it can be used to empower faculty, staff, and alumni to change the institution's image. (DMM)

  17. Overcoming resistance to change. (United States)

    McKay, L


    The pace of change in health care organizations challenges nursing administrators at all levels of management to be effective change agents. As resistance is an inevitable element in the process of planned change, inclusion of interventions to overcome resistance is critical to the change agent role. The author presents five theoretically-based strategies for reducing the levels of resistance to planned change.

  18. Cleanroom laboratory challenge overcome. (United States)

    Quinn, Ronan


    Ronan Quinn, managing director of interior construction specialist Ardmac, describes the challenges of building and fitting out a new cleanroom laboratory for blood and bone marrow therapeutic treatment at Our Lady's Children's Hospital Crumlin in Dublin. The "state-of-the-art" facility, which fully complies with the recent EU Directive concerning human tissues and cells, has been well received by the client and end-users alike, but, as he explains, there were many obstacles to overcome during its completion.

  19. 3-(Benzo[d][1,3]dioxol-5-ylamino)-N-(4-fluorophenyl)thiophene-2-carboxamide overcomes cancer chemoresistance via inhibition of angiogenesis and P-glycoprotein efflux pump activity. (United States)

    Mudududdla, Ramesh; Guru, Santosh K; Wani, Abubakar; Sharma, Sadhana; Joshi, Prashant; Vishwakarma, Ram A; Kumar, Ajay; Bhushan, Shashi; Bharate, Sandip B


    3-((Quinolin-4-yl)methylamino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2-carboxamide (OSI-930, 1) is a potent inhibitor of c-kit and VEGFR2, currently under phase I clinical trials in patients with advanced solid tumors. In order to understand the structure-activity relationship, a series of 3-arylamino N-aryl thiophene 2-carboxamides were synthesized by modifications at both quinoline and amide domains of the OSI-930 scaffold. All the synthesized compounds were screened for in vitro cytotoxicity in a panel of cancer cell lines and for VEGFR1 and VEGFR2 inhibition. Thiophene 2-carboxamides substituted with benzo[d][1,3]dioxol-5-yl and 2,3-dihydrobenzo[b][1,4]dioxin-6-yl groups 1l and 1m displayed inhibition of VEGFR1 with IC50 values of 2.5 and 1.9 μM, respectively. Compounds 1l and 1m also inhibited the VEGF-induced HUVEC cell migration, indicating its anti-angiogenic activity. OSI-930 along with compounds 1l and 1m showed inhibition of P-gp efflux pumps (MDR1, ABCB1) with EC50 values in the range of 35-74 μM. The combination of these compounds with doxorubicin led to significant enhancement of the anticancer activity of doxorubicin in human colorectal carcinoma LS180 cells, which was evident from the improved IC50 of doxorubicin, the increased activity of caspase-3 and the significant reduction in colony formation ability of LS180 cells after treatment with doxorubicin. Compound 1l showed a 13.8-fold improvement in the IC50 of doxorubicin in LS180 cells. The ability of these compounds to display dual inhibition of VEGFR and P-gp efflux pumps demonstrates the promise of this scaffold for its development as multi-drug resistance-reversal agents.

  20. A new 2α,5α,10β,14β-tetraacetoxy-4(20),11-taxadiene (SIA) derivative overcomes paclitaxel resistance by inhibiting MAPK signaling and increasing paclitaxel accumulation in breast cancer cells. (United States)

    Mei, Mei; Xie, Dan; Zhang, Yi; Jin, Jing; You, Feng; Li, Yan; Dai, Jungui; Chen, Xiaoguang


    Tumor resistance due to multiple mechanisms seriously hinders the efficacy of chemotherapy drugs such as paclitaxel. The most widely studied P-glycoprotein inhibitors still have limited ability to reverse resistance in the clinic. In this study, NPB304, a novel Sinenxan A (SIA) derivative, was found to significantly sensitize resistant breast cancer cells to paclitaxel in vitro and in vivo. Treatment with NPB304 increased paclitaxel-induced apoptosis in a p53-dependent manner through PARP cleavage. Importantly, NPB304 enhanced the antitumor effect of paclitaxel in resistant breast tumor xenografts in nude mice without significantly affecting weight loss. NPB304 regulated cell resistance through inhibition of MAPK pathway components, including p-ERK and p-p38. Moreover, NPB304 increased paclitaxel accumulation by affecting P-gp function. In addition to increasing Rhodamine 123 accumulation, NPB304 promoted bidirectional permeability but decreased the efflux ratio of paclitaxel in a Caco-2 monolayer model, thereby increasing the intracellular concentration of paclitaxel. Similarly, NPB304 increased the concentration of paclitaxel in the resistant tumor tissue. Hence, NPB304 is a novel compound that promotes the sensitization of resistant cells to paclitaxel through multiple mechanisms and has the potential for use in combination therapies to treat resistant breast cancer.

  1. A new 2α,5α,10β,14β-tetraacetoxy-4(20,11-taxadiene (SIA derivative overcomes paclitaxel resistance by inhibiting MAPK signaling and increasing paclitaxel accumulation in breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Mei Mei

    Full Text Available Tumor resistance due to multiple mechanisms seriously hinders the efficacy of chemotherapy drugs such as paclitaxel. The most widely studied P-glycoprotein inhibitors still have limited ability to reverse resistance in the clinic. In this study, NPB304, a novel Sinenxan A (SIA derivative, was found to significantly sensitize resistant breast cancer cells to paclitaxel in vitro and in vivo. Treatment with NPB304 increased paclitaxel-induced apoptosis in a p53-dependent manner through PARP cleavage. Importantly, NPB304 enhanced the antitumor effect of paclitaxel in resistant breast tumor xenografts in nude mice without significantly affecting weight loss. NPB304 regulated cell resistance through inhibition of MAPK pathway components, including p-ERK and p-p38. Moreover, NPB304 increased paclitaxel accumulation by affecting P-gp function. In addition to increasing Rhodamine 123 accumulation, NPB304 promoted bidirectional permeability but decreased the efflux ratio of paclitaxel in a Caco-2 monolayer model, thereby increasing the intracellular concentration of paclitaxel. Similarly, NPB304 increased the concentration of paclitaxel in the resistant tumor tissue. Hence, NPB304 is a novel compound that promotes the sensitization of resistant cells to paclitaxel through multiple mechanisms and has the potential for use in combination therapies to treat resistant breast cancer.

  2. Overcoming Multidrug Resistance in Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Karobi Moitra


    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. Family skills for overcoming adversity

    Directory of Open Access Journals (Sweden)

    Mónica Patricia Ardila Hernández


    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.

  4. Overcoming "the Valley of Death". (United States)

    McIntyre, Robin A


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

  5. a struggle to overcome inequality

    Directory of Open Access Journals (Sweden)

    Sergio Bolaños Cuellar


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

  6. Targeting efflux pumps to overcome antifungal drug resistance. (United States)

    Holmes, Ann R; Cardno, Tony S; Strouse, J Jacob; Ivnitski-Steele, Irena; Keniya, Mikhail V; Lackovic, Kurt; Monk, Brian C; Sklar, Larry A; Cannon, Richard D


    Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence-based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps.

  7. Overcoming Barriers to Shared Decision Making (United States)

    ... Thromboembolism Aortic Aneurysm More Overcoming Barriers to Shared Decision Making Updated:Mar 6,2017 Advanced heart failure is ... But charting a clear path through the shared decision-making process is possible, if you can recognize where ...

  8. Successful Writing: Five Roadblocks to Overcome (United States)

    King, Kathleen P.


    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…

  9. Overcoming the Limitations of Learning Objects (United States)

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


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

  10. Helping Chinese Overcome Stereotypes about American Culture

    Institute of Scientific and Technical Information of China (English)



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

  11. Overcoming Affective Barriers in College English Learning

    Institute of Scientific and Technical Information of China (English)



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

  12. Overcoming Challenges in Engineering the Genetic Code. (United States)

    Lajoie, M J; Söll, D; Church, G M


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

  13. Overcoming the Bradyon-Tachyon Barrier

    CERN Document Server

    Nanni, Luca


    In this study, the problem of overcoming the infinite energy barrier separating the bradyonic and tachyonic realms is investigated. Making use of the Majorana equation for particles with arbitrary spin and the Heisenberg uncertainty principle, it is proved that, under certain conditions of spatial confinement, quantum fluctuations allow particles with very small mass and velocity close to the speed of light to pass in the tachyonic realm, avoiding the problem of the infinite barrier. This theoretical approach allows an avoidance of the difficulties encountered in quantum field theory when it is extended to particles with imaginary rest mass.

  14. Overcoming semantic heterogeneity in spatial data infrastructures (United States)

    Lutz, M.; Sprado, J.; Klien, E.; Schubert, C.; Christ, I.


    In current spatial data infrastructures (SDIs), it is still often difficult to effectively exchange or re-use geographic data sets. A main reason for this is semantic heterogeneity, which occurs at different levels: at the metadata, the schema and the data content level. It is the goal of the work presented in this paper to overcome the problems caused by semantic heterogeneity on all three levels. We present a method based on ontologies and logical reasoning, which enhances the discovery, retrieval, interpretation and integration of geographic data in SDIs. Its benefits and practical use are illustrated with examples from the domains of geology and hydrology.

  15. Overcoming maladaptive plasticity through plastic compensation

    Institute of Scientific and Technical Information of China (English)

    Matthew R.J.MORRIS; Sean M.ROGERS


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

  16. Overcoming the isolation of disadvantaged housing areas

    DEFF Research Database (Denmark)

    Stender, Marie; Bech-Danielsen, Claus

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

  17. Innovative Strategies to Overcome Biofilm Resistance

    Directory of Open Access Journals (Sweden)

    Aleksandra Taraszkiewicz


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

  18. Overcoming some limitations of imprecise reliability models

    DEFF Research Database (Denmark)

    Kozine, Igor; Krymsky, Victor


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

  19. Overcoming strong metastabilities with the LLR method

    CERN Document Server

    Lucini, Biagio; Langfeld, Kurt


    In previous work, it has been shown that the recently proposed LLR method is very efficient at overcoming strong metastabilities that arise near first-order phase transition points. Here we present a systematic study of the performance of the algorithm near (pseudo-)critical points for $q$-state Potts models with $q$ as large as 20, in two and three dimensions. In particular, we shall focus our study on the ergodicity of the replica exchange step and the underlying physical mechanism. When compared with both analytical and numerical results present in the literature, our determinations of thermodynamic observables (including the order-disorder interface tension at criticality) show an impressive degree of relative accuracy (up to $2.5 \\times 10^{-6}$), which confirms the reliability and the efficiency of the proposed approach.

  20. Fear of Public Speaking: How Can I Overcome It? (United States)

    Fear of public speaking: How can I overcome it? How can I overcome my fear of public speaking? Answers from Daniel K. Hall-Flavin, M.D. Fear of public speaking is a common phobia. It can range from ...

  1. Towards an Approach to Overcome Software Brittleness

    Energy Technology Data Exchange (ETDEWEB)



    Development of bug-free, high-surety, complex software is quite difficult using current tools. The brittle nature of the programming constructs in popular languages such as C/C++ is one root cause. Brittle commands force the designer to rigidly specify the minutiae of tasks, e.g. using ''for(index=0;index>total;index++)'', rather than specifying the goals or intent of the tasks, e.g. ''ensure that all relevant data elements have been examined''. Specification of task minutiae makes code hard to comprehend, which in turn encourages design errors/limitations and makes future modifications quite difficult. This report describes an LDRD project to seed the development of a surety computer language, for stand-alone computing environments, to be implemented using the swarm intelligence of autonomous agents. The long term vision of this project was to develop a language with the following surety capabilities: (1) Reliability -- Autonomous agents can appropriate y decide when to act and when a task is complete, provide a natural means for avoiding brittle task specifications, and can overcome many hardware glitches. (2) Safety, security -- Watchdog safety and security agents can monitor other agents to prevent unauthorized or dangerous actions. (3) An immune system -- The small chunks of agent code can have an encryption scheme to enable detection and elimination of unauthorized and corrupted agents. This report describes the progress achieved during this small 9 month project and describes lessons learned.

  2. Overcoming HIV-1 resistance to RNA interference. (United States)

    Boden, Daniel; Pusch, Oliver; Ramratnam, Bharat


    RNAi refers to the sequence-specific degradation of RNA that follows the cellular introduction of homologous short interfering (si) RNA. RNAi has emerged as a powerful tool to probe the function of genes of known sequence in vitro and in vivo. Advances in vector design permit the effective expression of siRNA in human cells. Numerous recent investigations have described the ability of RNAi to decrease the replication of human immunodeficiency virus type 1 (HIV-1) in lymphocytic cells using siRNA targeting viral (e.g. tat, gag, rev) and host (e.g. CCR5, CD4) proteins. Can RNAi be used as a form of genetic therapy for HIV-1 infection? Recent data indicate that the dynamic replication kinetics of HIV-1 pose a considerable barrier to achieving durable virus suppression by RNAi with the rapid emergence of HIV-1 mutants resistant to siRNA. This review summarizes recent work on HIV-1 specific RNAi with a focus on potential strategies to overcome HIV-1 resistance to RNAi.

  3. 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


    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.

  4. 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


    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.


    Directory of Open Access Journals (Sweden)

    M. Mayer


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

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

    Directory of Open Access Journals (Sweden)

    Tang Y


    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

  7. Overcoming Residents Opportunity Apathy in Danish Social Housing Democracy

    DEFF Research Database (Denmark)

    Bertelsen, Olav W.


    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. Organizational barriers to effective communication and how to overcome them

    Institute of Scientific and Technical Information of China (English)



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

  9. 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...... authorities (and other intermediates in the energy saving area) for how they can interact with companies to assist them overcome different barriers and constrains taking a role and approach as a “reflective dialogue partner”....

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

    Indian Academy of Sciences (India)

    Maryam Hosseini Hasanabady; Fatemeh Kalalinia


    Breast cancer resistance protein (BCRP, ABCP or MXR) / ATP-binding cassette subfamily G member 2 (ABCG2) was characterized as a multidrug resistance efflux transporter in 1998. ABCG2 physiologically acts as a part of a self-defense mechanism for the organism; it enhances eliminating of toxic xenobiotic substances and harmful agents in the intestine, as well as through the blood-brain barrier and placental. ABCG2 recognizes and transports numerous anticancer drugs including conventional chemotherapeutic and new targeted small therapeutic molecules in clinical usage. Development of ABCG2 inhibitors for clinical usage may allow increased penetration of therapeutic agents into sanctuary sites and increased their intestinal absorption. In this report, we review the mechanisms that modulate MDR mediated by the ABC transporter ABCG2 in normal and cancer cells by different levels including, epigenetic modifications, transcriptional, posttranscriptional, translation and posttranslational regulation. Some clinical applications of ABCG2 inhibitors, also is explained.

  11. Tris DBA palladium overcomes hypoxia-mediated drug resistance in multiple myeloma. (United States)

    de la Puente, Pilar; Azab, Feda; Muz, Barbara; Luderer, Micah; Arbiser, Jack; Azab, Abdel Kareem


    Despite recent progress in novel and targeted therapies, multiple myeloma (MM) remains a therapeutically challenging incurable disease. The regulation of important cellular processes and its link to cancer presented Src as an attractive target for MM. We suggest a novel strategy to improve the treatment of MM and overcome the drug resistance for the current therapeutic agents by specific inhibition of Src in MM cells by Tris (Dibenzylideneacetone) dipalladium (Tris DBA). Tris DBA reduces proliferation, induces G1 arrest and apoptosis in MM cells. Tris DBA showed additive effect with proteasome inhibitors reducing proliferation, cell cycle signaling, and increasing apoptosis more than each drug alone. Tris DBA overcame hypoxia-induced effects such as enhanced chemotaxis or drug resistance to proteasome inhibitors by inhibition of HIF1α expression. Moreover, we found that Tris DBA is an effective anti-myeloma agent alone or in combination with other targeted drugs and that it reverses hypoxia-induced drug resistance in myeloma.

  12. Overcoming Obstacles: Opportunities of academically talented women in Iran

    Directory of Open Access Journals (Sweden)

    Shahla Alborzi, Ph.D


    Full Text Available The aim of the present research was to study the lifetime obstacles and opportunities of academically successful women working at Iran universities. Successful female academics in Iran are concerned about the social and personal barriers to pursuing successful careers in academia. These women continually work to overcome these barriers in an ongoing process called overcoming obstacles. This basic social process has five stages: perceiving inequality, conflicting, dissolving, empowering and acting purposefully. Throughout the process, these women have first become aware of gender inequities and then worked towards overcoming them using self-motivation properties and support from external sources such as family, mentors and colleagues. This substantive theory, though rooted in a specific country with a strong male dominated social structure, is applicable to all societies as they continue to work towards equitable access to high-level career opportunities.

  13. Effects of synthetic retinoids and retinoic acid isomers on the expression of alkaline phosphatase in F9 teratocarcinoma cells. (United States)

    Gianni, M; Zanotta, S; Terao, M; Garattini, S; Garattini, E


    Expression of ALP in F9 teratocarcinoma cells is induced by all-trans retinoic acid (ATRA) (Gianni' et al., Biochem. J. 274: 673-678, 1991). The specific ligand for retinoic acid related receptors (RXRs), 9-cis retinoic acid (9-cis RA), and three synthetic analogs binding to the alpha, beta and gamma forms of the retinoic acid receptors (RARs), AM580, CD2019, and CD437, were used to study their effects on alkaline phosphatase (ALP) enzymatic activity and mRNA levels. At concentrations close to the Kd for their respective receptors, 9-cis RA, AM580 (the RAR alpha agonist) and CD437 (the RAR gamma agonist) clearly upregulate the expression of the ALP gene, whereas the effect of CD2019 (the RAR beta agonist) is very modest. A specific inhibitor of the RAR alpha, Ro 41-5253, completely blocks the induction of ALP triggered by AM580, while it has minor effects on the upregulation caused by ATRA, 9-cis RA, CD437 and CD2019. The induction of ALP observed with the various retinoids is inhibited by the contemporaneous treatment with dibutyryl cAMP. The levels of the RAR alpha and gamma transcripts are unaltered, while RAR beta mRNAs are induced by ATRA, AM580, CD437 and to a lower extent by 9-cis RA and CD2019.

  14. Technology Adoption in Higher Education: Overcoming Anxiety through Faculty Bootcamp (United States)

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


    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…

  15. Overcoming Organizational Fixation: Creating and Sustaining an Innovation Culture (United States)

    Stempfle, Joachim


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

  16. Transforming the Albanian Armed Forces, Overcoming the Challenges (United States)


    Forces, Overcoming the Challenges FORMAT: Strategy Research Project DATE: 03 March 2009 WORD COUNT: 6,156 PAGES: 30 KEY TERMS: Resistance to Change , NATO...operating together. The strategic leadership today is more experienced to deal with the above sources of resistance to change . In 2006, the MOD and GS

  17. Overcoming Challenges Facing Advanced Therapies in the EU Market. (United States)

    Abou-El-Enein, Mohamed; Elsanhoury, Ahmed; Reinke, Petra


    While advanced therapy medicinal products offer great clinical promise, most EU-approved products have not achieved satisfactory commercial performance. Here we highlight a number of issues that prevent current products from obtaining commercial success and pitfalls that developers must overcome in future product development.

  18. KDD - Overcoming Massive Data Streams for Intelligence Tasks (United States)


    Level, Agencies Look for More Ways to Mine Data” 3 Jan Herring, “What is Intelligence Analysis?”, Competitive Intelligence Magazine, Vol. 1. No.2...Intelligence Analysis?", Competitive Intelligence Magazine, Vol. 1. No.2, July-Sep., 1998, p. 14. RTO-MP-IST-063 2 - 3 KDD – Overcoming Massive

  19. Overcoming Jealousy: An Experiential Analysis of Common Factors. (United States)

    Barrell, James J.; Richards, Anne C.


    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)

  20. Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors.

    Directory of Open Access Journals (Sweden)

    Shigeki Nanjo

    Full Text Available PURPOSE: Although EGF receptor tyrosine kinase inhibitors (EGFR-TKI have shown dramatic effects against EGFR mutant lung cancer, patients ultimately develop resistance by multiple mechanisms. We therefore assessed the ability of combined treatment with the Met inhibitor crizotinib and new generation EGFR-TKIs to overcome resistance to first-generation EGFR-TKIs. EXPERIMENTAL DESIGN: Lung cancer cell lines made resistant to EGFR-TKIs by the gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression and mice with tumors induced by these cells were treated with crizotinib and a new generation EGFR-TKI. RESULTS: The new generation EGFR-TKI inhibited the growth of lung cancer cells containing the gatekeeper EGFR-T790M mutation, but did not inhibit the growth of cells with Met amplification or HGF overexpression. In contrast, combined therapy with crizotinib plus afatinib or WZ4002 was effective against all three types of cells, inhibiting EGFR and Met phosphorylation and their downstream molecules. Crizotinib combined with afatinib or WZ4002 potently inhibited the growth of mouse tumors induced by these lung cancer cell lines. However, the combination of high dose crizotinib and afatinib, but not WZ4002, triggered severe adverse events. CONCLUSIONS: Our results suggest that the dual blockade of mutant EGFR and Met by crizotinib and a new generation EGFR-TKI may be promising for overcoming resistance to reversible EGFR-TKIs but careful assessment is warranted clinically.

  1. ROS-mediated upregulation of Noxa overcomes chemoresistance in chronic lymphocytic leukemia. (United States)

    Tonino, S H; van Laar, J; van Oers, M H; Wang, J Y; Eldering, E; Kater, A P


    In recent years considerable progress has been made in treatment strategies for chronic lymphocytic leukemia (CLL). However, the disease remains incurable because of the development of chemoresistance. Strategies to overcome resistance mechanisms are therefore highly needed. At least two mechanisms contribute to the development of resistance to drugs; acquired mutations resulting in a dysfunctional p53 response and shifts in the balance between apoptosis-regulating proteins. Platinum-based compounds have been successfully applied in relapsed lymphoma and recently also in high-risk CLL. In this study we investigated the efficacy and mechanism of action of cisplatinum (CDDP) in chemorefractory CLL. Independent of p53-functional status, CDDP acted synergistically with fludarabine (F-ara-A). The response involved generation of reactive oxygen species (ROS), which led to specific upregulation of the proapoptotic BH3-only protein Noxa. Induction of Noxa resulted in cell death by apoptosis as inhibition of caspase activation completely abrogated cell death. Furthermore, drug-resistance upon CD40-ligand stimulation, a model for the protective stimuli provided in lymph nodes, could also be overcome by CDDP/F-ara-A. ROS accumulation resulted in Noxa upregulation mainly at the transcriptional level and this was, at least in part, mediated by the mitogen-activated protein kinase p38. Finally, Noxa RNA-interference markedly decreased sensitivity to CDDP/F-ara-A, supporting a key role for Noxa as mediator between ROS signaling and apoptosis induction. Our data indicate that interference in the cellular redox balance can be exploited to overcome chemoresistance in CLL.

  2. Multiple Tune Jumps to Overcome Horizontal Depolarizing Resonances (United States)

    Huang, H.; Ahrens, L. A.; Bai, M.; Brown, K. A.; Dutheil, Y.; Gardner, C.; Glenn, J. W.; Lin, F.; Mackay, W. W.; Meot, F.; Poblaguev, A.; Ranjbar, V.; Roser, T.; Schoefer, V.; Tepikian, S.; Tsoupas, N.; Yip, K.; Zelenski, A.; Zeno, K.


    Imperfection and vertical intrinsic depolarizing resonances have been overcome by the two partial Siberian snakes in the Alternative Gradient Synchrotron(AGS). The relatively weak but numerous horizontal resonances are the main source of polarization loss in the AGS. A pair of horizontal tune jump quads have been used to overcome these weak resonances. The locations of the two quads have to be chosen such that the disturbance to the beam optics is minimum. The emittance growth has to be mitigated for this method to work. In addition, this technique needs very accurate jump timing. Using two partial Siberian snakes, with vertical tune inside the spin tune gap and 80% polarization at AGS injection, polarized proton beam had reached 1.5 × 1011 proton per bunch with 65% polarization. With the tune jump timing optimized and emittance preserved, more than 70% polarization with 2 × 1011 protons per bunch has been achieved.

  3. Factors Influencing the Success Of Autism Spectrum Disorders Overcoming

    Directory of Open Access Journals (Sweden)

    Gorbachevskaya N.L.


    Full Text Available No more than 10—20% of children with autism, as becoming adults can adapt to a relatively independent life. Despite many publications dedicated to autism, relatively little work has examined the output characteristics and pathomorphosis of psychic and cognitive disorders in people with autism spectrum disorders (ASD. Only few longitudinal studies allow us to represent what happens in later life with people who have ASD. For conducting effective correctional interventions overcomingwith children with ASD there is need to identify predictors of successful overcome of disorders. The basis for the study, conducted by a team of psychologists and neuroscientists, was the assumption that the information about the features of violations of basic neurobiological mechanisms in people with autism spectrum disorders should determine the tactics of assistance. Genetic, neurophysiological and psychological factors, causing more successful overcoming of these disorders in children are revealed.

  4. Nanoparticle therapeutics: Technologies and methods for overcoming cancer. (United States)

    Cerqueira, Brenda Brenner S; Lasham, Annette; Shelling, Andrew N; Al-Kassas, Raida


    It is anticipated that by 2030 approximately 13 million people will die of cancer. Common cancer therapy often fails due to the development of multidrug resistance (MDR), resulting in high morbidity and poor patient prognosis. Nanotechnology seeks to use drug delivery vehicles of 1-100 nm in diameter, made up of several different materials to deliver anti-cancer drugs selectively to cancer cells and potentially overcome MDR. Several technologies exist for manufacturing and functionalizing nanoparticles. When functionalized appropriately, nanoparticles have been shown to overcome several mechanisms of MDR in vivo and in vitro, reduce drug side effects and represent a promising new area of anti-cancer therapy. This review discusses the fundamental concepts of enhanced permeability and retention (EPR) effect and explores the mechanisms proposed to enhance preferential "retention" in the tumour. The overall objective of this review was to enhance our understanding in the design and development of therapeutic nanoparticles for treatment of cancer.

  5. Overcoming of energy barrier for irreversible magnetization in nanocomposite magnets (United States)

    Li, Zhu-bai; Zhang, Ying; Shen, Bao-gen; Zhang, Ming; Hu, Feng-xia; Sun, Ji-rong


    The irreversible magnetization occurs mainly in hard grains in nanocomposite magnets, and the domain wall involves a little part of defect region in irreversible magnetization due to the self-interaction. The investigation on thermal activation shows that the defect region involved in domain wall becomes narrower due to the TiNb addition in Pr2Fe14B/α-Fe magnets. The defect region augments the energy density in the negative direction of domain wall to overcome the energy barrier of perfect hard region. The soft phase, exchange-coupled with defect region at hard grain outer-layer, promotes magnetization reversal in defect region by exchange coupling. While the defect region plays a role as a ladder to overcome the energy barrier, resulting in the decrease of coecivity more or less depending upon the width and anisotropy of defect region.

  6. An action research to overcome undergraduates’ laboratory anxiety


    Acar Şeşen, Burçin; Mutlu (Karadaş), Ayfer


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

  7. Overcoming dormancy in seeds of cotton-silk tree


    Irinaldo Lima do Nascimento


    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,...

  8. [To overcome neglected tropical diseases by global health governance]. (United States)

    Yao, Jia-Wen; Zhou, Xiao-Nong


    Neglected tropical diseases (NTDs) are common infections of the poorest people of the world. The WHO publication of a roadmap that lays out the vision for ending the misery caused by NTDs has inspired the London Declaration on NTDs, which demonstrates that the global public-health agenda now embraces NTDs. This review discusses the advantages of global health governance in overcoming NTDs, and points out the potential ways of the involvement of China in global health through international collaboration.

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

    Directory of Open Access Journals (Sweden)

    Hobin Jennifer A


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

  10. Glutathione transferases and development of new principles to overcome drug resistance. (United States)

    Sau, Andrea; Pellizzari Tregno, Francesca; Valentino, Francesco; Federici, Giorgio; Caccuri, Anna Maria


    Chemoresistance is a multifactorial phenomenon and many studies clearly show that a coordinated expression of efflux transporter proteins and phase II conjugating enzymes in tumor cells is linked to the development of the multidrug resistance phenotype. In particular, the overexpression of glutathione S-transferases and efflux pumps in tumors may reduce the reactivity of various anticancer drugs. In recent years it has become evident that glutathione S-transferases are also involved in the control of apoptosis through the inhibition of the JNK signaling pathway. As such, the glutathione S-transferase superfamily has become the focus of extensive pharmaceutical research in attempt to generate more efficient anticancer agents. Here we present an overview of the GST inhibitors and the GST-activated pro-drugs utilized to date to overcome drug resistance.

  11. Overcoming violence - a basic task of Christian churches

    Directory of Open Access Journals (Sweden)

    Wolfgang Huber


    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.

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

    Energy Technology Data Exchange (ETDEWEB)

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


    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.

  13. Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors (United States)

    Chen, Yunching; Liu, Ya-Chi; Sung, Yun-Chieh; Ramjiawan, Rakesh R.; Lin, Ts-Ting; Chang, Chih-Chun; Jeng, Kuo-Shyang; Chang, Chiung-Fang; Liu, Chun-Hung; Gao, Dong-Yu; Hsu, Fu-Fei; Duyverman, Annique M.; Kitahara, Shuji; Huang, Peigen; Dima, Simona; Popescu, Irinel; Flaherty, Keith T.; Zhu, Andrew X.; Bardeesy, Nabeel; Jain, Rakesh K.; Benes, Cyril H.; Duda, Dan G.


    Sorafenib is a RAF inhibitor approved for several cancers, including hepatocellular carcinoma (HCC). Inhibition of RAF kinases can induce a dose-dependent “paradoxical” upregulation of the downstream mitogen-activated protein kinase (MAPK) pathway in cancer cells. It is unknown whether “paradoxical” ERK activation occurs after sorafenib therapy in HCC, and if so, if it impacts the therapeutic efficacy. Here, we demonstrate that RAF inhibition by sorafenib rapidly leads to RAF dimerization and ERK activation in HCCs, which contributes to treatment evasion. The transactivation of RAF dimers and ERK signaling promotes HCC cell survival, prevents apoptosis via downregulation of BIM and achieves immunosuppression by MAPK/NF-kB-dependent activation of PD-L1 gene expression. To overcome treatment evasion and reduce systemic effects, we developed CXCR4-targeted nanoparticles to co-deliver sorafenib with the MEK inhibitor AZD6244 in HCC. Using this approach, we preferentially and efficiently inactivated RAF/ERK, upregulated BIM and down-regulated PD-L1 expression in HCC, and facilitated intra-tumoral infiltration of cytotoxic CD8+ T cells. These effects resulted in a profound delay in tumor growth. Thus, this nano-delivery strategy to selectively target tumors and prevent the paradoxical ERK activation could increase the feasibility of dual RAF/MEK inhibition to overcome sorafenib treatment escape in HCC. PMID:28276530

  14. Latent inhibition in schizophrenia. (United States)

    Swerdlow, N R; Braff, D L; Hartston, H; Perry, W; Geyer, M A


    Latent inhibition (LI) refers to the retarded acquisition of a conditioned response that occurs if the subject being tested is first preexposed to the to-be-conditioned stimulus (CS) without the paired unconditioned stimulus (UCS). Because the 'irrelevance' of the to-be-conditioned stimulus is established during non-contingent preexposure, the slowed acquisition of the CS-UCS association is thought to reflect the process of overcoming this learned irrelevance. Latent inhibition has been reported to be diminished in acutely hospitalized schizophrenia patients. If acutely hospitalized schizophrenia patients are preexposed to the CS, they learn the association as fast as, and perhaps faster than, patients who are not preexposed to the CS. This finding has been interpreted as reflecting the inability of acute schizophrenia patients to ignore irrelevant stimuli. In this study, the LI paradigm was identical to the one used in previous reports of LI deficits in schizophrenia patients (Baruch et al., 1988). Latent inhibition was observed in normal control subjects (n = 73), including individuals identified as 'psychosis-prone' based on established screening criteria, and in anxiety (n = 19) and mood disorder (n = 13) patients. Learning scores (trials to criterion) in "acutely' hospitalized as well as "chronic' hospitalized schizophrenia patients (n = 45) were significantly elevated in both preexposed and non-preexposed subjects, compared to controls. Acute schizophrenia patients exhibited intact LI. Separate cohorts of acute and chronic schizophrenia patients (n = 23) and normal controls (n = 34) exhibited intact LI when tested in a new, easier-to-acquire computerized LI paradigm. These results fail to identify specific LI deficits in schizophrenia patients, and raise the possibility that previously observed LI deficits in schizophrenia patients may reflect, at least in part, performance deficits related to learning acquisition.

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

    Directory of Open Access Journals (Sweden)

    Siddhartha Ghosh

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

  16. 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.


    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.

  17. Overcoming losses with gain in a negative refractive index metamaterial. (United States)

    Wuestner, Sebastian; Pusch, Andreas; Tsakmakidis, Kosmas L; Hamm, Joachim M; Hess, Ortwin


    On the basis of a full-vectorial three-dimensional Maxwell-Bloch approach we investigate the possibility of using gain to overcome losses in a negative refractive index fishnet metamaterial. We show that appropriate placing of optically pumped laser dyes (gain) into the metamaterial structure results in a frequency band where the nonbianisotropic metamaterial becomes amplifying. In that region both the real and the imaginary part of the effective refractive index become simultaneously negative and the figure of merit diverges at two distinct frequency points.

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

    DEFF Research Database (Denmark)

    Nygaard, Ivan; Hansen, Ulrich Elmer

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

  19. Overcoming limitations of model-based diagnostic reasoning systems (United States)

    Holtzblatt, Lester J.; Marcotte, Richard A.; Piazza, Richard L.


    The development of a model-based diagnostic system to overcome the limitations of model-based reasoning systems is discussed. It is noted that model-based reasoning techniques can be used to analyze the failure behavior and diagnosability of system and circuit designs as part of the system process itself. One goal of current research is the development of a diagnostic algorithm which can reason efficiently about large numbers of diagnostic suspects and can handle both combinational and sequential circuits. A second goal is to address the model-creation problem by developing an approach for using design models to construct the GMODS model in an automated fashion.

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

    Institute of Scientific and Technical Information of China (English)


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

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

    Energy Technology Data Exchange (ETDEWEB)

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


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

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

    Energy Technology Data Exchange (ETDEWEB)

    Tom Kaiserski; Dan Lloyd


    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.

  3. Constricted Canals: A New Strategy to Overcome This Challenge

    Directory of Open Access Journals (Sweden)

    Ricardo Machado


    Full Text Available Negotiation of constricted canals can be a challenge during endodontic treatment. Over the years, several strategies have been presented in order to overcome the difficulties imposed by this anatomical feature. This paper presents three cases using a different protocol from that recommended by the manufacturer of the Protaper System in order to facilitate the negotiation of constricted canals. These cases suggest that the modified protocol shown is able to perform the shaping process with less resistance, reducing the risk of instrument separation and performing an effective process to reach the apical thirds in constricted canals.

  4. Lipocortin inhibition of extracellular and intracellular phospholipases A2 is substrate concentration dependent

    NARCIS (Netherlands)

    Aarsman, A.J.; Mynbeek, G.; Bosch, H. van den; Rothhut, B.; Prieur, B.; Comera, C.; Jordan, J.; Russo-Marie, F.


    Hydrolysis of Escherichia coli membrane phospholipids by pancreatic phospholipase A2 was inhibited by lipocortin from human monocytes in a substrate dependent manner. Inhibition was completely overcome at substrate concentrations above 250 μM. Lipocortin also inhibited partially purified preparation

  5. Inula Viscosa Extracts Induces Telomere Shortening and Apoptosis in Cancer Cells and Overcome Drug Resistance. (United States)

    Merghoub, Nawal; El Btaouri, Hassan; Benbacer, Laila; Gmouh, Saïd; Trentesaux, Chantal; Brassart, Bertrand; Terryn, Christine; Attaleb, Mohammed; Madoulet, Claudie; Benjouad, Abdelaziz; Amzazi, Saaïd; El Mzibri, Mohammed; Morjani, Hamid


    Telomerase is activated in human papillomavirus (HPV) positive cervical cancer and targeting telomeres offers a novel anticancer therapeutic strategy. In this study, the telomere targeting properties, the cytotoxic as well as the pro-apoptotic effects of hexane (IV-HE) and dichloromethane (IV-DF) fractions from Inula viscosa L. extracts were investigated on human cervical HeLa and SiHa cancer cells. Our data demonstrate that IV-HE and IV-DF extracts were able to inhibit cell growth in HeLa and SiHa cells in a dose-dependent manner and studied resistant cell lines exhibited a resistance factor less than 2 when treated with the extracts. IV-HE and IV-DF extracts were able to inhibit telomerase activity and to induce telomere shortening as shown by telomeric repeat amplification protocol and TTAGGG telomere length assay, respectively. The sensitivity of fibroblasts to the extracts was increased when telomerase was expressed. Finally, IV-HE and IV-DF were able to induce apoptosis as evidenced by an increase in annexin-V labeling and caspase-3 activity. This study provides the first evidence that the IV-HE and IV-DF extracts from Inula viscosa L. target telomeres induce apoptosis and overcome drug resistance in tumor cells. Future studies will focus on the identification of the molecules involved in the anticancer activity.

  6. Overcoming Learning Aversion in Evaluating and Managing Uncertain Risks. (United States)

    Cox, Louis Anthony Tony


    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.

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

    Directory of Open Access Journals (Sweden)

    Pollyanna Freire Montenegro Agra


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

  8. Targeted therapy of the XIAP/proteasome pathway overcomes TRAIL-resistance in carcinoma by switching apoptosis signaling to a Bax/Bak-independent 'type I' mode. (United States)

    Gillissen, B; Richter, A; Richter, A; Overkamp, T; Essmann, F; Hemmati, P G; Preissner, R; Belka, C; Daniel, P T


    TRAIL is a promising anticancer agent, capable of inducing apoptosis in a wide range of treatment-resistant tumor cells. In 'type II' cells, the death signal triggered by TRAIL requires amplification via the mitochondrial apoptosis pathway. Consequently, deregulation of the intrinsic apoptosis-signaling pathway, for example, by loss of Bax and Bak, confers TRAIL-resistance and limits its application. Here, we show that despite resistance of Bax/Bak double-deficient cells, TRAIL-treatment resulted in caspase-8 activation and complete processing of the caspase-3 proenzymes. However, active caspase-3 was degraded by the proteasome and not detectable unless the XIAP/proteasome pathway was inhibited. Direct or indirect inhibition of XIAP by RNAi, Mithramycin A or by the SMAC mimetic LBW-242 as well as inhibition of the proteasome by Bortezomib overcomes TRAIL-resistance of Bax/Bak double-deficient tumor cells. Moreover, activation and stabilization of caspase-3 becomes independent of mitochondrial death signaling, demonstrating that inhibition of the XIAP/proteasome pathway overcomes resistance by converting 'type II' to 'type I' cells. Our results further demonstrate that the E3 ubiquitin ligase XIAP is a gatekeeper critical for the 'type II' phenotype. Pharmacological manipulation of XIAP therefore is a promising strategy to sensitize cells for TRAIL and to overcome TRAIL-resistance in case of central defects in the intrinsic apoptosis-signaling pathway.

  9. Rational drug design approach for overcoming drug resistance: application to pyrimethamine resistance in malaria. (United States)

    McKie, J H; Douglas, K T; Chan, C; Roser, S A; Yates, R; Read, M; Hyde, J E; Dascombe, M J; Yuthavong, Y; Sirawaraporn, W


    Pyrimethamine acts by selectively inhibiting malarial dihydrofolate reductase-thymidylate synthase (DHFR-TS). Resistance in the most important human parasite, Plasmodium falciparum, initially results from an S108N mutation in the DHFR domain, with additional mutation (most commonly C59R or N51I or both) imparting much greater resistance. From a homology model of the 3-D structure of DHFR-TS, rational drug design techniques have been used to design and subsequently synthesize inhibitors able to overcome malarial pyrimethamine resistance. Compared to pyrimethamine (Ki 1.5 nM) with purified recombinant DHFR fromP. falciparum, the Ki value of the m-methoxy analogue of pyrimethamine was 1.07 nM, but against the DHFR bearing the double mutation (C59R + S108N), the Ki values for pyrimethamine and the m-methoxy analogue were 71.7 and 14.0 nM, respectively. The m-chloro analogue of pyrimethamine was a stronger inhibitor of both wild-type DHFR (with Ki 0.30 nM) and the doubly mutant (C59R +S108N) purified enzyme (with Ki 2.40 nM). Growth of parasite cultures of P. falciparum in vitro was also strongly inhibited by these compounds with 50% inhibition of growth occurring at 3.7 microM for the m-methoxy and 0.6 microM for the m-chloro compounds with the K1 parasite line bearing the double mutation (S108N + C59R), compared to 10.2 microM for pyrimethamine. These inhibitors were also found in preliminary studies to retain antimalarial activity in vivo in P. berghei-infected mice.

  10. Epirubicin loaded with propylene glycol liposomes significantly overcomes multidrug resistance in breast cancer. (United States)

    Zhao, Ying-Zheng; Dai, Dan-Dan; Lu, Cui-Tao; Chen, Li-Juan; Lin, Min; Shen, Xiao-Tong; Li, Xiao-Kun; Zhang, Ming; Jiang, Xi; Jin, Rong-Rong; Li, Xing; Lv, Hai-Feng; Cai, Lu; Huang, Pin-Tong


    Multidrug resistance (MDR) is one of the major reasons for the failure of cancer chemotherapy. A newly reported liposome carrier, propylene glycol liposomes (EPI-PG-liposomes) were made to load epirubicin (EPI) which enhanced EPI absorption in MDR tumor cells to overcome the drug resistance. MDA-MB 435 and their mutant resistant (MDA-MB 435/ADR) cells were used to examine the cellular uptake and P-gp function in vitro for EPI-PG-liposomes by fluorescence microscopy and FCM, respectively. Mammary tumor model was also established to investigate the tumor growth inhibition and pharmacodynamics of EPI-PG-liposomes in vivo. Morphology evaluation showed that EPI-PG-liposomes had a homogeneous spherical shape with an average diameter of 182 nm. Based on cell viability assay, fluorescent microscopy examination, and EPI uptake assay, EPI-PG-liposomes exhibited an effective growth inhibition not only in MDA-MB-435 cells, but also in MDA-MB 435/ADR cells. EPI-PG-liposomes have high permeability not only on tumor cell membrane, but also on cell nucleus membrane. P-gp function assay showed that the anticancer action of EPI-PG-liposomes was not related to P-gp efflux pump, suggesting that PG-liposomes would not affect the normal physiological functions of membrane proteins. EPI-PG-liposomes also showed a better antitumor efficacy compared to EPI solution alone. With high entrapment efficiency, spherical morphology and effective inhibition on MDR cancer cells, EPI-PG-liposomes may represent a better chemotherapeutic vectors for cancer targeted therapy.

  11. Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia. (United States)

    Zeng, Xian; Zhao, Hui; Li, Yubin; Fan, Jiajun; Sun, Yun; Wang, Shaofei; Wang, Ziyu; Song, Ping; Ju, Dianwen


    The frontline tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, drug resistance is the major clinical challenge in the treatment of CML. The Hedgehog (Hh) signaling pathway and autophagy are both related to tumorigenesis, cancer therapy, and drug resistance. This study was conducted to explore whether the Hh pathway could regulate autophagy in CML cells and whether simultaneously regulating the Hh pathway and autophagy could induce cell death of drug-sensitive or -resistant BCR-ABL(+) CML cells. Our results indicated that pharmacological or genetic inhibition of Hh pathway could markedly induce autophagy in BCR-ABL(+) CML cells. Autophagic inhibitors or ATG5 and ATG7 silencing could significantly enhance CML cell death induced by Hh pathway suppression. Based on the above findings, our study demonstrated that simultaneously inhibiting the Hh pathway and autophagy could markedly reduce cell viability and induce apoptosis of imatinib-sensitive or -resistant BCR-ABL(+) cells. Moreover, this combination had little cytotoxicity in human peripheral blood mononuclear cells (PBMCs). Furthermore, this combined strategy was related to PARP cleavage, CASP3 and CASP9 cleavage, and inhibition of the BCR-ABL oncoprotein. In conclusion, this study indicated that simultaneously inhibiting the Hh pathway and autophagy could potently kill imatinib-sensitive or -resistant BCR-ABL(+) cells, providing a novel concept that simultaneously inhibiting the Hh pathway and autophagy might be a potent new strategy to overcome CML drug resistance.

  12. Supramolecular nanoparticles that target phosphoinositide-3-kinase overcome insulin resistance and exert pronounced antitumor efficacy. (United States)

    Kulkarni, Ashish A; Roy, Bhaskar; Rao, Poornima S; Wyant, Gregory A; Mahmoud, Ayaat; Ramachandran, Madhumitha; Sengupta, Poulomi; Goldman, Aaron; Kotamraju, Venkata Ramana; Basu, Sudipta; Mashelkar, Raghunath A; Ruoslahti, Erkki; Dinulescu, Daniela M; Sengupta, Shiladitya


    The centrality of phosphoinositide-3-kinase (PI3K) in cancer etiology is well established, but clinical translation of PI3K inhibitors has been limited by feedback signaling, suboptimal intratumoral concentration, and an insulin resistance "class effect." This study was designed to explore the use of supramolecular nanochemistry for targeting PI3K to enhance antitumor efficacy and potentially overcome these limitations. PI3K inhibitor structures were rationally modified using a cholesterol-based derivative, facilitating supramolecular nanoassembly with L-α-phosphatidylcholine and DSPE-PEG [1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polythylene glycol)]. The supramolecular nanoparticles (SNP) that were assembled were physicochemically characterized and functionally evaluated in vitro. Antitumor efficacy was quantified in vivo using 4T1 breast cancer and K-Ras(LSL/+)/Pten(fl/fl) ovarian cancer models, with effects on glucose homeostasis evaluated using an insulin sensitivity test. The use of PI103 and PI828 as surrogate molecules to engineer the SNPs highlighted the need to keep design principles in perspective; specifically, potency of the active molecule and the linker chemistry were critical principles for efficacy, similar to antibody-drug conjugates. We found that the SNPs exerted a temporally sustained inhibition of phosphorylation of Akt, mTOR, S6K, and 4EBP in vivo. These effects were associated with increased antitumor efficacy and survival as compared with PI103 and PI828. Efficacy was further increased by decorating the nanoparticle surface with tumor-homing peptides. Notably, the use of SNPs abrogated the insulin resistance that has been associated widely with other PI3K inhibitors. This study provides a preclinical foundation for the use of supramolecular nanochemistry to overcome current challenges associated with PI3K inhibitors, offering a paradigm for extension to other molecularly targeted therapeutics being explored for cancer

  13. 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.

  14. Bacterial mechanisms to overcome inhibitory effects of dietary tannins

    NARCIS (Netherlands)

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


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

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

    Directory of Open Access Journals (Sweden)

    Veretelnikova Yu.Ya.


    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.

  16. Overcoming design fixation through education and creativity methods

    DEFF Research Database (Denmark)

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


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

  17. Overcoming resistance to change in business innovation processes

    Directory of Open Access Journals (Sweden)

    Jose Vicente Berna-Martinez


    Full Text Available This paper summarizes the experience gained in dealing with resistance to change appeared in the companies when they develop innovative processes related to the adoption of new technologies,tools, equipment, infrastructure and methodologies. Technological innovation is rapidly absorbed by society on a personal level. But at the enterprise level, resistance to innovation can occur at anyhierarchical level of the company and may appear with different intensity. Depending on the type of enterprise, the hierarchical level of the employee, the intensity of resistance and other factors, the measures taken are different. In this paper we summarize our experience in the cataloging of the resistance to innovation in terms of impact on workers and showing how technology education andbusiness training can help overcome these resistance forces. This paper describes the experience acquired over 22 projects deployed in the period 2005 to 2011 and that has affected a total of 264 workers of different cultural, technological, business and hierarchical levels.

  18. Overcoming Obstacles to Colour-Kinematics Duality at Two Loops

    CERN Document Server

    Mogull, Gustav


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

  19. Enhancing T cell therapy by overcoming the immunosuppressive tumor microenvironment. (United States)

    Arina, Ainhoa; Corrales, Leticia; Bronte, Vincenzo


    Immune response to tumors can be successfully oriented for therapeutic purposes, as shown by the clinical efficacy of checkpoint blockade in extending the survival of patients with certain solid and hematologic neoplasms. Nonetheless, numerous patients do not benefit from these new treatments. Tumor-specific CD8(+) T lymphocytes, either endogenously revived by checkpoint interference or adoptively transferred after in vitro expansion and retargeting, can be extremely efficient in controlling metastatic disease but have to overcome a number of restraints imposed by growing tumors. This immune escape relies on a profound modification of the tumor environment, which is rendered less permissive to lymphocyte arrival, persistence, and functional activity. We review here emerging findings on the main negative circuits limiting the efficacy of cancer immunotherapy, as well as novel and conventional approaches that can translate into rational combination therapies.

  20. Overcoming tumor immune evasion with an unique arbovirus. (United States)

    Lyday, Bruce; Chen, Tony; Kesari, Santosh; Minev, Boris


    Combining dendritic cell vaccination with the adjuvant effect of a strain of dengue virus may be a way to overcome known tumor immune evasion mechanisms. Dengue is unique among viruses as primary infections carry lower mortality than the common cold, but secondary infections carry significant risk of hypovolemic shock. While current immuno-therapies rely on a single axis of attack, this approach combines physiological (hyperthermic reduction of tumor perfusion), immunological (activation of effector cells of the adaptive and innate immune system), and apoptosis-inducing pathways (sTRAIL) to destroy tumor cells. The premise of using multiple mechanisms of action in synergy with a decline in the ability of the tumor cells to employ resistance methods suggests the potential of this combination approach in cancer immunotherapy.

  1. How insects overcome two-component plant chemical defence

    DEFF Research Database (Denmark)

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


    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......-component chemical defence. These adaptations include host plant choice, non-disruptive feeding guilds and various physiological adaptations as well as metabolic enzymatic strategies of the insect’s digestive system. Furthermore, insect adaptations often act in combination, may exist in both generalists...

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

    Directory of Open Access Journals (Sweden)

    Iwata K


    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

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

    Directory of Open Access Journals (Sweden)

    Gaskon Ibarretxe


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

  4. Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer (United States)

    Uchibori, Ken; Inase, Naohiko; Araki, Mitsugu; Kamada, Mayumi; Sato, Shigeo; Okuno, Yasushi; Fujita, Naoya; Katayama, Ryohei


    Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR-TKI resistance. In the present study, we identify brigatinib to be effective against triple-mutation-harbouring cells in vitro and in vivo. Our original computational simulation demonstrates that brigatinib fits into the ATP-binding pocket of triple-mutant EGFR. The structure-activity relationship analysis reveals the key component in brigatinib to inhibit the triple-mutant EGFR. The efficacy of brigatinib is enhanced markedly by combination with anti-EGFR antibody because of the decrease of surface and total EGFR expression. Thus, the combination therapy of brigatinib with anti-EGFR antibody is a powerful candidate to overcome triple-mutant EGFR.

  5. Antarlides: A New Type of Androgen Receptor (AR) Antagonist that Overcomes Resistance to AR-Targeted Therapy. (United States)

    Saito, Shun; Fujimaki, Takahiro; Panbangred, Watanalai; Igarashi, Yasuhiro; Imoto, Masaya


    Prostate cancer is treated with androgen receptor (AR) antagonists but most patients experience disease progression after long-term treatment with these compounds. Therefore, new AR antagonists are required for patient follow-up treatment. In the course of screening for a new AR antagonist, we isolated the novel compounds antarlides A-E (1-5) from Streptomyces sp. BB47. Antarlides are mutually isomeric with respect to the double bond and have a 22-membered-ring macrocyclic structure. The full stereostructure of 1 was established by chemical modifications, including methanolysis, the Trost method, acetonide formation, and the PGME method. 1-5 inhibited the binding of androgen to ARs in vitro. In addition, 2 inhibited the transcriptional activity of not only wild-type AR but also mutant ARs, which are seen in patients with acquired resistance to clinically used AR antagonists. Therefore, antarlides are a potent new generation of AR antagonists that overcome resistance.

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

    Directory of Open Access Journals (Sweden)

    María Ángela Mattar Yunes


    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

  7. Mechanistic basis for overcoming platinum resistance using copper chelating agents. (United States)

    Liang, Zheng D; Long, Yan; Tsai, Wen-Bin; Fu, Siqing; Kurzrock, Razelle; Gagea-Iurascu, Mihai; Zhang, Fan; Chen, Helen H W; Hennessy, Bryan T; Mills, Gordon B; Savaraj, Niramol; Kuo, Macus Tien


    Platinum-based antitumor agents are widely used in cancer chemotherapy. Drug resistance is a major obstacle to the successful use of these agents because once drug resistance develops, other effective treatment options are limited. Recently, we conducted a clinical trial using a copper-lowering agent to overcome platinum drug resistance in ovarian cancer patients and the preliminary results are encouraging. In supporting this clinical study, using three pairs of cisplatin (cDDP)-resistant cell lines and two ovarian cancer cell lines derived from patients who had failed in platinum-based chemotherapy, we showed that cDDP resistance associated with reduced expression of the high-affinity copper transporter (hCtr1), which is also a cDDP transporter, can be preferentially resensitized by copper-lowering agents because of enhanced hCtr1 expression, as compared with their drug-sensitive counterparts. Such a preferential induction of hCtr1 expression in cDDP-resistant variants by copper chelation can be explained by the mammalian copper homeostasis regulatory mechanism. Enhanced cell-killing efficacy by a copper-lowering agent was also observed in animal xenografts bearing cDDP-resistant cells. Finally, by analyzing a public gene expression dataset, we found that ovarian cancer patients with elevated levels of hCtr1 in their tumors, but not ATP7A and ATP7B, had more favorable outcomes after platinum drug treatment than those expressing low hCtr1 levels. This study reveals the mechanistic basis for using copper chelation to overcome cDDP resistance in clinical investigations.

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

    Directory of Open Access Journals (Sweden)

    Bogunović Blanka


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

  9. 75 FR 58347 - Information Collection; Overcoming Barriers to Wildland Fire Defensible Space Behaviors (United States)


    ...; ] DEPARTMENT OF AGRICULTURE Forest Service Information Collection; Overcoming Barriers to Wildland Fire Defensible Space Behaviors AGENCY: Forest Service, USDA. ACTION: Notice; request for comment. SUMMARY: In... interested individuals and organizations on the new information collection, Overcoming Barriers to...

  10. 38 CFR 17.152 - Devices to assist in overcoming the handicap of deafness. (United States)


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


    Directory of Open Access Journals (Sweden)

    T. V. Danylova


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

  12. Overcoming the obstacles: Life stories of scientists with learning disabilities (United States)

    Force, Crista Marie

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

  13. Overcoming phytoremediation limitations. A case study of Hg contaminated soil (United States)

    Barbafieri, Meri


    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

  14. Sertraline Reduces IL-1β and TNF-α mRNA Expression and Overcomes Their Rise Induced by Seizures in the Rat Hippocampus


    María Sitges; Gómez, Carlos D.; Blanca I Aldana


    We recently discovered that the antidepressant sertraline is an effective inhibitor of hippocampus presynaptic Na+ channel permeability in vitro and of tonic-clonic seizures in animals in vivo. Several studies indicate that the pro-inflammatory cytokines in the central nervous system are increased in epilepsy and depression. On the other hand inhibition of Na+ channels has been shown to decrease pro-inflammatory cytokines in microglia. Therefore, the possibility that sertraline could overcome...

  15. Overcoming Critical Slowing Down in Quantum Monte Carlo Simulations (United States)

    Evertz, Hans Gerd; Marcu, Mihai

    The classical d+1-dimensional spin systems used for the simulation of quantum spin systems in d dimensions are, quite generally, vertex models. Standard simulation methods for such models strongly suffer from critical slowing down. Recently, we developed the loop algorithm, a new type of cluster algorithm that to a large extent overcomes critical slowing down for vertex models. We present the basic ideas on the example of the F model, a special case of the 6-vertex model. Numerical results clearly demonstrate the effectiveness of the loop algorithm. Then, using the framework for cluster algorithms developed by Kandel and Domany, we explain how to adapt our algorithm to the cases of the 6-vertex model and the 8-vertex model, which are relevant for spin 1/2 systems. The techniqes presented here can be applied without modification to 2-dimensional spin 1/2 systems, provided that in the Suzuki-Trotter formula the Hamiltonian is broken up into 4 sums of link terms. Generalizations to more complicated situations (higher spins, different uses of the Suzuki-Trotter formula) are, at least in principle, straightforward.

  16. Overcoming horizontal depolarizing resonances with multiple tune jumps (United States)

    Huang, H.; Ahrens, L. A.; Bai, M.; Brown, K. A.; Dutheil, Y.; Gardner, C.; Glenn, J. W.; Lin, F.; MacKay, W. W.; Meot, F.; Poblaguev, A.; Ranjbar, V.; Roser, T.; Schoefer, V.; Tepikian, S.; Tsoupas, N.; Yip, K.; Zelenski, A.; Zeno, K.


    In a medium energy proton synchrotron, strong enough partial Siberian snakes can be used to avoid both imperfection and vertical intrinsic depolarizing resonances. However, partial snakes tilt the stable spin direction away from vertical, which generates depolarizing resonances associated with horizontal tune. The relatively weak but numerous horizontal intrinsic resonances are the main source of the residual polarization losses. A pair of horizontal tune jump quads have been used in the Brookhaven Alternating Gradient Synchrotron to overcome these weak resonances. The locations of the two quads have to be chosen such that the disturbance to the beam optics is minimum. The emittance growth has to be mitigated for this method to work. In addition, this technique needs very accurate jump timing. Using two partial Siberian snakes, with vertical tune inside the spin tune gap and 80% polarization at the Alternating Gradient Synchrotron injection, polarized proton beam had reached 1.5×1011 proton per bunch with 65% polarization. With the tune jump timing optimized and emittance preserved, more than 70% polarization with 2×1011 protons per bunch has been achieved. The polarization transport efficiency is close to 90%.

  17. Nondestructive analysis of Portuguese "dinheiros" using XRF: overcoming patina constraints (United States)

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


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

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

    Directory of Open Access Journals (Sweden)

    James Fitzsimons


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

  19. Advances in Overcoming Immune Responses following Hemophilia Gene Therapy. (United States)

    Miao, Carol H


    Both Clinical trials and pre-clinical experiments for hemophilia gene therapy showed that it is important to overcome potential immune responses against gene transfer vectors and/or transgene products to ensure the success of gene therapy. Recently various approaches have been investigated to prevent or modulate such responses. Gene transfer vectors have been specifically engineered and immunosuppressive regimens have been administered to avoid or manipulate the immune responses against the vectors. In order to prevent cytotoxic lymphocyte or antibody formation induced by transgene expression, novel approaches have been developed, including methods to manipulate antigen presentation, development of variant genes encoding less immunogenic proteins or gene transfer protocols to evade immune responses, as well as immunosuppressive strategies to target either T and/or B cell responses. Most of these successful protocols involve the induction of activated regulatory T cells to create a regulatory immune environment during tolerance induction. Recent development of these strategies to evade vector-specific immune responses and induce long-term immune tolerance specific to the transgene product will be discussed.

  20. Computational technique to overcome the limit of a photomask writer (United States)

    Choi, Jin; Shin, In Kyun; Jeon, Chan-Uk


    We present the limit of a conventional photomask writer and new possibilities to meet various requirements of tight specifications for a sub-10 nm device. The issues of a variable shaped beam (VSB) writer and how to overcome the limit by computational techniques are discussed. Because VSB writing can use only one rectangular or triangular beam per shot, the complex design for computational lithography results in the increase of shot number to implement rounded or angled pattern. Based on model-based-fracturing, we have confirmed that the ideal curvilinear pattern can be optimized by using overlapping shots, and that they have the same patterning performance in mask and wafer. On the other hand, the multibeam writer can make ideally any kinds of shapes, even curvilinear design because the combination of small spots writes a design. In a real situation, each spot of multibeam writer is defined at fixed mesh and each beam has discrete dose level, so that there are fidelity errors if the pixel size is large or the dose level is not enough large. Here, we propose a "Buddhist cross" design as the evaluation pattern of digitization error in a multibeam writer. The "fidelity error" smaller than 0.5 nm error requires 5 nm pixel size and the required minimum number for dose level is 7 to implement a smaller error than 0.05 nm at one edge. To realize new technology for mass production, new data flow, model based pattern verification, and required computing power have been presented.

  1. Overcoming multicollinearity in multiple regression using correlation coefficient (United States)

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


    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.

  2. Continuous evolution of Bacillus thuringiensis toxins overcomes insect resistance. (United States)

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


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

  3. Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations

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    Nourah Mohammad Obaid


    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.

  4. The new concepts on overcoming drug resistance in lung cancer

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    Zhang W


    Full Text Available Weisan Zhang,1 Ping Lei,1 Xifeng Dong,2 Cuiping Xu31Department of Geriatrics, 2Department of Hematology-Oncology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 3Qianfoshan Hospital, Shandong University, Jinan, People’s Republic of ChinaAbstract: Lung cancer is one of the most deadly diseases worldwide. The current first-line therapies include chemotherapy using epidermal growth factor receptor tyrosine kinase inhibitors and radiotherapies. With the current progress in identifying new molecular targets, acquired drug resistance stands as an obstacle for good prognosis. About half the patients receiving epidermal growth factor receptor-tyrosine kinase inhibitor treatments develop resistance. Although extensive studies have been applied to elucidate the underlying mechanisms, evidence is far from enough to establish a well-defined picture to correct resistance. In the review, we will discuss four different currently developed strategies that have the potential to overcome drug resistance in lung cancer therapies and facilitate prolonged anticancer effects of the first-line therapies.Keywords: ALK receptors cancer stem cell, chemotherapy, EGFR-TKI, target therapy, pharmacology, molecular biology, biotherapy

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

    CERN Document Server

    Bañuls, Mari Carmen; Cirac, J Ignacio; Jansen, Karl; Kühn, Stefan; Saito, Hana


    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 a...

  6. Photonic ADC: overcoming the bottleneck of electronic jitter. (United States)

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


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

  7. Methods for overcoming dormancy in Stryphnodendron pulcherrimum seeds

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    Adriano Gonçalves Pereira


    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.

  8. Overcoming dormancy in seeds of cotton-silk tree

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    Irinaldo Lima do Nascimento


    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.

  9. Emerging role of mammalian autophagy in ketogenesis to overcome starvation. (United States)

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


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

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

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    Zlatan Magajna


    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.

  11. Dormancy overcome and seedling quality of pecan in nursery

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    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.

  12. Barriers to women engaging in collective action to overcome sexism. (United States)

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


    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

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

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    Bolaños Cuellar Sergio


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

  14. Overcoming PV grid issues in the urban areas

    Energy Technology Data Exchange (ETDEWEB)

    Ehara, T.


    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.

  15. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors. (United States)

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


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

  16. Multifunctional hyaluronic acid modified graphene oxide loaded with mitoxantrone for overcoming drug resistance in cancer (United States)

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


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

  17. Overcoming the susceptibility gap between maternal antibody disappearance and auto-antibody production. (United States)

    Yosipovich, Roni; Aizenshtein, Elina; Shadmon, Roy; Krispel, Simcha; Shuster, Efrat; Pitcovski, Jacob


    In the first 10-14 days of a chick's life, protection is conferred by maternal antibodies. Further broiler protection is achieved by active vaccination. However, the high level of maternal antibodies interferes with the induction of an effective immune response by vaccination at a young age. As a result, there is a gap between the reduction in protective maternal antibodies and elevation of self-produced antibodies following active vaccination. The major aim of this study was to test an approach consisting of passive and active vaccination to overcome this gap and to provide continuous resistance to infectious viral diseases during the broiler's growth period. Newcastle disease virus (NDV), which is one of the world's most prevalent infectious diseases of poultry, was tested as a model. Following subcutaneous injection of 18 hemagglutination-inhibiting (HI) units of anti-NDV immunoglobulin Y per 1-day-old chick, protective log2 antibody titers above 4 could be detected to at least 17 days of age. The combination of passive immunization on day 1 of age with attenuated live vaccination on day 10 led to high protective titers throughout the entire growth period, up to 41 days of age. Moreover, the HI titers in the group of birds immunized with the combined vaccination were significantly more homogeneous than those in the group vaccinated only with live virus. Thus, full protection against NDV of all broilers in flock during their entire growth period was achieved by a vaccination regime that combines passive immunization and live vaccination.

  18. Repurposing of tetracyclines to overcome resistance pathways associated with photochemotherapy in cancer (Conference Presentation) (United States)

    Liu, Joyce; Huang, Huang-Chiao; Rizvi, Imran; Hasan, Tayyaba


    Given the consistently poor prognoses for some of the most difficult-to-treat cancers, rapidly translatable treatment regimens that offer improvements in outcomes are much needed. The repurposing of FDA approved non-cancer drugs presents an opportunity to design clinically feasible, novel combinations of therapies with a mechanistic rationale, to overcome resistance and survival pathways that render many current treatments ineffective. Tetracyclines are a class of antibiotics that demonstrate potential for such repurposing, as they have also been shown by others to affect a wide range of targets in cancer. Notably, the unique structure of tetracyclines allows them to act through both light activated and non-light mediated mechanisms. While light activation of tetracyclines can result in singlet oxygen production, their non-light mediated targets include inhibition of DNA repair enzymes and modulation of hypoxia-inducible markers, among others. With these mechanisms in mind, we seek to elucidate the benefit of including tetracyclines as part of an already promising, mechanistically cooperative photochemotherapy combination for ovarian cancer. In ovarian cancer, the dismal rates of recurrence and survival associated with the aggressive disease further emphasize the need to mechanistically reinforce treatments regimens. Thus, the results will highlight insights into the cooperative effect of repurposed tetracyclines on treatment response and molecular markers, both in vitro and in a challenging mouse model of disseminated ovarian cancer.

  19. Overcoming challenges of catastrophe modelling in data poor regions (United States)

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


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

  20. The return to keynesianism in overcoming cyclical fluctuations?

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    Praščević Aleksandra


    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.

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

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    Magdalena Lesmana


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

  2. Midwives unable to overcome language barriers in prenatal care

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    Mirjam P. Fransen


    Full Text Available

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

    Methods: midwives from 24 Dutch midwifery practices in Rotterdam completed a structured webbased questionnaire (n=57. Data were obtained on perceived ethnic-related differences and barriers in providing information on prenatal screening, preparedness to provide cultural competent care, and the use of translated materials and professional translators. A group interview was conducted to further explore the results emerging from the questionnaire (n=23.

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

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

  3. Detouring of cisplatin to access mitochondrial genome for overcoming resistance. (United States)

    Marrache, Sean; Pathak, Rakesh K; Dhar, Shanta


    Chemoresistance of cisplatin therapy is related to extensive repair of cisplatin-modified DNA in the nucleus by the nucleotide excision repair (NER). Delivering cisplatin to the mitochondria to attack mitochondrial genome lacking NER machinery can lead to a rationally designed therapy for metastatic, chemoresistant cancers and might overcome the problems associated with conventional cisplatin treatment. An engineered hydrophobic mitochondria-targeted cisplatin prodrug, Platin-M, was constructed using a strain-promoted alkyne-azide cycloaddition chemistry. Efficient delivery of Platin-M using a biocompatible polymeric nanoparticle (NP) based on biodegradable poly(lactic-co-glycolic acid)-block-polyethyleneglycol functionalized with a terminal triphenylphosphonium cation, which has remarkable activity to target mitochondria of cells, resulted in controlled release of cisplatin from Platin-M locally inside the mitochondrial matrix to attack mtDNA and exhibited otherwise-resistant advanced cancer sensitive to cisplatin-based chemotherapy. Identification of an optimized targeted-NP formulation with brain-penetrating properties allowed for delivery of Platin-M inside the mitochondria of neuroblastoma cells resulting in ∼17 times more activity than cisplatin. The remarkable activity of Platin-M and its targeted-NP in cisplatin-resistant cells was correlated with the hyperpolarization of mitochondria in these cells and mitochondrial bioenergetics studies in the resistance cells further supported this hypothesis. This unique dual-targeting approach to controlled mitochondrial delivery of cisplatin in the form of a prodrug to attack the mitochondrial genome lacking NER machinery and in vivo distribution of the delivery vehicle in the brain suggested previously undescribed routes for cisplatin-based therapy.

  4. Neisseria meningitidis, pathogenetic mechanisms to overcome the human immune defences. (United States)

    Gasparini, R; Amicizia, D; Lai, P L; Panatto, D


    Neisseria meningitidis is hosted only by humans and colonizes the nasopharynx; it survives in the human body by reaching an equilibrium with its exclusive host. Indeed, while cases of invasive disease are rare, the number of asymptomatic Neisseria meningitides carriers is far higher. The aim of this paper is to summarize the current knowledge of survival strategies of Neisseria meningitides against the human immune defences. Neisseria meningitidis possesses a variety of adaptive characteristics which enable it to avoid being killed by the immune system, such as the capsule, the lipopolysaccharide, groups of proteins that block the action of the antimicrobial proteins (AMP), proteins that inhibit the complement system, and components that prevent both the maturation and the perfect functioning of phagocytes. The main means of adhesion of Neisseria meningitides to the host cells are Pili, constituted by several proteins of whom the most important is Pilin E. Opacity-associated proteins (Opa) and (Opc) are two proteins that make an important contribution to the process of adhesion to the cell. Porins A and B contribute to neisserial adhesion and penetration into the cells, and also inhibit the complement system. Factor H binding protein (fhbp) binds factor H, allowing the bacteria to survive in the blood. Neisserial adhesin A (NadA) is a minor adhesin that is expressed by 50% of the pathogenic strains. NadA is known to be involved in cell adhesion and invasion and in the induction of proinflammatory cytokines. Neisserial heparin binding antigen (NHBA) binds heparin, thus increasing the resistance of the bacterium in the serum.

  5. The Genesis and Mechanisms to Overcome Systemic Economic Crises

    Directory of Open Access Journals (Sweden)

    Gennadii Anatol’evich Shcherbakov


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

  6. 20% Wind by 2030: Overcoming the Challenges in West Virginia

    Energy Technology Data Exchange (ETDEWEB)

    Patrick Mann; Christine Risch


    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

  7. 42 CFR 436.1003 - Recipients overcoming certain conditions of eligibility. (United States)


    ... THE VIRGIN ISLANDS Federal Financial Participation (FFP) Ffp for Expenditures for Determining Eligibility and Providing Services § 436.1003 Recipients overcoming certain conditions of eligibility. FFP...

  8. SIRT1 controls cell proliferation by regulating contact inhibition. (United States)

    Cho, Elizabeth H; Dai, Yan


    Contact inhibition keeps cell proliferation in check and serves as a built-in protection against cancer development by arresting cell division upon cell-cell contact. Yet the complete mechanism behind this anti-cancer process remains largely unclear. Here we present SIRT1 as a novel regulator of contact inhibition. SIRT1 performs a wide variety of functions in biological processes, but its involvement in contact inhibition has not been explored to date. We used NIH3T3 cells, which are sensitive to contact inhibition, and H460 and DU145 cancer cells, which lack contact inhibition, to investigate the relationship between SIRT1 and contact inhibition. We show that SIRT1 overexpression in NIH3T3 cells overcomes contact inhibition while SIRT1 knockdown in cancer cells restores their lost contact inhibition. Moreover, we demonstrate that p27 protein expression is controlled by SIRT1 in contact inhibition. Overall, our findings underline the critical role of SIRT1 in contact inhibition and suggest SIRT1 inhibition as a potential strategy to suppress cancer cell growth by restoring contact inhibition.

  9. Assets for policy making in health promotion: overcoming political barriers inhibiting women in difficult life situations to access sport facilities. (United States)

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


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

  10. TET2 Inhibits Differentiation of Embryonic Stem Cells but Does Not Overcome Methylation-Induced Gene Silencing

    Directory of Open Access Journals (Sweden)

    Louis Norman


    Full Text Available TET2 is a methylcytosine dioxygenase that is frequently mutated in myeloid malignancies, notably myelodysplasia and acute myeloid leukemia. TET2 catalyses the conversion of 5′-methylcytosine to 5′-hydroxymethylcytosine within DNA and has been implicated in the process of genomic demethylation. However, the mechanism by which TET2 loss of function results in hematopoietic dysplasia and leukemogenesis is poorly understood. Here, we show that TET2 is expressed in undifferentiated embryonic stem cells and that its knockdown results in reduction of 5′-hydroxymethylcytosine in genomic DNA. We also present DNA methylation data from bone marrow samples obtained from patients with TET2-mutated myelodysplasia. Based on these findings, we sought to identify the role of TET2 in regulating pluripotency and differentiation. We show that overexpression of TET2 in a stably integrated transgene leads to increased alkaline phosphatase expression in differentiating ES cells and impaired differentiation in methylcellulose culture. We speculate that this effect is due to TET2-mediated expression of stem cell genes in ES cells via hydroxylation of 5′-methylcytosines at key promoter sequences within genomic DNA. This leads to relative hypomethylation of gene promoters as 5′-hydroxymethylcytosine is not a substrate for DNMT1-mediated maintenance methylation. We sought to test this hypothesis by cotransfecting the TET2 gene with methylated reporter genes. The results of these experiments are presented.

  11. Plasticity Related Gene 3 (PRG3) overcomes myelin-associated growth inhibition and promotes functional recovery after spinal cord injury (United States)

    Broggini, Thomas; Schnell, Lisa; Ghoochani, Ali; Mateos, José María; Buchfelder, Michael; Wiendieck, Kurt; Schäfer, Michael K.; Eyupoglu, Ilker Y.; Savaskan, Nicolai E.


    The Plasticity Related Gene family covers five, brain-specific, transmembrane proteins (PRG1-5, also termed LPPR1-5) that operate in neuronal plasticity during development, aging and brain trauma. Here we investigated the role of the PRG family on axonal and filopodia outgrowth. Comparative analysis revealed the strongest outgrowth induced by PRG3 (LPPR1). During development, PRG3 is ubiquitously located at the tip of neuronal processes and at the plasma membrane and declines with age. In utero electroporation of PRG3 induced dendritic protrusions and accelerated spine formations in cortical pyramidal neurons. The neurite growth promoting activity of PRG3 requires RasGRF1 (RasGEF1/Cdc25) mediated downstream signaling. Moreover, in axon collapse assays, PRG3-induced neurites resisted growth inhibitors such as myelin, Nogo-A (Reticulon/RTN-4), thrombin and LPA and impeded the RhoA-Rock-PIP5K induced neurite repulsion. Transgenic adult mice with constitutive PRG3 expression displayed strong axonal sprouting distal to a spinal cord lesion. Moreover, fostered PRG3 expression promoted complex motor-behavioral recovery compared to wild type controls as revealed in the Schnell swim test (SST). Thus, PRG3 emerges as a developmental RasGRF1-dependent conductor of filopodia formation and axonal growth enhancer. PRG3-induced neurites resist brain injury-associated outgrowth inhibitors and contribute to functional recovery after spinal cord lesions. Here, we provide evidence that PRG3 operates as an essential neuronal growth promoter in the nervous system. Maintaining PRG3 expression in aging brain may turn back the developmental clock for neuronal regeneration and plasticity. PMID:27744421

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

    DEFF Research Database (Denmark)

    Andersen, Stine L; Backman Nøhr, Susanne; Wu, Chun S;


    ). The pregnant women reported on intake of iodine-containing supplements during pregnancy and Tg in maternal serum at delivery and in cord serum were analyzed. RESULTS: In a context of mild-to-moderate iodine deficiency, smoking mothers had significantly higher serum Tg than nonsmoking mothers (mean Tg smokers...... maternal smoking, but compensatory autoregulation of iodide transport differs between organs. The extent of autoregulation of placental iodide transport remains to be clarified. OBJECTIVE: To compare the impact of maternal smoking on thyroglobulin (Tg) levels in maternal serum at delivery and in cord serum...... as markers of maternal and fetal iodine deficiency. METHODS: One hundred and forty healthy, pregnant women admitted for delivery and their newborns were studied before the iodine fortification of salt in Denmark. Cotinine in urine and serum classified mothers as smokers (n=50) or nonsmokers (n=90...

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

    Directory of Open Access Journals (Sweden)

    Wilfried Posch


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

  14. ALK and crizotinib: after the honeymoon…what else? Resistance mechanisms and new therapies to overcome it. (United States)

    Rolfo, Christian; Passiglia, Francesco; Castiglia, Marta; Raez, Luis E; Germonpre, Paul; Gil-Bazo, Ignacio; Zwaenepoel, Karen; De Wilde, Annemieke; Bronte, Giuseppe; Russo, Antonio; Van Meerbeeck, Jan P; Van Schil, Paul; Pauwels, Patrick


    The last few decades have witnessed a silent revolution in the war against NSCLC, thanks to the discovery of "oncogenic drivers" and the subsequent development of targeted therapies. The discovery of the EML4-ALK fusion gene in a subgroup of patients with NSCLC and the subsequent clinical development of crizotinib has been an amazing success story in lung cancer translational-research, and its accelerated approval [only 4 years from the discovery of ALK rearrangement in NSCLC to the approval by the Food and Drug Administration (FDA)] marked the beginning of the new decade of targeted therapy. However, common to all targeted therapies, despite an initial benefit, patients inevitably experience tumor progression, due to the development of resistance. Several molecular mechanisms are responsible for acquired resistance, such as secondary mutations of ALK kinase domain or amplification of ALK fusion gene, or the activation of other oncogenic drivers, which may cause resistance independently of ALK genetic alterations. Pre-clinical data and early clinical trials showed the promising efficacy of a new class of ALK-inhibitors in overcoming acquired resistance. The inhibition of the molecular chaperone, HSP90, represents another promising strategy to overcome crizotinib resistance in ALK-rearranged NSCLC. Several molecules are currently under investigation in order to establish their specific role in the treatment of ALK-rearranged NSCLC.

  15. Dodecanedioic acid overcomes metabolic inflexibility in type 2 diabetic subjects. (United States)

    Salinari, Serenella; Bertuzzi, Alessandro; Gandolfi, Alberto; Greco, Aldo V; Scarfone, Antonino; Manco, Melania; Mingrone, Geltrude


    Metabolically healthy skeletal muscle possesses the ability to switch easily between glucose and fat oxidation in response to homeostatic signals. In type 2 diabetes mellitus and obesity, the skeletal muscle shows a great reduction in this metabolic flexibility. A substrate like dodecanedioic acid (C-12), able to increase skeletal muscle glycogen stores via succinyl-CoA formation, might both postpone the fatigue and increase fatty acid utilization, since it does not affect insulin secretion. In healthy volunteers and in type 2 diabetic subjects, the effect of an oral C-12 load was compared with a glucose or water load during prolonged, moderate-intensity, physical exercise. C-12 metabolism was analyzed by a mathematical model. After C-12, diabetics were able to complete the 2 h of exercise. Nonesterified fatty acids increased both during and after the exercise in the C-12 session. C-12 oxidation provided 14% of total energy expenditure, and the sum of C-12 plus lipids oxidized after the C-12 meal was significantly greater than lipids oxidized after the glucose meal (P < 0.025). The fraction of C-12 that entered the central compartment was 47% of that ingested. During the first phase of the exercise ( approximately 60 min), the mean C-12 clearance from the central compartment toward tissues was 2.57 and 1.30 l/min during the second phase of the exercise. In conclusion, C-12 seems to be a suitable energy substrate during exercise, since it reduces muscle fatigue, is rapidly oxidized, and does not stimulate insulin secretion, which implies that lipolysis is not inhibited as reported after glucose ingestion.

  16. Peptide-22 and Cyclic RGD Functionalized Liposomes for Glioma Targeting Drug Delivery Overcoming BBB and BBTB. (United States)

    Chen, Cuitian; Duan, Ziqing; Yuan, Yan; Li, Ruixiang; Pang, Liang; Liang, Jianming; Xu, Xinchun; Wang, Jianxin


    Chemotherapy outcomes for the treatment of glioma remain unsatisfied due to the inefficient drug transport across BBB/BBTB and poor drug accumulation in the tumor site. Nanocarriers functionalized with different targeting ligands are considered as one of the most promising alternatives. However, few studies were reported to compare the targeting efficiency of the ligands and develop nanoparticles to realize BBB/BBTB crossing and brain tumor targeting simultaneously. In this study, six peptide-based ligands (Angiopep-2, T7, Peptide-22, c(RGDfK), D-SP5 and Pep-1), widely used for brain delivery, were selected to decorate liposomes, respectively, so as to compare their targeting ability to BBB or BBTB. Based on the in vitro cellular uptake results on BCECs and HUVECs, Peptide-22 and c(RGDfK) were picked to construct a BBB/BBTB dual-crossing, glioma-targeting liposomal drug delivery system c(RGDfK)/Pep-22-DOX-LP. In vitro cellular uptake demonstrated that the synergetic effect of c(RGDfK) and Peptide-22 could significantly increase the internalization of liposomes on U87 cells. In vivo imaging further verified that c(RGDfK)/Pep-22-LP exhibited higher brain tumor distribution than single ligand modified liposomes. The median survival time of glioma-bearing mice treated with c(RGDfK)/Pep-22-DOX-LP (39.5 days) was significantly prolonged than those treated with free doxorubicin or other controls. In conclusion, the c(RGDfK) and Peptide-22 dual-modified liposome was constructed based on the targeting ability screening of various ligands. The system could effectively overcome BBB/BBTB barriers, target to tumor cells and inhibit the growth of glioma, which proved its potential for improving the efficacy of chemotherapeutics for glioma therapy.

  17. Overcoming the Educational Time Warp: Anticipating a Different Future

    Directory of Open Access Journals (Sweden)

    Garry Jacobs


    Full Text Available Education abridges the time required for individual and social progress by preserving and propagating the essence of human experience. It delivers to youth the accumulated knowledge of countless past generations in an organized and abridged form, so that future generations can start off with all the capacities acquired by their predecessors. However, today education confronts a serious dilemma. We are living in an educational time warp. There is a growing gap between contemporary human experience and what is taught in our educational system and that gap is widening rapidly with each passing year. Today humanity confronts challenges of unprecedented scope, magnitude and intensity. The incremental development of educational content and pedagogy in recent decades has not kept with the ever-accelerating pace of technological and social evolution. Education is also subject to a generational time warp resulting from the fact that many of today’s teachers were educated decades ago during very different times and based on different values and perspectives. The challenge of preparing youth for the future is exasperated by the fact that the future for which we are educating youth does not yet exist and to a large extent is unknown or unknowable. The resulting gap between the content of education and societal needs inhibits our capacity to anticipate and effectively respond to social problems. All these factors argue for a major reorientation of educational content and pedagogy from transmission of acquired knowledge based on past experience to development of the knowledge, skills and capacities of personality needed in a future we cannot clearly envision. We may not be able to anticipate the precise nature of the future, but we can provide an education based on the understanding that it will be very different from the present. In terms of content, the emphasis needs to shift from facts regarding the actual state of affairs in the past, present and

  18. Opportunities to overcome the current limitations and challenges for efficient microbial production of optically pure lactic acid. (United States)

    Abdel-Rahman, Mohamed Ali; Sonomoto, Kenji


    There has been growing interest in the microbial production of optically pure lactic acid due to the increased demand for lactic acid-derived environmentally friendly products, for example biodegradable plastic (poly-lactic acid), as an alternative to petroleum-derived materials. To maximize the market uptake of these products, their cost should be competitive and this could be achieved by decreasing the production cost of the raw material, that is, lactic acid. It is of great importance to isolate and develop robust and highly efficient microbial lactic acid producers. Alongside the fermentative substrate and concentration, the yield and productivity of lactic acid are key parameters and major factors in determining the final production cost of lactic acid. In this review, we will discuss the current limitations and challenges for cost-efficient microbial production of optically pure lactic acid. The main obstacles to effective fermentation are the use of food resources, indirect utilization of polymeric sugars, sensitivity to inhibitory compounds released during biomass treatments, substrate inhibition, decreased lactic acid yield and productivity, inefficient utilization of mixed sugars, end product inhibition, increased use of neutralizing agents, contamination problems, and decreased optical purity of lactic acid. Furthermore, opportunities to address and overcome these limitations, either by fermentation technology or metabolic engineering approaches, will be introduced and discussed.

  19. DNA Isn't Destiny: Healthy Living Can Overcome Genes Linked to Heart Disease (United States)

    ... page: DNA Isn't Destiny: Healthy Living Can Overcome Genes ... unhealthy lifestyle choices. "For heart attack at least, DNA is not destiny," Kathiresan said. "You have control ...

  20. Higher Education in Michigan: Overcoming Challenges to Expand Access. Fact Sheet (United States)

    Cunningham, Alisa F.; Erisman, Wendy; Looney, Shannon E.


    This fact sheet presents a snapshot of important facts from "Higher Education in Michigan: Overcoming Challenges to Expand Access," which examines access to postsecondary degrees and institutions in underserved regions of Michigan. [For the full report, see ED501512.

  1. Overcoming Autophagy to Induce Apoptosis in Castration-Resistant Prostate Cancer (United States)


    AWARD NUMBER: W81XWH-12-1-0529 TITLE: Overcoming Autophagy to Induce Apoptosis in...code) Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 October 2014 Overcoming Autophagy to Induce Apoptosis in Castration...survival mechanism and led cells to undergo apoptosis . Survival mechanisms elicited by CRPC C4-2B cells when treated with Enza may be blocked by

  2. Co-delivery nanoparticles with characteristics of intracellular precision release drugs for overcoming multidrug resistance

    Directory of Open Access Journals (Sweden)

    Zhang DD


    Full Text Available DanDan Zhang,1 Yan Yan Kong,1 Jia Hui Sun,1 Shao Jie Huo,1 Min Zhou,2 Yi Ling Gui,1 Xu Mu,1 Huan Chen,1 Shu Qin Yu,1 Qian Xu3 1Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 2School of Pharmacy, Jiangsu Food and Pharmaceutical Science College, Huai’an, 3Ministry of Education Key Laboratory of Environmental Medicine and Engineering, School of Public Health, Southeast University, Nanjing, People’s Republic of China Abstract: Combination chemotherapy in clinical practice has been generally accepted as a feasible strategy for overcoming multidrug resistance (MDR. Here, we designed and successfully prepared a co-delivery system named S-D1@L-D2 NPs, where denoted some smaller nanoparticles (NPs carrying a drug doxorubicin (DOX were loaded into a larger NP containing another drug (vincristine [VCR] via water-in-oil-in-water double-emulsion solvent diffusion-evaporation method. Chitosan-alginate nanoparticles carrying DOX (CS-ALG-DOX NPs with a smaller diameter of about 20 nm formed S-D1 NPs; vitamin E D-α-tocopheryl polyethylene glycol 1000 succinate-modified poly(lactic-co-glycolic acid nanoparticles carrying VCR (TPGS-PLGA-VCR NPs with a larger diameter of about 200 nm constituted L-D2 NPs. Some CS-ALG-DOX NPs loaded into TPGS-PLGA-VCR NPs formed CS-ALG-DOX@TPGS-PLGA-VCR NPs. Under the acidic environment of cytosol and endosome or lysosome in MDR cell, CS-ALG-DOX@TPGS-PLGA-VCR NPs released VCR and CS-ALG-DOX NPs. VCR could arrest cell cycles at metaphase by inhibiting microtubule polymerization in the cytoplasm. After CS-ALG-DOX NPs escaped from endosome, they entered the nucleus through the nuclear pore and released DOX in the intra-nuclear alkaline environment, which interacted with DNA to stop the replication of MDR cells. These results indicated that S-D1@L-D2 NPs was a co-delivery system of intracellular precision release loaded drugs with p

  3. Co-delivery nanoparticles with characteristics of intracellular precision release drugs for overcoming multidrug resistance (United States)

    Zhang, DanDan; Kong, Yan Yan; Sun, Jia Hui; Huo, Shao Jie; Zhou, Min; Gui, Yi Ling; Mu, Xu; Chen, Huan; Yu, Shu Qin; Xu, Qian


    Combination chemotherapy in clinical practice has been generally accepted as a feasible strategy for overcoming multidrug resistance (MDR). Here, we designed and successfully prepared a co-delivery system named S-D1@L-D2 NPs, where denoted some smaller nanoparticles (NPs) carrying a drug doxorubicin (DOX) were loaded into a larger NP containing another drug (vincristine [VCR]) via water-in-oil-in-water double-emulsion solvent diffusion-evaporation method. Chitosan-alginate nanoparticles carrying DOX (CS-ALG-DOX NPs) with a smaller diameter of about 20 nm formed S-D1 NPs; vitamin E D-α-tocopheryl polyethylene glycol 1000 succinate-modified poly(lactic-co-glycolic acid) nanoparticles carrying VCR (TPGS-PLGA-VCR NPs) with a larger diameter of about 200 nm constituted L-D2 NPs. Some CS-ALG-DOX NPs loaded into TPGS-PLGA-VCR NPs formed CS-ALG-DOX@TPGS-PLGA-VCR NPs. Under the acidic environment of cytosol and endosome or lysosome in MDR cell, CS-ALG-DOX@TPGS-PLGA-VCR NPs released VCR and CS-ALG-DOX NPs. VCR could arrest cell cycles at metaphase by inhibiting microtubule polymerization in the cytoplasm. After CS-ALG-DOX NPs escaped from endosome, they entered the nucleus through the nuclear pore and released DOX in the intra-nuclear alkaline environment, which interacted with DNA to stop the replication of MDR cells. These results indicated that S-D1@L-D2 NPs was a co-delivery system of intracellular precision release loaded drugs with pH-sensitive characteristics. S-D1@L-D2 NPs could obviously enhance the in vitro cytotoxicity and the in vivo anticancer efficiency of co-delivery drugs, while reducing their adverse effects. Overall, S-D1@L-D2 NPs can be considered an innovative platform for the co-delivery drugs of clinical combination chemotherapy for the treatment of MDR tumor.

  4. Overcome shyness

    Institute of Scientific and Technical Information of China (English)



    Shyness means feeling frightened when you are the center of attention.In fact,eye,one gets a little shy sometimes,even the great people in history.Most people have red faces and talk in broken sentences when they get shy.It isn’t a very big problem.But someone become so shy that they can’t do the

  5. Overcoming Loneliness

    Institute of Scientific and Technical Information of China (English)

    Ellen Goodman



  6. NL-103, a novel dual-targeted inhibitor of histone deacetylases and hedgehog pathway, effectively overcomes vismodegib resistance conferred by Smo mutations. (United States)

    Zhao, Jie; Quan, Haitian; Xie, Chengying; Lou, Liguang


    Misregulation of hedgehog (Hh) signaling has been implicated in the pathogenesis of basal cell carcinoma (BCC) and medulloblastoma. Vismodegib, an orally bioavailable Hh signal pathway inhibitor targeting Smo, has been approved for the treatment of advanced BCC. However, acquired drug resistance to vismodegib induced by point mutation in Smo is emerging as a major problem to vismodegib treatment. In this study, we designed and synthesized a novel chimeric compound NL-103, which comprises structural elements of Hh pathway inhibitor vismodegib, and histone deacetylase (HDAC) inhibitor vorinostat. NL-103 simultaneously and significantly inhibited both HDACs and Hh pathway. Importantly, NL-103, as well as vorinostat, effectively overcame vismodegib resistance induced by Smoothened point mutations. Moreover, NL-103 and vorinostat, but not vismodegib, significantly downregulated the expression of Gli2 which plays an important role in Hh pathway. These results indicate that HDAC inhibitory activity is essential for NL-103 to overcome vismodegib resistance and that dual inhibition of HDAC and Hh signaling pathway may be a rational strategy for overcoming vismodegib resistance. Our findings suggest that NL-103 may be a promising compound for clinical development as a more effective Hh pathway inhibitor.

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

    Directory of Open Access Journals (Sweden)

    Rufus Duits


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

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

    Directory of Open Access Journals (Sweden)

    Gözde AKYÜZ


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

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

    Institute of Scientific and Technical Information of China (English)

    Xue Xue; Xing-Jie Liang


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

  10. Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma. (United States)

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


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

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

    DEFF Research Database (Denmark)

    Vilmann, Peter; Seicean, Andrada; Săftoiu, Adrian


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

  12. Modelling Difficulties and Their Overcoming Strategies in the Solution of a Modelling Problem (United States)

    Dede, Ayse Tekin


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

  13. Overcoming Unintelligibility in Aphasia: The Impact of Non-Verbal Interactive Strategies (United States)

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


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

  14. Explaining the Effects of Narrative in an Entertainment Television Program: Overcoming Resistance to Persuasion (United States)

    Moyer-Guse, Emily; Nabi, Robin L.


    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…

  15. A Teacher Accountability Model for Overcoming Self-Exclusion of Pupils (United States)

    Jamal, Abu-Hussain; Tilchin, Oleg; Essawi, Mohammad


    Self-exclusion of pupils is one of the prominent challenges of education. In this paper we propose the TERA model, which shapes the process of creating formative accountability of teachers to overcome the self-exclusion of pupils. Development of the model includes elaboration and integration of interconnected model components. The TERA model…

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

    Energy Technology Data Exchange (ETDEWEB)

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


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

  17. 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


    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)

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

    CERN Document Server

    Davis Kendrick, Kaetrena


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

  19. Comments by ABCT's first female president on overcoming the glass ceiling. (United States)

    Nelson-Gray, Rosemery O


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

  20. A Literature Review of School Practices to Overcome School Failure. OECD Education Working Papers, No. 68 (United States)

    Faubert, Brenton


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

  1. Overcoming Low Self-Efficacy Beliefs in Teaching English to Young Learners (United States)

    Wyatt, Mark


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

  2. Dental Hygiene Entry-Level Program Administrators' Strategies for Overcoming Challenges of Distance Education (United States)

    Buchanan, Bette A.


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

  3. Agent Behavior alignment : A mechanism to overcome problems in agent interactions during runtime

    NARCIS (Netherlands)

    Meyer, Gerben G.; Szirbik, Nick B.; Klusch, M; Hindriks, K; Papazoglou, MP; Strerling, L


    When two or more agents interacting, their behaviors are not necessarily matching. Automated ways to overcome conflicts in the behavior of agents can make the execution of interactions more reliable. Such an alignment mechanism will reduce the necessary human intervention. This paper shows how to de

  4. Math Is Like a Scary Movie? Helping Young People Overcome Math Anxiety (United States)

    Kulkin, Margaret


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

  5. Using Appropriate Digital Tools to Overcome Barriers to Collaborative Learning in Classrooms (United States)

    Wardlow, Liane; Harm, Eian


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

  6. Overcoming Pedagogical Solitude: The Transformative Power of Discipline-Specific Faculty Learning Communities (United States)

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


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

  7. Utility of Concept Cartoons in Diagnosing and Overcoming Misconceptions Related to Photosynthesis (United States)

    Ekici, Fatma; Ekici, Erhan; Aydin, Fatih


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

  8. Development of a Scale to Measure Death Perspectives: Overcoming and Participating. (United States)

    Petty, Eric; Hayslip, Bert; Caballero, Daniela M; Jenkins, Sharon Rae


    Kastenbaum and Aisenberg have suggested that persons can cope with the impact of death and dying by altering their understanding of what each means to them as well as by changing their behavioral responses to such experiences. The present study's purpose was to develop a reliable and valid measure to assess an individual's particular death perspective based on Kastenbaum and Aisenberg's distinctions between overcomers and participators. The Death Perspective Scale developed here assessed the extent to which individuals utilize either an overcoming or participating approach to (a) assigning meaning to dying and death and (b) behaviorally responding to death-related experiences. Based upon the data collected from 168 adults varying by age and gender, findings suggested that both overcoming and participating could be reliably assessed, correlated with measures of death anxiety and death attitudes, and varied reliably (p death and dying and were less accepting in this respect, while participators reported fewer death-related fears and were more accepting. Women and older adults were more participating, while men and younger adults were more overcoming, though such effects varied depending upon whether meaning versus response to death was considered. The consistency between the present findings and the predictions Kastenbaum and Aisenberg suggests that while person's orientations to death and dying seem to transcend sociocultural change, empirically based efforts to better understand how our death system impacts persons need to move forward.

  9. Overcoming Low Self-Efficacy Beliefs in Teaching English to Young Learners (United States)

    Wyatt, Mark


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

  10. Using Ontological Engineering to Overcome AI-ED Problems: Contribution, Impact and Perspectives (United States)

    Mizoguchi, Riichiro; Bourdeau, Jacqueline


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

  11. Use of chemosensitization to overcome fludioxonil-resistance in Penicillium expansum (United States)

    Resistance in two mutant strains of Penicillium expansum to the fungicide fludioxonil was overcome by co-application of natural phenolic chemosensitizing agents that targeted various elements of the oxidative stress-response pathway. Fludioxonil resistance in these strains resulted from cell-linked ...


    Directory of Open Access Journals (Sweden)

    Maria Pascal (căs. Andriescu


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

  13. Overcoming Deformations of the Legal Consciousness of Teenagers through the Medium of Teaching Humanities Subjects



    This article proposes a model for teaching humanities subjects, which is oriented towards overcoming deformations of the legal consciousness of teenagers. The author provides a description of the model’s aims, content, stages, and procedural characteristics. The author views the learning process as the opportunity to forestall illicit behavior by the underage.

  14. Overcoming Deformations of the Legal Consciousness of Teenagers through the Medium of Teaching Humanities Subjects

    Directory of Open Access Journals (Sweden)

    Elena N. Katysheva


    Full Text Available This article proposes a model for teaching humanities subjects, which is oriented towards overcoming deformations of the legal consciousness of teenagers. The author provides a description of the model’s aims, content, stages, and procedural characteristics. The author views the learning process as the opportunity to forestall illicit behavior by the underage.

  15. Reciprocal inhibition in man. (United States)

    Crone, C


    Reciprocal inhibition is the automatic antagonist alpha motor neurone inhibition which is evoked by contraction of the agonist muscle. This so-called natural reciprocal inhibition is a ubiquitous and pronounced phenomenon in man and must be suspected of playing a major role in the control of voluntary movements. The spinal pathways underlying this inhibitory phenomenon were studied. The disynaptic reciprocal Ia inhibitory pathway between the tibial anterior muscle and the soleus alpha motor neurones was identified and described in man. It was shown that the inhibition can be evoked in most healthy subjects at rest, but the degree of inhibition varies considerably from one subject to another. It was concluded that it corresponds to the disynaptic reciprocal Ia inhibitory pathway which has been extensively described in animal experiments. The disynaptic reciprocal inhibition was shown to increase during the dynamic phase of a dorsiflexion movement of the foot, but not during the tonic phase. However, when the peripheral afferent feedback from the contracting muscle was blocked by ischaemia, an increase of the inhibition was revealed also during the tonic phase of the dorsiflexion. The concealment of this increase during unrestrained peripheral feedback from the muscle was thought to be due to the post-activation depression mechanism; a mechanism which was described further and which probably involves reduced transmitter release at Ia afferent terminals as a result of previous activation of these afferent fibers. Hence the hypothesis was supported that alpha motor neurones and the corresponding inhibitory interneurones, which project reciprocal inhibition to the antagonist motor neurones, are activated in parallel during voluntary contraction of agonist muscles. An additional reciprocal inhibitory mechanism, the long latency reciprocal inhibition, was described between the tibial anterior muscle and the soleus alpha motor neurones. It was shown to be evoked by group I

  16. How to overcome the Courant-Friedrichs-Lewy condition of explicit discretizations?

    CERN Document Server

    Dutykh, Denys


    This manuscript contains some thoughts on the discretization of the classical heat equation. Namely, we discuss the advantages and disadvantages of explicit and implicit schemes. Then, we show how to overcome some disadvantages while preserving some advantages. However, since there is no free lunch, there is a price to pay for any improvement in the numerical scheme. This price will be thoroughly discussed below.In particular, we like explicit discretizations for the ease of their implementation even for nonlinear problems. Unfortunately, when these schemes are applied to parabolic equations, severe stability limits appear for the time step magnitude making the explicit simulations prohibitively expensive. Implicit schemes remove the stability limit, but each time step requires now the solution of linear (at best) or even nonlinear systems of equations. However, there exists a number of tricks to overcome (or at least to relax) severe stability limitations of explicit schemes without going into the trouble of...

  17. Vaccines for established cancer: overcoming the challenges posed by immune evasion. (United States)

    van der Burg, Sjoerd H; Arens, Ramon; Ossendorp, Ferry; van Hall, Thorbald; Melief, Cornelis J M


    Therapeutic vaccines preferentially stimulate T cells against tumour-specific epitopes that are created by DNA mutations or oncogenic viruses. In the setting of premalignant disease, carcinoma in situ or minimal residual disease, therapeutic vaccination can be clinically successful as monotherapy; however, in established cancers, therapeutic vaccines will require co-treatments to overcome immune evasion and to become fully effective. In this Review, we discuss the progress that has been made in overcoming immune evasion controlled by tumour cell-intrinsic factors and the tumour microenvironment. We summarize how therapeutic benefit can be maximized in patients with established cancers by improving vaccine design and by using vaccines to increase the effects of standard chemotherapies, to establish and/or maintain tumour-specific T cells that are re-energized by checkpoint blockade and other therapies, and to sustain the antitumour response of adoptively transferred T cells.

  18. Overcoming gaps to advance global health equity: a symposium on new directions for research. (United States)

    Frenk, Julio; Chen, Lincoln


    The 20th anniversary of the groundbreaking report of the Commission on Health Research for Development inspired a Symposium to assess progress made in strengthening essential national health research capacity in developing countries and in global research partnerships. Significant aspects of the health gains achieved in the 20th century can be attributed to the advancement and translation of knowledge, and knowledge continues to occupy center stage amidst growing complexity that characterizes the global health field. The way forward will entail a reinvigoration of research-generated knowledge as a crucial ingredient for global cooperation and global health advances. To do this we will need to overcome daunting gaps, including the divides between domestic and global health, among the disciplines of research (biomedical, clinical, epidemiological, health systems), between clinical and public health approaches, public and private investments, and between knowledge gained and action implemented. Overcoming systematically these obstacles can accelerate progress towards research for equity in health and development.

  19. Overcoming gaps to advance global health equity: a symposium on new directions for research

    Directory of Open Access Journals (Sweden)

    Chen Lincoln


    Full Text Available Abstract The 20th anniversary of the groundbreaking report of the Commission on Health Research for Development inspired a Symposium to assess progress made in strengthening essential national health research capacity in developing countries and in global research partnerships. Significant aspects of the health gains achieved in the 20th century can be attributed to the advancement and translation of knowledge, and knowledge continues to occupy center stage amidst growing complexity that characterizes the global health field. The way forward will entail a reinvigoration of research-generated knowledge as a crucial ingredient for global cooperation and global health advances. To do this we will need to overcome daunting gaps, including the divides between domestic and global health, among the disciplines of research (biomedical, clinical, epidemiological, health systems, between clinical and public health approaches, public and private investments, and between knowledge gained and action implemented. Overcoming systematically these obstacles can accelerate progress towards research for equity in health and development.

  20. Intracellular Self-Assembly of Taxol Nanoparticles for Overcoming Multidrug Resistance. (United States)

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


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

  1. Quantum Error-Correction-Enhanced Magnetometer Overcoming the Limit Imposed by Relaxation. (United States)

    Herrera-Martí, David A; Gefen, Tuvia; Aharonov, Dorit; Katz, Nadav; Retzker, Alex


    When incorporated in quantum sensing protocols, quantum error correction can be used to correct for high frequency noise, as the correction procedure does not depend on the actual shape of the noise spectrum. As such, it provides a powerful way to complement usual refocusing techniques. Relaxation imposes a fundamental limit on the sensitivity of state of the art quantum sensors which cannot be overcome by dynamical decoupling. The only way to overcome this is to utilize quantum error correcting codes. We present a superconducting magnetometry design that incorporates approximate quantum error correction, in which the signal is generated by a two qubit Hamiltonian term. This two-qubit term is provided by the dynamics of a tunable coupler between two transmon qubits. For fast enough correction, it is possible to lengthen the coherence time of the device beyond the relaxation limit.

  2. An AS1411 aptamer-conjugated liposomal system containing a bubble-generating agent for tumor-specific chemotherapy that overcomes multidrug resistance. (United States)

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


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

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

    DEFF Research Database (Denmark)

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


    regard the anatomical locations and cell subsets that harbor persistent HIV. Combinatorial research challenges pertain to the order of administration, timing of administration and specific combinations of compounds to be administered during HIV eradication therapy. Overcoming these challenges...... for directly addressing these research challenges. The aim of this manuscript is to provide a comprehensive review of these recent translational advances made in animal models of HIV persistence....

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

    Directory of Open Access Journals (Sweden)

    Zeljko Maric


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

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


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


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

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

    Directory of Open Access Journals (Sweden)

    Nikiema Béatrice


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

  7. Meiosis in a Bottle: New Approaches to Overcome Mammalian Meiocyte Study Limitations

    Directory of Open Access Journals (Sweden)

    Montserrat Garcia Caldes


    Full Text Available The study of meiosis is limited because of the intrinsic nature of gametogenesis in mammals. One way to overcome these limitations would be the use of culture systems that would allow meiotic progression in vitro. There have been some attempts to culture mammalian meiocytes in recent years. In this review we will summarize all the efforts to-date in order to culture mammalian sperm and oocyte precursor cells.

  8. Meiosis in a Bottle : New Approaches to Overcome Mammalian Meiocyte Study Limitations


    Montserrat Garcia Caldes; Ignasi Roig; Miguel Angel Brieno-Enriquez


    The study of meiosis is limited because of the intrinsic nature of gametogenesis in mammals. One way to overcome these limitations would be the use of culture systems that would allow meiotic progression in vitro. There have been some attempts to culture mammalian meiocytes in recent years. In this review we will summarize all the efforts to-date in order to culture mammalian sperm and oocyte precursor cells.

  9. Public private partnership - a way of overcoming the budget process investment restrictions in european transport infrastructure


    Cernaianu, Nicolae; Achim, Marian Lucian


    One of the ways to overcome, to some extent, the budgetary restrictions on the state's financial resources for investment in transport infrastructure is a public-private partnership. Thus, we considered it useful to express our own opinions as well as reiterating the presentation of world and European experiences by experts in the field of benefits and risks of public-private partnership, and the study which useful lessons can be drawn. We are not just for copying or taking of these experienc...

  10. Balloon-Assisted Tracking to Overcome Radial Spasm during Transradial Coronary Angiography: A Case Report


    Verouden, N. J. W.; Kiemeneij, F.


    Spasm of the radial artery is the most important cause of failure to perform coronary angiography via the transradial approach. Spasmolytic cocktail may prevent radial artery spasm but is relatively contraindicated in patients with aortic stenosis or diminished left ventricular function. In this case report we describe a recently published technique to overcome severe radial spasm during transradial coronary angiography in a patient with moderate aortic valve stenosis.

  11. Balloon-Assisted Tracking to Overcome Radial Spasm during Transradial Coronary Angiography: A Case Report. (United States)

    Verouden, N J W; Kiemeneij, F


    Spasm of the radial artery is the most important cause of failure to perform coronary angiography via the transradial approach. Spasmolytic cocktail may prevent radial artery spasm but is relatively contraindicated in patients with aortic stenosis or diminished left ventricular function. In this case report we describe a recently published technique to overcome severe radial spasm during transradial coronary angiography in a patient with moderate aortic valve stenosis.

  12. Balloon-Assisted Tracking to Overcome Radial Spasm during Transradial Coronary Angiography: A Case Report

    Directory of Open Access Journals (Sweden)

    N. J. W. Verouden


    Full Text Available Spasm of the radial artery is the most important cause of failure to perform coronary angiography via the transradial approach. Spasmolytic cocktail may prevent radial artery spasm but is relatively contraindicated in patients with aortic stenosis or diminished left ventricular function. In this case report we describe a recently published technique to overcome severe radial spasm during transradial coronary angiography in a patient with moderate aortic valve stenosis.

  13. Can Hare's two-level utilitarianism overcome the problems facing act-utilitarianism?


    Roberts, Emma


    In order to provide a positive defence of utilitarianism, R.M Hare presented his own theory of 'two-level' utilitarianism, claiming that it overcame the main objections directed towards traditional act utilitarianism. This essay firstly outlines the main problems associated with utilitarianism and examines whether Hare's theory is indeed able to successfully overcome them. It then goes on to examine the coherence of two-level utilitarianism itself, and thus determine whether it can provide a ...

  14. Mycophenolic Acid Overcomes Imatinib and Nilotinib Resistance of Chronic Myeloid Leukemia Cells by Apoptosis or a Senescent-Like Cell Cycle Arrest

    Directory of Open Access Journals (Sweden)

    Claire Drullion


    Full Text Available We used K562 cells sensitive or generated resistant to imatinib or nilotinib to investigate their response to mycophenolic acid (MPA. MPA induced DNA damage leading to cell death with a minor contribution of apoptosis, as revealed by annexin V labeling (up to 25%. In contrast, cell cycle arrest and positive staining for senescence-associated β-galactosidase activity were detected for a large cell population (80%. MPA-induced cell death was potentialized by the inhibition of autophagy and this is associated to the upregulation of apoptosis. In contrast, senescence was neither decreased nor abrogated in autophagy deficient K562 cells. Primary CD34 cells from CML patients sensitive or resistant to imatinib or nilotinib respond to MPA although apoptosis is mainly detected. These results show that MPA is an interesting tool to overcome resistance in vitro and in vivo mainly in the evolved phase of the disease.

  15. Is it possible to overcome suicidal ideation and suicide attempts? A study of the elderly. (United States)

    Figueiredo, Ana Elisa Bastos; da Silva, Raimunda Magalhães; Vieira, Luiza Jane Eyre Souza; Mangas, Raimunda Matilde do Nascimento; de Sousa, Girliani Silva; Freitas, Jarlideire Soares; Conte, Marta; Sougey, Everton Botelho


    This study presents a qualitative analysis of how older people who had attempted suicide began to overcome the desire and the urge to take their own life. This article is based on a survey of 87 Brazilian men and women aged 60 and over, living in different regions of Brazil, who have demonstrated suicidal behaviour; twenty of whom gave important information about their coping strategies. The analysis in this article only refers to the aforementioned twenty participants. All the participants were heard through semi-structured interviews, which included questions about the process of overcoming suicidal ideation and suicide attempts. The central focus of the analysis - overcoming suicidal ideation and suicide attempts - was based on the following concepts: coping strategies, autonomy, and emotional balance. Irrespective of the gender of the respondents, five centers of meaning emerged from the discourses of the elderly, which highlighted the effectiveness of the following factors: religiosity and religious practices; social and family support; the support of health services; contact with pets; and the recovery of the autonomy to manage their own lives. This study can help to support the primary and secondary prevention of suicidal behavior in older people.

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

    Directory of Open Access Journals (Sweden)

    Amanda Badenhorst


    Full Text Available Background: Reverse logistics is a complex process, and many organisations experience operational barriers that prevent them from successfully managing the process. This study overcomes the gap in research regarding the most important practices that organisations can implement to overcome operational barriers in reverse logistics.Objectives: The study aims to identify operational barriers preventing the efficient performance of the reverse logistics process, matching them to applicable practices by means of a theoretical framework and prioritising the implementation of appropriate practices with the inputs of practitioners.Method: The study used a survey method, and data were collected by means of a questionnaire based on a theoretical framework that was sent to organisations that offered reverse logistics as a service or specialised in reverse logistics in South Africa. The study used descriptive statistics to conduct a gap-and-opportunity analysis.Results: Respondents were asked to indicate the importance of the practices and how difficult they would be to implement. Results showed that all the practices are important to at least a moderate extent but some are more difficult to implement.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.

  17. Synthetic lethal screening reveals FGFR as one of the combinatorial targets to overcome resistance to Met-targeted therapy. (United States)

    Kim, B; Wang, S; Lee, J M; Jeong, Y; Ahn, T; Son, D-S; Park, H W; Yoo, H-s; Song, Y-J; Lee, E; Oh, Y M; Lee, S B; Choi, J; Murray, J C; Zhou, Y; Song, P H; Kim, K-A; Weiner, L M


    Met is a receptor tyrosine kinase that promotes cancer progression. In addition, Met has been implicated in resistance of tumors to various targeted therapies such as epidermal growth factor receptor inhibitors in lung cancers, and has been prioritized as a key molecular target for cancer therapy. However, the underlying mechanism of resistance to Met-targeting drugs is poorly understood. Here, we describe screening of 1310 genes to search for key regulators related to drug resistance to an anti-Met therapeutic antibody (SAIT301) by using a small interfering RNA-based synthetic lethal screening method. We found that knockdown of 69 genes in Met-amplified MKN45 cells sensitized the antitumor activity of SAIT301. Pathway analysis of these 69 genes implicated fibroblast growth factor receptor (FGFR) as a key regulator for antiproliferative effects of Met-targeting drugs. Inhibition of FGFR3 increased target cell apoptosis through the suppression of Bcl-xL expression, followed by reduced cancer cell growth in the presence of Met-targeting drugs. Treatment of cells with the FGFR inhibitors substantially restored the efficacy of SAIT301 in SAIT301-resistant cells and enhanced the efficacy in SAIT301-sensitive cells. In addition to FGFR3, integrin β3 is another potential target for combination treatment with SAIT301. Suppression of integrin β3 decreased AKT phosphorylation in SAIT301-resistant cells and restored SAIT301 responsiveness in HCC1954 cells, which are resistant to SAIT301. Gene expression analysis using CCLE database shows that cancer cells with high levels of FGFR and integrin β3 are resistant to crizotinib treatment, suggesting that FGFR and integrin β3 could be used as predictive markers for Met-targeted therapy and provide a potential therapeutic option to overcome acquired and innate resistance for the Met-targeting drugs.

  18. Rational combination of targeted therapies as a strategy to overcome the mechanisms of resistance to inhibitors of EGFR signaling. (United States)

    Bianco, Roberto; Damiano, Vincenzo; Gelardi, Teresa; Daniele, Gennaro; Ciardiello, Fortunato; Tortora, Giampaolo


    The epidermal growth factor receptor (EGFR) has been widely used as a target for novel anticancer agents, such as blocking antibodies and small molecular weight tyrosine kinase compounds. In spite of recent advances in cancer cell biology, leading to the introduction of clinically active new drugs, such as cetuximab, panitumumab and erlotinib, unfortunately disease control remains unsuccessful due to the presence of constitutive resistance to EGFR inhibitors in most patients and the development of acquired resistance in the responders. A large number of molecular abnormalities in tumor cells seem to partly contribute to their resistance to anti-EGFR therapy: increased angiogenesis, constitutive activation of downstream mediators, overexpression of other tyrosine kinase receptors. Moreover, some mutations in the EGFR receptor kinase domain seem to play a crucial role in determining the sensitivity of cancer cells to specific inhibitors by altering the conformation of the receptor and its activity. The development of rational combinations of anticancer agents and EGFR inhibitors, able to exert synergistic cytotoxic interactions, has been widely accepted and used in both preclinical and clinical studies. Although the failure of large clinical trial based on empirical combination of anti-EGFR and classic chemotherapeutic agents, several preclinical data seems to support the hypothesis that combining EGFR inhibitors and other novel agents could efficiently inhibit tumor growth and overcome intrinsic resistance to a single-agent based therapy. This review focuses on the role of complementary signalling pathways in the development of resistance to EGFR targeting agents and the rationale to combine novel inhibitors as anticancer therapy.

  19. Overcoming Resistance to Change: An Analysis to the Department of Defense’s Anthrax Vaccine Immunization Program (United States)


    strategies for overcoming resistance to change , in the midst of a proposed initiative that has become stalled as a result of mistrust and cynicism. The results...published similarities and differences in the areas Change Management, Organizational Change, Resistance to Change , Overcoming Resistance to Change , and

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

    Jonas, Mark E.


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

  1. Potentiation of latent inhibition. (United States)

    Rodriguez, Gabriel; Hall, Geoffrey


    Rats were given exposure either to an odor (almond) or a compound of odor plus taste (almond plus saline), prior to training in which the odor served as the conditioned stimulus. It was found, for both appetitive and aversive procedures, that conditioning was retarded by preexposure (a latent inhibition effect), and the extent of the retardation was greater in rats preexposed to the compound (i.e., latent inhibition to the odor was potentiated by the presence of the taste). In contrast, the presence of the taste during conditioning itself overshadowed learning about the odor. We argue that the presence of the salient taste in compound with the odor enhances the rate of associative learning, producing a rapid loss in the associability of the odor. This loss of associability will generate both overshadowing and the potentiation of latent inhibition that is observed after preexposure to the compound.

  2. Overcoming acquired drug resistance in colorectal cancer cells by targeted delivery of 5-FU with EGF grafted hollow mesoporous silica nanoparticles (United States)

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


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

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

    Directory of Open Access Journals (Sweden)

    Kirsten Barnicot

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

  4. Overcoming Barriers to Skills Training in Borderline Personality Disorder: A Qualitative Interview Study. (United States)

    Barnicot, Kirsten; Couldrey, Laura; Sandhu, Sima; Priebe, Stefan


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

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

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


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

  6. Hedgehog Signaling Overcomes an EZH2-Dependent Epigenetic Barrier to Promote Cholangiocyte Expansion (United States)

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


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

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

    Directory of Open Access Journals (Sweden)

    Nina Aminah


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


    Directory of Open Access Journals (Sweden)

    E. I. Marukovich


    Full Text Available The main difficulties of the modern theory of crystallization of metal fusion are imperfect ideas of a structure of fusions, processes of origin and growth of crystals and influence of nonmetallic particles and the dissolved gases. In order to overcome these difficulties it is necessary to assume: fusions consist of stable nanocrystals and atomic unstructured zones; the centers of crystallization of phases are formed of nanocrystals of these phases; the basic construction elements of crystals are not atoms, but nanocrystals; nonmetallic particles play a supporting role in the course of crystallization; the dissolved gases exert direct impact on formation of crystals and their morphology.

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

    Directory of Open Access Journals (Sweden)

    Isola Ajiferuke


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

  10. Right to assisted reproductive technology: overcoming infertility in low-resource countries. (United States)

    Inhorn, Marcia C


    This article examines the high prevalence of primary and secondary infertility in low-resource countries. Provision of assisted reproductive technology (ART) to overcome both female and male infertility is in line with the reproductive rights agenda developed at the International Conference on Population and Development (ICPD) in Cairo 15 years ago. In addition to the right to control fertility, reproductive rights must encompass the right to facilitate fertility when fertility is threatened. Facilitation of fertility may require resort to ART, among both men and women. Egypt is highlighted as a positive example of progress in this regard.

  11. Overcoming instability and low solubility of new cytostatic compounds: A comparison of two approaches

    DEFF Research Database (Denmark)

    di Cagno, M.; Stein, P. C.; Styskala, J.


    of the antioxidant activity of the specific surfactant used, combined with the low amount of water present in the center of the micelles. On this regard, H-1 NMR and UV-vis spectroscopy result as efficient tools to verify that the drug molecules are indeed placed in the core of the micelles. Moreover, freeze......-drying provides a very easy and powerful technique to obtain solid formulations starting from micellar dispersions. On the contrary, cyclodextrins could potentially be used as solubilizing agents, but the drawback connected to degradation in aqueous media could not be overcome with this type of solubilizer. (C...

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

    CERN Document Server

    Settle-Murphy, Nancy M


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


    Energy Technology Data Exchange (ETDEWEB)



    Dual partial snake scheme has provided polarized proton beams with 1.5 x 10{sup 11} intensity and 65% polarization for the Relativistic Heavy Ion Collider (RHIC) spin program. To overcome the residual polarization loss due to horizontal resonances in the Brookhaven Alternating Gradient Synchrotron (AGS), a new string of quadrupoles have been added. The horizontal tune can then be set in the spin tune gap generated by the two partial snakes, such that horizontal resonances can also be avoided. This paper presents the accelerator setup and preliminary results.

  14. Overcoming Obstacles to Collecting Narrative Data from Eye Care Professionals at the Point-of-Care (United States)

    Silvey, Garry M.; Lobach, David F.; Macri, Jennifer M.; Hunt, Megan; Kacmaz, Roje O.; Lee, Paul P.


    Capturing the nuances of clinical observations in an electronic format has been a major challenge in implementing electronic health records. In a formative evaluation study using three different methodologies, we identified that the greatest obstacle to point-of-care data entry for eye care was supporting free text annotation of clinical observations. To overcome this obstacle, we developed an approach that captures an image of a free text entry and associates this image with related data elements in an encounter note. Through simulated patient studies, we observed that this approach successfully supported complex documentation at the point of care by clinicians. PMID:16779403

  15. Overcoming the concentration-dependence of responsive probes for magnetic resonance imaging (United States)

    Ekanger, Levi A.


    In magnetic resonance imaging, contrast agents are molecules that increase the contrast-to-noise ratio of non-invasively acquired images. The information gained from magnetic resonance imaging can be increased using responsive contrast agents that undergo chemical changes, and consequently changes to contrast enhancement, for example in response to specific biomarkers that are indicative of diseases. A major limitation with modern responsive contrast agents is concentration-dependence that requires the concentration of contrast agent to be known: an extremely challenging task in vivo. Here, we review advances in several strategies aimed at overcoming the concentration-dependent nature of responsive contrast agents. PMID:25579206

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

    DEFF Research Database (Denmark)

    Israelsen, Poul; Jørgensen, Brian


    which distorts the economic effects of modularization at the level of the individual product. This has the implication that decisions on modularization can only be made by top management if decision authority and relevant information are to be aligned. To overcome this problem, we suggest a solution...... that aligns the descriptions of the economic consequences of modularization at the project and portfolio level which makes it possible to decentralize decision making while making sure that local goals are congruent with the global ones in order to avoid suboptimal behaviour....

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

    Energy Technology Data Exchange (ETDEWEB)



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


    Directory of Open Access Journals (Sweden)

    Ambar Sari Dewi


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

  19. The pan-HER family tyrosine kinase inhibitor afatinib overcomes HER3 ligand heregulin-mediated resistance to EGFR inhibitors in non-small cell lung cancer. (United States)

    Yonesaka, Kimio; Kudo, Keita; Nishida, Satomi; Takahama, Takayuki; Iwasa, Tsutomu; Yoshida, Takeshi; Tanaka, Kaoru; Takeda, Masayuki; Kaneda, Hiroyasu; Okamoto, Isamu; Nishio, Kazuto; Nakagawa, Kazuhiko


    Afatinib is a second generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) characterized as an irreversible pan-human EGFR (HER) family inhibitor. Afatinib remains effective for a subpopulation of patients with non-small cell lung cancer (NSCLC) with acquired resistance to first generation EGFF-TKIs such as erlotinib. Heregulin activates HER3 in an autocrine fashion and causes erlotinib resistance in NSCLC. Here we examine whether afatinib is effective against heregulin-overexpressing NSCLCs harboring EGFR activating mutations. Afatinib but not erlotinib decreased EGFR mutant NSCLC PC9HRG cell proliferation in vitro and in mouse xenografts. Afatinib inhibited phosphorylation of the cell signaling pathway proteins HER3, EGFR, HER2, and HER4, likely by prevention of trans-phosphorylation as HER3 kinase activity is inadequate for auto-phosphorylation. Afatinib, unlike erlotinib, inhibited AKT activation, resulting in elevated apoptosis in PC9HRG cells. Clinically, a subpopulation of 33 patients with EGFR mutations and NSCLC who had received first generation EGFR-TKIs exhibited elevated plasma heregulin levels compared to healthy volunteers; one of these achieved a response with afatinib therapy despite having previously developed erlotinib resistance. Afatinib can overcome heregulin-mediated resistance to erlotinib in EGFR mutant NSCLC. Further studies are necessary to determine whether heregulin can predict afatinib efficacy after development offirst generation EGFR-TKI resistance.

  20. Prox1 regulates the notch1-mediated inhibition of neurogenesis.

    Directory of Open Access Journals (Sweden)

    Valeria Kaltezioti

    Full Text Available Activation of Notch1 signaling in neural progenitor cells (NPCs induces self-renewal and inhibits neurogenesis. Upon neuronal differentiation, NPCs overcome this inhibition, express proneural genes to induce Notch ligands, and activate Notch1 in neighboring NPCs. The molecular mechanism that coordinates Notch1 inactivation with initiation of neurogenesis remains elusive. Here, we provide evidence that Prox1, a transcription repressor and downstream target of proneural genes, counteracts Notch1 signaling via direct suppression of Notch1 gene expression. By expression studies in the developing spinal cord of chick and mouse embryo, we showed that Prox1 is limited to neuronal precursors residing between the Notch1+ NPCs and post-mitotic neurons. Physiological levels of Prox1 in this tissue are sufficient to allow binding at Notch1 promoter and they are critical for proper Notch1 transcriptional regulation in vivo. Gain-of-function studies in the chick neural tube and mouse NPCs suggest that Prox1-mediated suppression of Notch1 relieves its inhibition on neurogenesis and allows NPCs to exit the cell cycle and differentiate. Moreover, loss-of-function in the chick neural tube shows that Prox1 is necessary for suppression of Notch1 outside the ventricular zone, inhibition of active Notch signaling, down-regulation of NPC markers, and completion of neuronal differentiation program. Together these data suggest that Prox1 inhibits Notch1 gene expression to control the balance between NPC self-renewal and neuronal differentiation.

  1. Enzyme inhibition by iminosugars

    DEFF Research Database (Denmark)

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


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

  2. Counter-stereotypical pictures as a strategy for overcoming spontaneous gender stereotypes. (United States)

    Finnegan, Eimear; Oakhill, Jane; Garnham, Alan


    The present research investigated the use of counter-stereotypical pictures as a strategy for overcoming spontaneous gender stereotypes when certain social role nouns and professional terms are read. Across two experiments, participants completed a judgment task in which they were presented with word pairs comprised of a role noun with a stereotypical gender bias (e.g., beautician) and a kinship term with definitional gender (e.g., brother). Their task was to quickly decide whether or not both terms could refer to one person. In each experiment they completed two blocks of such judgment trials separated by a training session in which they were presented with pictures of people working in gender counter-stereotypical (Experiment 1) or gender stereotypical roles (Experiment 2). To ensure participants were focused on the pictures, they were also required to answer four questions on each one relating to the character's leisure activities, earnings, job satisfaction, and personal life. Accuracy of judgments to stereotype incongruent pairings was found to improve significantly across blocks when participants were exposed to counter-stereotype images (9.87%) as opposed to stereotypical images (0.12%), while response times decreased significantly across blocks in both studies. It is concluded that exposure to counter-stereotypical pictures is a valuable strategy for overcoming spontaneous gender stereotype biases in the short term.

  3. Inorganic nanoparticle-based drug codelivery nanosystems to overcome the multidrug resistance of cancer cells. (United States)

    Chen, Yu; Chen, Hangrong; Shi, Jianlin


    Biocompatible inorganic material-based nanosystems provide a novel choice to effectively circumvent the intrinsic drawbacks of traditional organic materials in biomedical applications, especially in overcoming the multidrug resistance (MDR) of cancer cells due to their unique structural and compositional characteristics, for example, high stability, large surface area, tunable compositions, abundant physicochemical multifunctionalities, and specific biological behaviors. In this review, we focus on the recent developments in the construction of inorganic nanoparticles-based drug codelivery nanosystems (mesoporous SiO2, Fe3O4, Au, Ag, quantum dots, carbon nanotubes, graphene oxide, LDH, etc.) to efficiently circumvent the MDR of cancer cells, including the well-known codelivery of small molecular anticancer drug/macromolecular therapeutic gene and codelivery of small molecular chemosensitizer/anticancer drug, and very recently explored codelivery of targeting ligands/anticancer drug, codelivery of energy/anticancer drug, and codelivery of contrast agent for diagnostic imaging and anticancer drug. The unsolved issues, future developments, and potential clinical translations of these codelivery nanosystems are also discussed. These elaborately designed biocompatible inorganic materials-based nanosystems offer an unprecedented opportunity and show the encouraging bright future for overcoming the MDR of tumors in clinic personalized medicine and the pharmaceutical industry.

  4. OAK-based cochleates as a novel approach to overcome multidrug resistance in bacteria. (United States)

    Livne, L; Epand, R F; Papahadjopoulos-Sternberg, B; Epand, R M; Mor, A


    Antibiotic resistance has become a worldwide medical problem. To find new ways of overcoming this phenomenon, we investigated the role of the membrane-active oligo-acyl-lysyl (OAK) sequence C(12)K-7α(8), in combination with essentially ineffective antibiotics. Determination of minimal inhibitory concentration (MIC) against gram-negative multidrug-resistant strains of Escherichia coli revealed combinations with sub-MIC OAK levels that acted synergistically with several antibiotics, thus lowering their MICs by several orders of magnitude. To shed light into the molecular basis for this synergism, we used both mutant strains and biochemical assays. Our results suggest that bacterial sensitization to antibiotics was derived mainly from the OAK's capacity to overcome the efflux-enhanced resistance mechanism, by promoting backdoor entry of otherwise excluded antibiotics. To facilitate simultaneous delivery of the pooled drugs to an infection site, we developed a novel OAK-based cochleate system with demonstrable stability in whole blood. To assess the potential therapeutic use of such cochleates, we performed preliminary experiments that imitate systemic treatment of neutropenic mice infected with lethal inoculums of multidrug resistance E. coli. Single-dose administration of erythromycin coencapsulated in OAK-based cochleates has decreased drug toxicity and increased therapeutic efficacy in a dose-dependent manner. Collectively, our findings suggest a potentially useful approach for fighting efflux-enhanced resistance mechanisms.

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

    Directory of Open Access Journals (Sweden)

    Rachna Verma


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

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

    Directory of Open Access Journals (Sweden)

    Adam Simning


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

  7. The Role of Carrier Geometry in Overcoming Biological Barriers to Drug Delivery. (United States)

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


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

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

    Institute of Scientific and Technical Information of China (English)



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


    Directory of Open Access Journals (Sweden)



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

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

    Directory of Open Access Journals (Sweden)

    Rodrigo Ramos Lopes


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

  11. [High-dose chemotherapy as a strategy to overcome drug resistance in solid tumors]. (United States)

    Selle, Frédéric; Gligorov, Joseph; Soares, Daniele G; Lotz, Jean-Pierre


    The concept of high-doses chemotherapy was developed in the 1980s based on in vitro scientific observations. Exposure of tumor cells to increasing concentrations of alkylating agents resulted in increased cell death in a strong dose-response manner. Moreover, the acquired resistance of tumor cells could be overcome by dose intensification. In clinic, dose intensification of alkylating agents resulted in increased therapeutic responses, however associated with significant hematological toxicity. Following the development of autologous stem cells transplantation harvesting from peripheral blood, the high-doses of chemotherapy, initially associated with marked toxic effects, could be more easily tolerated. As a result, the approach was evaluated in different types of solid tumors, including breast, ovarian and germ cell tumors, small cell lung carcinoma, soft tissue sarcomas and Ewing sarcoma. To date, high-doses chemotherapy with hematopoietic stem cells support is only used as a salvage therapy to treat poor prognosis germ cell tumors patients with chemo-sensitive disease. Regarding breast and ovarian cancer, high-doses chemotherapy should be considered only in the context of clinical trials. However, intensive therapy as an approach to overcome resistance to standard treatments is still relevant. Numerous efforts are still ongoing to identify novel therapeutic combinations and active treatments to improve patients' responses.

  12. Harnessing atomistic simulations to predict the rate at which dislocations overcome obstacles (United States)

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


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

  13. Overcoming drug crystallization in electrospun fibers--Elucidating key parameters and developing strategies for drug delivery. (United States)

    Seif, Salem; Franzen, Lutz; Windbergs, Maike


    For the development of novel therapeutics, uncontrolled crystallization of drugs within delivery systems represents a major challenge. Especially for thin and flexible polymeric systems such as oral films or dermal wound dressings, the formation and growth of drug crystals can significantly affect drug distribution and release kinetics as well as physical storage stability. In this context, electrospinning was introduced as a fabrication technique with the potential to encapsulate drugs within ultrafine fibers by rapid solvent evaporation overcoming drug crystallization during fabrication and storage. However, these effects could so far only be shown for specific drug-polymer combinations and an in-depth understanding of the underlying processes of drug-loaded fiber formation and influencing key parameters is still missing. In this study, we systematically investigated crystal formation of caffeine as a model drug in electrospun fibers comparing different polymers. The solvent polarity was found to have a major impact on the drug crystal formation, whereas only a minor effect was attributed to the electrospinning process parameters. Based on an in-depth understanding of the underlying processes determining drug crystallization processes in electrospun fibers, key parameters could be identified which allow for the rational development of drug-loaded electrospun fibers overcoming drug crystallization.

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

    Energy Technology Data Exchange (ETDEWEB)

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


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

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

    Directory of Open Access Journals (Sweden)

    Eimear eFinnegan


    Full Text Available The present research investigated the use of counter-stereotypical pictures as a strategy for overcoming spontaneous gender stereotypes when certain social role nouns and professional terms are read. Across two experiments, participants completed a judgement task in which they were presented with word pairs comprised of a role noun with a stereotypical gender bias (e.g. beautician and a kinship term with definitional gender (e.g. brother. Their task was to quickly decide whether or not both terms could refer to one person. In each experiment they completed 2 blocks of such judgement trials separated by a training session in which they were presented with pictures of people working in gender counter-stereotypical (Experiment 1 or gender stereotypical roles (Experiment 2. To ensure participants were focused on the pictures, they were also required to answer 4 questions on each one relating to the character’s leisure activities, earnings, job satisfaction and personal life. Accuracy of judgements to stereotype incongruent pairings was found to improve significantly across blocks when participants were exposed to counter-stereotype images (9.87% as opposed to stereotypical images (0.12%, while response times decreased significantly across blocks in both studies. It is concluded that exposure to counter-stereotypical pictures is a valuable strategy for overcoming spontaneous gender stereotype biases in the short term.

  16. A useful method to overcome the difficulties of applying silicone gel sheet on irregular surfaces. (United States)

    Grella, Roberto; Nicoletti, Gianfranco; D'Ari, Antonio; Romanucci, Vincenza; Santoro, Mariangela; D'Andrea, Francesco


    To date, silicone gel and silicone occlusive plates are the most useful and effective treatment options for hypertrophic scars (surgical and traumatic). Use of silicone sheeting has also been demonstrated to be effective in the treatment of minor keloids in association with corticosteroid intralesional infiltration. In our practice, we encountered four problems: maceration, rashes, pruritus and infection. Not all patients are able to tolerate the cushion, especially children, and certain anatomical regions as the face and the upper chest are not easy to dress for obvious social, psychological and aesthetic reasons. In other anatomical regions, it is also difficult to obtain adequate compression and occlusion of the scar. To overcome such problems of applying silicone gel sheeting, we tested the use of liquid silicone gel (LSG) in the treatment of 18 linear hypertrophic scars (HS group) and 12 minor keloids (KS group) as an alternative to silicone gel sheeting or cushion. Objective parameters (volume, thickness and colour) and subjective symptoms such as pain and pruritus were examined. Evaluations were made when the therapy started and after 30, 90 and 180 days of follow-up. After 90 days of treatment with silicone gel alone (two applications daily), HS group showed a significant improvement in terms of volume decrease, reduced inflammation and redness and improved elasticity. In conclusion, on the basis of our clinical data, we find LSG to be a useful method to overcome the difficulties of applying silicone gel sheeting on irregular surface.

  17. Factors in Overcoming Barriers to Implementing Co-management in British Columbia Salmon Fisheries

    Directory of Open Access Journals (Sweden)

    Evelyn Pinkerton


    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.

  18. Overcoming constraints to the implementation of water demand management in southern Africa (United States)

    Mwendera, E. J.; Hazelton, D.; Nkhuwa, D.; Robinson, P.; Tjijenda, K.; Chavula, G.

    This paper presents results of a study on water demand management status and overcoming constraints to implementation of water demand management in the southern African region, as part of Phase II of water demand management (WDM) programme implemented by the IUCN (The World Conservation Union). The study was conducted in Malawi, Namibia, South Africa, Swaziland, Zambia and Zimbabwe. The study methodology consisted of a survey of literature, and interviewing and communicating with stakeholders in order to learn from stakeholders on the critical constraints to WDM implementation and strategies to overcome them. The study has shown that, despite the potential savings that would accrue from implementation of WDM, the water sector across the southern African region continues to focus on water supply augmentation. There are inadequate financial and human resources for rehabilitation, operation and maintenance of water conveyance systems resulting in system leaks, which contribute to high levels of unaccounted-for water, a situation that masks the potential benefits of WDM. In most countries, the water sector operates on ad-hoc sub-sector water user objectives, which provided guidelines only for development and management purposes. Most of the institutional frameworks have remained diffuse, resulting into poor performance in the sector, and into crisis management in the water resources development. Though the WDM policy in most countries is already accessible through guidelines for catchment management institutions and water supply institutions; there is a lack of broad commitment to implementing them. In other countries the instruments are relatively new and have not been applied widely. Similarly, the effectiveness of instruments has not been well evaluated in most countries. In countries where policy is weak there is often a lack of clarity as to who is responsible for WDM implementation, and even less clarity on who is responsible for facilitating and monitoring

  19. Plastics for corrosion inhibition

    CERN Document Server

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


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

  20. Inhibition and Brain Work


    Buzsáki, György; Kaila, Kai; Raichle, Marcus


    The major part of the brain’s energy budget (~60%–80%) is devoted to its communication activities. While inhibition is critical to brain function, relatively little attention has been paid to its metabolic costs. Understanding how inhibitory interneurons contribute to brain energy consumption (brain work) is not only of interest in understanding a fundamental aspect of brain function but also in understanding functional brain imaging techniques which rely on measurements related to blood flow...

  1. Midfrontal theta dynamics reflect the ability to overcome motivational biases in decision making

    NARCIS (Netherlands)

    Swart, J.C.; Määttä, J.I.M.; Cools, R.; Ouden, H.E.M. den


    19th biennial IPEG Meeting: Nijmegen, The Netherlands. 26-30 October 2016. Our motivations influence our actions in predictable ways. The promise of a reward promotes behavioural activation, while the threat of a punishment context promotes inhibition. However, these motivational biases can at times

  2. 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.

  3. Overcoming challenges to gender equality in the workplace leadership and innovation

    CERN Document Server

    Flynn, Patricia M; Kilgour, Maureen A


    Many businesses and organizations are increasingly aware of the case for promoting gender equality, both within and outside their organizational boundaries. Evidence suggests that gender equality in the workplace boosts performance, and legal frameworks in many countries mandate specific action on gender inequality in the workplace. However, despite organizational policies on promoting equality and equal opportunities, there remain challenges to be overcome in many businesses, including throughout their supply chains. The book provides research rationales as to why responsible organizations must address the issue of gender equality in the workplace. It also presents case studies, action research and examples of good practices, describing how businesses and organizations are working to promote gender equality in various contexts. The book is designed to support the rationale for gender equality in business and organizations, provide evidence of implementation of gender equality in the workplace, and how to dea...

  4. Overcoming asymmetric goals in teams: the interactive roles of team learning orientation and team identification. (United States)

    Pearsall, Matthew J; Venkataramani, Vijaya


    Although members of teams share a common, ultimate objective, they often have asymmetric or conflicting individual goals that shape the way they contribute to, and pursue, the shared goal of the team. Compounding this problem, they are frequently unaware of the nature of these goal asymmetries or even the fact that such differences exist. Drawing on, and integrating, social interdependence and representational gaps theories, we identify 2 emergent states that combine interactively to enable teams to overcome asymmetric goals: team identification and team learning orientation. Using data from long-term, real-life teams that engaged in a computer simulation designed to create both asymmetric goals and representational gaps about those goals, we found that teams were most effective when they had a high learning orientation coupled with high team identification and that this effect was mediated by teams' ability to form more accurate team goal mental models and engage in effective planning processes. Implications for theory and practice are discussed.

  5. Overcoming Challenges: Breathing Hope Through Teamwork and Long-Distance Thoracic Transplantation. (United States)

    Villalon, Ernie


    Lung donation and transplantation is increasing in volume annually, yet there continues to be a shortage of available organs for transplant. Despite this shortage, suitable lungs are occasionally not transplanted due to logistical issues. Issues such as time and distance can be a major barrier in deceased donor organ recovery and transplantation. This single case study serves as an example of the teamwork and cooperation that resulted in the successful transplantation of lungs in spite of long-distance logistical issues between the donor and the recipient. All of the members who contributed to this collaboration recognized the need and urgency to overcome these challenges. The organ procurement organization's collaboration with multiple transplant centers across multiple regions resulted in a successful outcome for the lung recipient.

  6. Fast emergency paths schema to overcome transient link failures in ospf routing

    CERN Document Server

    Barreto, Fernando; Nacamura, Luiz; 10.5121/ijcnc.2012.4202


    A reliable network infrastructure must be able to sustain traffic flows, even when a failure occurs and changes the network topology. During the occurrence of a failure, routing protocols, like OSPF, take from hundreds of milliseconds to various seconds in order to converge. During this convergence period, packets might traverse a longer path or even a loop. An even worse transient behaviour is that packets are dropped even though destinations are reachable. In this context, this paper describes a proactive fast rerouting approach, named Fast Emergency Paths Schema (FEP-S), to overcome problems originating from transient link failures in OSPF routing. Extensive experiments were done using several network topologies with different dimensionality degrees. Results show that the recovery paths, obtained by FEPS, are shorter than those from other rerouting approaches and can improve the network reliability by reducing the packet loss rate during the routing protocols convergence caused by a failure.

  7. Overcoming the Pigou-Downs Paradox Using Advanced Traffic Signal Control (United States)

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


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

  8. Structure-based drug design to overcome drug resistance: challenges and opportunities. (United States)

    Ferreira, Rafaela S; Andricopulo, Adriano D


    Drug resistance is a common concern for the development of novel antiviral, antimicrobial and anticancer therapies. To overcome this problem, several strategies have been developed, many of which involving the theme of this review, the use of structure-based drug design (SBDD) approaches. These include the successful design of new compounds that target resistant mutant proteins, as well as the development of drugs that target multiple proteins involved in specific biochemical pathways. Finally, drug resistance can also be considered in the early stages of drug discovery, through the use of strategies to delay the development of resistance. The purpose of this brief review is to underline the usefulness of SBDD approaches based on case studies, highlighting present challenges and opportunities in drug design.

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

    DEFF Research Database (Denmark)

    Trapp, Stefan; Schwartz, S.


    The noti®cation of new chemicals in the European Union requires a risk assessment. A Technical Guidance Document (TGD) was prepared for assistance. The TGD proposes QSARs, regressions and models from various sources. Each method has its own range of applicability and its own restrictions. Regress......The noti®cation of new chemicals in the European Union requires a risk assessment. A Technical Guidance Document (TGD) was prepared for assistance. The TGD proposes QSARs, regressions and models from various sources. Each method has its own range of applicability and its own restrictions......, it is shown that in certain cases uptake is underestimated by the model due to processes not considered. This may lead to a wrong security in risk assessment. To overcome these limitations, a set of alternative models with di€erent application ranges should be developed. When no applicable method is available...


    Directory of Open Access Journals (Sweden)

    Ion Gr. IONESCU


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

  11. "Closing the Loop": Overcoming barriers to locally sourcing food in Fort Collins, Colorado (United States)

    DeMets, C. M.


    Environmental sustainability has become a focal point for many communities in recent years, and restaurants are seeking creative ways to become more sustainable. As many chefs realize, sourcing food locally is an important step towards sustainability and towards building a healthy, resilient community. Review of literature on sustainability in restaurants and the local food movement revealed that chefs face many barriers to sourcing their food locally, but that there are also many solutions for overcoming these barriers that chefs are in the early stages of exploring. Therefore, the purpose of this research is to identify barriers to local sourcing and investigate how some restaurants are working to overcome those barriers in the city of Fort Collins, Colorado. To do this, interviews were conducted with four subjects who guide purchasing decisions for restaurants in Fort Collins. Two of these restaurants have created successful solutions and are able to source most of their food locally. The other two are interested in and working towards sourcing locally but have not yet been able to overcome barriers, and therefore only source a few local items. Findings show that there are four barriers and nine solutions commonly identified by each of the subjects. The research found differences between those who source most of their food locally and those who have not made as much progress in local sourcing. Based on these results, two solution flowcharts were created, one for primary barriers and one for secondary barriers, for restaurants to assess where they are in the local food chain and how they can more successfully source food locally. As there are few explicit connections between this research question and climate change, it is important to consider the implicit connections that motivate and justify this research. The question of whether or not greenhouse gas emissions are lower for locally sourced food is a topic of much debate, and while there are major developments

  12. Adjuvants Based on Hybrid Antibiotics Overcome Resistance in Pseudomonas aeruginosa and Enhance Fluoroquinolone Efficacy. (United States)

    Gorityala, Bala Kishan; Guchhait, Goutam; Fernando, Dinesh M; Deo, Soumya; McKenna, Sean A; Zhanel, George G; Kumar, Ayush; Schweizer, Frank


    The use of adjuvants that rescue antibiotics against multidrug-resistant (MDR) pathogens is a promising combination strategy for overcoming bacterial resistance. While the combination of β-lactam antibiotics and β-lactamase inhibitors has been successful in restoring antibacterial efficacy in MDR bacteria, the use of adjuvants to restore fluoroquinolone efficacy in MDR Gram-negative pathogens has been challenging. We describe tobramycin-ciprofloxacin hybrid adjuvants that rescue the activity of fluoroquinolone antibiotics against MDR and extremely drug-resistant Pseudomonas aeruginosa isolates in vitro and enhance fluoroquinolone efficacy in vivo. Structure-activity studies reveal that the presence of both tobramycin and ciprofloxacin, which are separated by a C12 tether, is critical for the function of the adjuvant. Mechanistic studies indicate that the antibacterial modes of ciprofloxacin are retained while the role of tobramycin is limited to destabilization of the outer membrane in the hybrid.

  13. Microbial advanced biofuels production: overcoming emulsification challenges for large-scale operation. (United States)

    Heeres, Arjan S; Picone, Carolina S F; van der Wielen, Luuk A M; Cunha, Rosiane L; Cuellar, Maria C


    Isoprenoids and alkanes produced and secreted by microorganisms are emerging as an alternative biofuel for diesel and jet fuel replacements. In a similar way as for other bioprocesses comprising an organic liquid phase, the presence of microorganisms, medium composition, and process conditions may result in emulsion formation during fermentation, hindering product recovery. At the same time, a low-cost production process overcoming this challenge is required to make these advanced biofuels a feasible alternative. We review the main mechanisms and causes of emulsion formation during fermentation, because a better understanding on the microscale can give insights into how to improve large-scale processes and the process technology options that can address these challenges.

  14. Overcoming ICP-QMS instrumental limitations for (99)Tc determination in environmental solid samples using radiochemistry. (United States)

    Mas, José Luis; García-León, M; Bolívar, J P


    Besides its capabilities, quadrupole-based ICP-MS counting establishes several limitations on (99)Tc analysis in environmental samples. Overcoming these limitations requires the use of radiochemical methods. We have developed a new method for the detection of (99)Tc by ICP-QMS in solid environmental samples. In order to improve the limit of detection of the technique, high amounts of solid samples (> or = 100g) are used. Hence, great amounts of the interfering elements are involved in the process, and therefore special emphasis is put on achieving a good commitment between adequate matrix elements removal and a minimization of the limit of detection. The performances of the method are analyzed in terms of conveniently defined figures of merit. The developed method is applied to several fallout level samples. In this way, the real performances and especially the real limitations of this method are shown.

  15. Disinvestments in practice: overcoming resistance to change through a sociotechnical approach with local stakeholders. (United States)

    Airoldi, Mara


    For health care, economists have developed cost-effectiveness analysis (CEA) as a "rational," analytic tool to set priorities. Attempts to use CEA to decide how to cut expenditures, however, have been met with stakeholders' resistance. This article presents an illustrative case study of the application of an approach explicitly designed to engage stakeholders with conflicting objectives in confronting tightening budgets. The outcome of this process, which engaged a group of stakeholders including patients, caregivers, clinicians, and managers, was a strategy that reconfigured services to produce more health gain at reduced total cost. I argue that the key factors that led to overcoming resistance to change were (1) the collective character of the deliberations; (2) the analysis of the whole pathway; (3) the presence of patients; and (4) the development of a model based on CEA principles, which provided a credible rationale for difficult decisions.

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

    CERN Document Server

    Moynihan, Glenn; O'Regan, David D


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

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

    CERN Document Server

    Kulikov, Sergey


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

  18. Overcoming the slow recovery of MOX gas sensors through a system modeling approach. (United States)

    Monroy, Javier G; González-Jiménez, Javier; Blanco, Jose Luis


    Metal Oxide Semiconductor (MOX) gas transducers are one of the preferable technologies to build electronic noses because of their high sensitivity and low price. In this paper we present an approach to overcome to a certain extent one of their major disadvantages: their slow recovery time (tens of seconds), which limits their suitability to applications where the sensor is exposed to rapid changes of the gas concentration. Our proposal consists of exploiting a double first-order model of the MOX-based sensor from which a steady-state output is anticipated in real time given measurements of the transient state signal. This approach assumes that the nature of the volatile is known and requires a precalibration of the system time constants for each substance, an issue that is also described in the paper. The applicability of the proposed approach is validated with several experiments in real, uncontrolled scenarios with a mobile robot bearing an e-nose.

  19. Translational selection frequently overcomes genetic drift in shaping synonymous codon usage patterns in vertebrates. (United States)

    Doherty, Aoife; McInerney, James O


    Synonymous codon usage patterns are shaped by a balance between mutation, drift, and natural selection. To date, detection of translational selection in vertebrates has proven to be a challenging task, obscured by small long-term effective population sizes in larger animals and the existence of isochores in some species. The consensus is that, in such species, natural selection is either completely ineffective at overcoming mutational pressures and genetic drift or perhaps is effective but so weak that it is not detectable. The aim of this research is to understand the interplay between mutation, selection, and genetic drift in vertebrates. We observe that although variation in mutational bias is undoubtedly the dominant force influencing codon usage, translational selection acts as a weak additional factor influencing synonymous codon usage. These observations indicate that translational selection is a widespread phenomenon in vertebrates and is not limited to a few species.

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

    CERN Document Server

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


    In this paper we describe a new integration method for the groups $U(N)$ and $SU(N)$, for which we verified numerically that it is polynomially exact for $N\\le 3$. The method is applied to the example of 1-dimensional QCD with a chemical potential. We explore, in particular, regions of the parameter space in which the sign problem appears due the presence of the chemical potential. While Markov Chain Monte Carlo fails in this region, our new integration method still provides results for the chiral condensate on arbitrary precision, demonstrating clearly that it overcomes the sign problem. Furthermore, we demonstrate that our new method leads to orders of magnitude reduced errors also in other regions of parameter space.

  1. NatVent. A better way to work: Overcoming barriers to natural ventilation

    Energy Technology Data Exchange (ETDEWEB)

    Wouters, P.; Demeester, J. (eds.)


    NatVent is a European project which is being carried out by a consortium of nine partners, across seven countries - Great Britain, Belgium, Denmark, the Netherlands, Sweden, Norway and Switzerland. The main objective of this project was to reduce primary energy use consumption in buildings by overcoming barriers which prevent the uptake of natural ventilation for office-type buildings. It is intended for countries with low winter and moderate summer temperatures and where summer overheating from solar and internal gains can be significantly reduced by good natural ventilation. The project has investigated and developed 'smart' components to provide natural ventilation for office-type building which could be naturally ventilated, but because of various technical barriers are, at present, inadequately ventilated, fully mechanically ventilated or air-conditioned. (ed)

  2. NatVent. A better way to work: Overcoming barriers to natural ventilation

    Energy Technology Data Exchange (ETDEWEB)

    Wouters, P.; Demeester, J. [eds.


    NatVent is a European project which is being carried out by a consortium of nine partners, across seven countries - Great Britain, Belgium, Denmark, the Netherlands, Sweden, Norway and Switzerland. The main objective of this project was to reduce primary energy use consumption in buildings by overcoming barriers which prevent the uptake of natural ventilation for office-type buildings. It is intended for countries with low winter and moderate summer temperatures and where summer overheating from solar and internal gains can be significantly reduced by good natural ventilation. The project has investigated and developed `smart` components to provide natural ventilation for office-type building which could be naturally ventilated, but because of various technical barriers are, at present, inadequately ventilated, fully mechanically ventilated or air-conditioned. (ed)

  3. Overcoming the limited availability of human milk oligosaccharides: challenges and opportunities for research and application. (United States)

    Bode, Lars; Contractor, Nikhat; Barile, Daniela; Pohl, Nicola; Prudden, Anthony R; Boons, Geert-Jan; Jin, Yong-Su; Jennewein, Stefan


    Human milk oligosaccharides (HMOs) are complex sugars highly abundant in human milk but currently not present in infant formula. Rapidly accumulating evidence from in vitro and in vivo studies, combined with epidemiological associations and correlations, suggests that HMOs benefit infants through multiple mechanisms and in a variety of clinical contexts. Until recently, however, research on HMOs has been limited by an insufficient availability of HMOs. Most HMOs are found uniquely in human milk, and thus far it has been prohibitively tedious and expensive to isolate and synthesize them. This article reviews new strategies to overcome this lack of availability by generating HMOs through chemoenzymatic synthesis, microbial metabolic engineering, and isolation from human donor milk or dairy streams. Each approach has its advantages and comes with its own challenges, but combining the different methods and acknowledging their limitations creates new opportunities for research and application with the goal of improving maternal and infant health.

  4. Overcoming Privacy Preserving Federalism: A multiscalar approach to the Swiss and German shifts in Gender Regime

    Directory of Open Access Journals (Sweden)

    Olivier Giraud


    Full Text Available This contribution provides a comparative overview of the transformation of gender regulations in two federal countries, Germany and Switzerland, drawing upon federalist analysis and gender regime approaches. Both countries have witnessed important legislative reforms towards gender equality from the end of the 1990’s. Mobilizing a multiscalar analytical grid, we situate this shift within the broader context of a social historical transformation of gender regimes that articulates changes in the relations between public and private regulation as well as between different territorial levels. We demonstrate how the federalist privacy deadlock, historically characterizing both countries, has been overcome. Nevertheless, in the field of childcare, the multiscalar grid reveals that both countries follow different trajectories towards equality. In Germany, top-down regulation has eventually supplanted bottom-up processes and there is a modest influence of public regulation over the definition of gender roles. Such changes were not achieved via a similar mode in Switzerland.

  5. Collective Action “Going Digital”: Overcoming Institutional and Micro-Structural Constraints through Technology Use

    Directory of Open Access Journals (Sweden)

    Carol Soon


    Full Text Available Traditionally, macro-level and micro-level approaches have been used in silos to explain and determine the threshold where one crosses from non-participation to participation in social movements. Technological advancements have enriched but also complicated the process of collective action. This qualitative study is based on the premise that a confluence between political economy approaches, micro-structural analysis and Internet studies is needed to dissect the dynamics behind technology use in collective action. Through in-depth interviews with 26 activist bloggers in Singapore, this study sheds light on how Internet technologies are used by activists to overcome issues of collective incentives, structural proximity and structural availability, and negotiate the institutional terrain.


    DEFF Research Database (Denmark)

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

    into that the heart endures physical activity. In addition to serving as physical guidance, exercise-based cardiac rehabilitation offers valuable mental support. The patients find help to overcome an initial anxiety and move forward towards a physically active life featuring a feeling of improved health and new......Purpose. Patients face demanding and challenging processes when they experience cardiac problems. Exercise-based cardiac rehabilitation is established to enable these patients to move forward to lead a satisfying life. It is recognised that patients fail to join all sessions of the rehabilitation......, and it seems to be crucial to further emphasise the individuals lived experiences when exercise-based cardiac rehabilitation is followed. Hence this study aims to investigate how patients experience exercise-based cardiac rehabilitation in a hospital setting. Methods. This study, which included nine men...

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

    CERN Document Server

    Taigman, Yaniv


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

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

  9. Measuring and overcoming limits of the Saffman-Delbrück model for soap film viscosities. (United States)

    Vivek, Skanda; Weeks, Eric R


    We observe tracer particles diffusing in soap films to measure the two-dimensional (2D) viscous properties of the films. Saffman-Delbrück type models relate the single-particle diffusivity to parameters of the film (such as thickness h) for thin films, but the relation breaks down for thicker films. Notably, the diffusivity is faster than expected for thicker films, with the crossover at h/d = 5.2 ± 0.9 using the tracer particle diameter d. This indicates a crossover from purely 2D diffusion to diffusion that is more three-dimensional. We demonstrate that measuring the correlations of particle pairs as a function of their separation overcomes the limitations of the Saffman-Delbrück model and allows one to measure the viscosity of a soap film for any thickness.

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

    Directory of Open Access Journals (Sweden)

    Verónica Montes de Oca Zavala


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

  11. Educational pathways of Black women physicists: Stories of experiencing and overcoming obstacles in life (United States)

    Rosa, Katemari; Mensah, Felicia Moore


    [This paper is part of the Focused Collection on Gender in Physics.] This is an empirical study on the underrepresentation of people of color in scientific careers. Grounded in critical race theory, the paper examines the lived experiences of six Black women physicists and addresses obstacles faced in their career paths and strategies used to overcome these obstacles. Data for this study were collected through semistructured interviews and coded for emergent themes. The findings reveal that college recruitment and funding were fundamental for these women to choose physics over other STEM fields. In addition, Black women experience unique challenges of socialization in STEM, particularly by exclusion of study groups. We suggest physics departments provide a more inclusive environment to support Black women in science.

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

    Energy Technology Data Exchange (ETDEWEB)

    Cole, Pamala C.; Halverson, Mark A.


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


    Directory of Open Access Journals (Sweden)

    Ratna Istriyani


    Full Text Available A stereotype appears and describes that Islam is the cause of a series of terror. Therefore, some states are worried and suspicious toward Muslims (Islamophobia up to the present. Islamophobia associated with negative prejudices against Muslims and Islam, and lead to construction of anti-Islam. Prejudice is based on a claim that Islam is an inferior religion and can threat the dominant values in society. The phenomenon of Islamophobia can be assessed by two perspectives: sociological and psychological. In the case of Islamophobia, media became the object of analysis because it has the dichotomy function. They become the cause for the outbreak of Islamophobia symptoms (latent functions. On the other hand, the media is an information agent which has role to provide education and social change effects (manifest functions. Thus, the media can be an instrument or strategy to overcome the turmoil of Islamophobia by involving a synergy of government, Islamic organizations, and institutions of higher education.

  14. Overcoming the resolution limit in retinal imaging using the scattering properties of the sclera (Conference Presentation) (United States)

    Carpentras, Dino; Laforest, Timothé; Psaltis, Demetri; Moser, Christophe


    In-vivo imaging of the eye's fundus is widely used to study eye's health. State of the art Adaptive Optics devices can resolve features up to a lateral resolution of 1.5 um. This resolution is still above what is needed to observe sub-cellular structures such as cone cells (1-1.25 um diameter). This limit in resolution is due to the small numerical aperture of the eye when the pupil is fully dilated (max 0.24). In our work, we overcome this limit using a non-standard illumination scheme. A laser beam is shined on the lateral choroid layer, whose scattered light is illuminating the eye's fundus. Thanks to a Spatial Light Modulator the scattered light from the choroid layer can be manipulated to produce a scanning focus spot on the fundus. The intensity of the reflected light from the fundus is collected from the pupil and used for reconstructing the image.

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

    CERN Document Server

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


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

  16. The Factors that Induce or Overcome Freezing of Gait in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    S. Rahman


    Full Text Available Freezing of gait (FoG, a transient halt in walking, is a major mobility problem for patients with Parkinson’s disease (PD. This study examined the factors that induce FoG, and identified the cues and strategies that help overcome it through a postal survey of 130 PD patients. 72% reported FoG. The factors that commonly induced FoG were turning, fatigue, confined spaces and stressful situations, in addition to emotional factors. FoG was also ameliorated by various attentional and external cueing strategies. The concept of paradoxical kinesis, the potential neural substrates of such external cueing effects, and their importance for rehabilitation in PD are discussed.

  17. Nanocomplexes for gene therapy of respiratory diseases: Targeting and overcoming the mucus barrier. (United States)

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


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

  18. Right supramarginal gyrus is crucial to overcome emotional egocentricity bias in social judgments. (United States)

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


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

  19. Overcoming undernutrition with local resources in Africa, Asia and Latin America. (United States)

    Krawinkel, Michael B


    Even in the 21st century, undernutrition is a challenge to be overcome. In the year 2009, 1.02 billion people were reported as food insecure and 180 million children were undernourished. Food insecurity and undernutrition are more than a lack of food energy: they are not reflected countrywide by prevalence means; they are mostly not permanent but seasonal; they are mostly not caused by insufficient amounts of food being produced; and they first affect parents and later children. Food insecurity and undernutrition often manifest themselves as micronutrient deficiency. While undernutrition is still a challenge for global nutrition, a second challenge has arisen: preventing caloric overnutrition. In various countries, food pyramids or food circles have been plotted supporting nutrition education and illustrating the challenge. Such integrative approaches are desirable for all countries of the world, as in all countries, to a smaller or larger extent, undernutrition and caloric overnutrition are the problems of today and tomorrow. The International Assessment of Agriculture for Science Technology and Development (IAASTD) has paid attention to the inescapable interconnectedness of agriculture's different roles and functions in the world and in all societies. Overcoming undernutrition with local resources means first protecting and promoting the use of local resources against imports of low-priced processed foods from subsidised production in industrialised countries; second, it means developing education and training material for regional food production with a nutrition orientation; and third, the experiences of organic farming can contribute much to support farmers in developing countries in planting their indigenous varieties and applying integrated pest management strategies.

  20. Carrion crows cannot overcome impulsive choice in a quantitative exchange task. (United States)

    Wascher, Claudia A F; Dufour, Valerie; Bugnyar, Thomas


    The ability to control an immediate impulse in return for a more desirable - though delayed - outcome has long been thought to be a uniquely human feature. However, studies on non-human primates revealed that some species are capable of enduring delays in order to get food of higher quality or quantity. Recently two corvid species, common raven (Corvus corax) and carrion crow (Corvus corone corone), exchanged food for a higher quality reward though seemed less capable of enduring delays when exchanging for the same food type in a higher quantity. In the present study, we specifically investigated the ability of carrion crows to overcome an impulsive choice in a quantitative exchange task. After a short delay, individuals were asked to give back an initial reward (cheese) to the human experimenter in order to receive a higher amount of the same reward (two, four, or eight pieces). We tested six captive crows - three individuals never exchanged the initial reward for a higher quantity; the other three birds did exchange though at very low rates. We performed a preference test between one or more pieces of cheese in order to address whether crow poor performance could be due to an inability to discriminate between different quantities or not attributing a higher value to the higher quantities. All birds chose the higher quantities significantly more often, indicating that they can discriminate between quantities and that higher quantities are more desirable. Taken together, these results suggest that, although crows may possess the cognitive abilities to judge quantities and to overcome an impulsive choice, they do so only in order to optimize the qualitative but not quantitative output in the exchange paradigm.


    Directory of Open Access Journals (Sweden)

    Patricia de Sá Freire


    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.

  2. Wee-1 kinase inhibition overcomes cisplatin resistance associated with high-risk TP53 mutations in head and neck cancer through mitotic arrest followed by senescence. (United States)

    Osman, Abdullah A; Monroe, Marcus M; Ortega Alves, Marcus V; Patel, Ameeta A; Katsonis, Panagiotis; Fitzgerald, Alison L; Neskey, David M; Frederick, Mitchell J; Woo, Sang Hyeok; Caulin, Carlos; Hsu, Teng-Kuei; McDonald, Thomas O; Kimmel, Marek; Meyn, Raymond E; Lichtarge, Olivier; Myers, Jeffrey N


    Although cisplatin has played a role in "standard-of-care" multimodality therapy for patients with advanced squamous cell carcinoma of the head and neck (HNSCC), the rate of treatment failure remains particularly high for patients receiving cisplatin whose tumors have mutations in the TP53 gene. We found that cisplatin treatment of HNSCC cells with mutant TP53 leads to arrest of cells in the G2 phase of the cell cycle, leading us to hypothesize that the wee-1 kinase inhibitor MK-1775 would abrogate the cisplatin-induced G2 block and thereby sensitize isogenic HNSCC cells with mutant TP53 or lacking p53 expression to cisplatin. We tested this hypothesis using clonogenic survival assays, flow cytometry, and in vivo tumor growth delay experiments with an orthotopic nude mouse model of oral tongue cancer. We also used a novel TP53 mutation classification scheme to identify which TP53 mutations are associated with limited tumor responses to cisplatin treatment. Clonogenic survival analyses indicate that nanomolar concentration of MK-1775 sensitizes HNSCC cells with high-risk mutant p53 to cisplatin. Consistent with its ability to chemosensitize, MK-1775 abrogated the cisplatin-induced G2 block in p53-defective cells leading to mitotic arrest associated with a senescence-like phenotype. Furthermore, MK-1775 enhanced the efficacy of cisplatin in vivo in tumors harboring TP53 mutations. These results indicate that HNSCC cells expressing high-risk p53 mutations are significantly sensitized to cisplatin therapy by the selective wee-1 kinase inhibitor, supporting the clinical evaluation of MK-1775 in combination with cisplatin for the treatment of patients with TP53 mutant HNSCC.

  3. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. (United States)

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


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

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

    DEFF Research Database (Denmark)

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


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

  5. Prasugrel or double-dose clopidogrel to overcome clopidogrel low-response

    DEFF Research Database (Denmark)

    Dridi, Nadia Paarup; Johansson, Pär Ingemar; Clemmensen, Peter


    High on-treatment platelet reactivity (HTPR) is associated with poor prognosis in patients undergoing percutaneous coronary intervention (PCI). The antiplatelet effect and safety of prasugrel was compared to that of double-dose clopidogrel in patients with stable coronary artery disease or acute...... coronary syndrome (ACS) exhibiting HTPR on clopidogrel and treated with PCI, using multiple electrode aggregometry (MEA) to assess platelet reactivity. Of 923 patients screened, 237 (25.7%) exhibited HTPR. Of these, 106 were eligible for participation in a randomized trial comparing two intensified...... antiplatelet regimen: 52 were assigned to double maintenance-dose clopidogrel and 54 to standard-dose prasugrel. At 1 month, tailoring antiplatelet therapy improved platelet inhibition to a level considered as therapeutic in 73.1% of patients. Prasugrel entailed greater platelet inhibition (p = 0...

  6. Beneficial bacteria inhibit cachexia. (United States)

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


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

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

    Directory of Open Access Journals (Sweden)

    Anjel Toczu


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

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

    Directory of Open Access Journals (Sweden)

    Leon David A


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

  9. Telemedicine in emergency neurological service provision in Singapore: using technology to overcome limitations. (United States)

    Singh, Rajinder; Ng, Wai Hoe; Lee, Kim En; Wang, Ernest; Ng, Ivan; Lee, Wei Ling


    Medical emergencies form a significant proportion of neurological and neurosurgical practice. The highly specialized nature of neurology and neurosurgery limits expertise to a small number of highly specialized centers; hence, many neurological emergencies will be managed in regional hospitals without comprehensive support. The common theme in neurological emergencies lies with prompt diagnosis, rapid access to scans, accurate scan interpretation, and quick institution of appropriate treatment. Failure in any one of these can result in devastating and permanent neurological deficits or death. The judicious use of information and communication technology can overcome some of the limitations imposed by scarce resources. Multimedia messaging service can be used to transmit important scan images to experienced staff to faciliate accurate and prompt diagnosis and commence optimal treatment. Telestroke based on the remote evaluation of acute ishemic stroke model can also be utilized so that selected stroke patients can be given intravenous tissue plasminogen activator in the emergency department of a regional hospital with the supervision of a stroke neurologist. We describe our experience with these technological initiatives to improve clinical care and outcome in our patients.

  10. Overcoming charge noise decoherence by photon-assisted pair-breaking in a charge qubit (United States)

    de Graaf, Sebastian; Leppäkangas, Juha; Adamyan, Astghik; Danilov, Andrey; Lindström, Tobias; Fogelström, Mikael; Johansson, Göran; Kubatkin, Sergey


    We report on recent measurements of a charge qubit, a Cooper-pair box, coupled to a high-Q microwave cavity in the strong driving regime. This we model using a dressed state formalism, and we find evidence for a process that involves energy transfer corresponding to a large number (~14) of photons. This energy is sufficient to break a Cooper-pair on the island, and it results in a new relaxation channel for the qubit. Specifically, this relaxation resets the qubit into a charge state determined by the static bias conditions, resulting in a sudden population inversion around each dressed state degeneracy point. At low driving strengths, decoherence is governed by charge noise in the environment, while in the discovered strong driving regime the relaxation rate due to pair-breaking can overcome the environmental charge relaxation rate. This results in a regime that is especially attractive for charge sensing since the qubit response becomes immune to non-equilibrium quasiparticle poisoning and less susceptible to its charge noise environment.

  11. Overcoming Instability of Antibody-Nanomaterial Conjugates: Next Generation Targeted Nanomedicines Using Bispecific Antibodies. (United States)

    Howard, Christopher B; Fletcher, Nicholas; Houston, Zachary H; Fuchs, Adrian V; Boase, Nathan R B; Simpson, Joshua D; Raftery, Lyndon J; Ruder, Tim; Jones, Martina L; de Bakker, Christopher J; Mahler, Stephen M; Thurecht, Kristofer J


    Targeted nanomaterials promise improved therapeutic efficacy, however their application in nanomedicine is limited due to complexities associated with protein conjugations to synthetic nanocarriers. A facile method to generate actively targeted nanomaterials is developed and exemplified using polyethylene glycol (PEG)-functional nanostructures coupled to a bispecific antibody (BsAb) with dual specificity for methoxy PEG (mPEG) epitopes and cancer targets such as epidermal growth factor receptor (EGFR). The EGFR-mPEG BsAb binds with high affinity to recombinant EGFR (KD : 1 × 10(-9) m) and hyperbranched polymer (HBP) consisting of mPEG (KD : 10 × 10(-9) m) and demonstrates higher avidity for HBP compared to linear mPEG. The binding of BsAb-HBP bioconjugate to EGFR on MDA-MB-468 cancer cells is investigated in vitro using a fluorescently labeled polymer, and in in vivo xenograft models by small animal optical imaging. The antibody-targeted nanostructures show improved accumulation in tumor cells compared to non-targeted nanomaterials. This demonstrates a facile approach for tuning targeting ligand density on nanomaterials, by modulating surface functionality. Antibody fragments are tethered to the nanomaterial through simple mixing prior to administration to animals, overcoming the extensive procedures encountered for developing targeted nanomedicines.

  12. Overcoming Barriers in Kidney Health-Forging a Platform for Innovation. (United States)

    Linde, Peter G; Archdeacon, Patrick; Breyer, Matthew D; Ibrahim, Tod; Inrig, Jula K; Kewalramani, Reshma; Lee, Celeste Castillo; Neuland, Carolyn Y; Roy-Chaudhury, Prabir; Sloand, James A; Meyer, Rachel; Smith, Kimberly A; Snook, Jennifer; West, Melissa; Falk, Ronald J


    Innovation in kidney diseases is not commensurate with the effect of these diseases on human health and mortality or innovation in other key therapeutic areas. A primary cause of the dearth in innovation is that kidney diseases disproportionately affect a demographic that is largely disenfranchised, lacking sufficient advocacy, public attention, and funding. A secondary and likely consequent cause is that the existing infrastructure supporting nephrology research pales in comparison with those for other internal medicine specialties, especially cardiology and oncology. Citing such inequities, however, is not enough. Changing the status quo will require a coordinated effort to identify and redress the existing deficits. Specifically, these deficits relate to the need to further develop and improve the following: understanding of the disease mechanisms and pathophysiology, patient engagement and activism, clinical trial infrastructure, and investigational clinical trial designs as well as coordinated efforts among critical stakeholders. This paper identifies potential solutions to these barriers, some of which are already underway through the Kidney Health Initiative. The Kidney Health Initiative is unique and will serve as a current and future platform from which to overcome these barriers to innovation in nephrology.

  13. Overcoming barriers to exercise among parents: a social cognitive theory perspective. (United States)

    Mailey, Emily L; Phillips, Siobhan M; Dlugonski, Deirdre; Conroy, David E


    Parents face numerous barriers to exercise and exhibit high levels of inactivity. Examining theory-based determinants of exercise among parents may inform interventions for this population. The purpose of this study was to test a social-cognitive model of parental exercise participation over a 12-month period. Mothers (n = 226) and fathers (n = 70) of children <16 completed measures of exercise, barriers self-efficacy, perceived barriers, and exercise planning at baseline and 1 year later. Panel analyses were used to test the hypothesized relationships. Barriers self-efficacy was related to exercise directly and indirectly through perceived barriers and prioritization/planning. Prioritization and planning also mediated the relationship between perceived barriers and exercise. These paths remained significant at 12 months. These results suggest efforts to increase exercise in parents should focus on improving confidence to overcome exercise barriers, reducing perceptions of barriers, and helping parents make specific plans for prioritizing and engaging in exercise.

  14. Progress in Overcoming Materials Challenges with S-CO2 RCBCs

    Energy Technology Data Exchange (ETDEWEB)

    Walker, Matthew S. [Sandia National Lab. (SNL-CA), Livermore, CA (United States). Materials Chemistry Group; Kruizenga, Alan Michael [Sandia National Lab. (SNL-CA), Livermore, CA (United States). Materials Chemistry Group; Weck, Philippe F. [Sandia National Lab. (SNL-CA), Livermore, CA (United States). Storage and Transportation Technologies Group; Withey, Elizabeth Ann [Sandia National Lab. (SNL-CA), Livermore, CA (United States). Materials Chemistry Group; Fleming, Darryn D. [Sandia National Lab. (SNL-CA), Livermore, CA (United States). Advanced Nuclear Concepts Group


    The supercritical carbon dioxide (S-CO2) Brayton Cycle has gained significant attention in the last decade as an advanced power cycle capable of achieving high efficiency power conversion. Sandia National Laboratories, with support from the U.S. Department of Energy Office of Nuclear Energy (US DOE-NE), has been conducting research and development in order to deliver a technology that is ready for commercialization. There are a wide range of materials-related challenges that must be overcome to ensure the success of this technology. At Sandia, recent work has focused on the following main areas: (1) Investigating the potential for system cost reduction through the introduction of low-cost alloys in low temperature loop sections; (2) identifying material options for 10MW RCBC systems; (3) understanding and resolving turbine degradation; (4) identifying gas foil bearing behavior in CO2; and (5) identifying the influence of gas chemistry on alloy corrosion. Progress in each of these areas is detailed in this report.

  15. Mucosal Vaccination Overcomes the Barrier to Recombinant Vaccinia Immunization Caused by Preexisting Poxvirus Immunity (United States)

    Belyakov, Igor M.; Moss, Bernard; Strober, Warren; Berzofsky, Jay A.


    Overcoming preexisting immunity to vaccinia virus in the adult population is a key requirement for development of otherwise potent recombinant vaccinia vaccines. Based on our observation that s.c. immunization with vaccinia induces cellular and antibody immunity to vaccinia only in systemic lymphoid tissue and not in mucosal sites, we hypothesized that the mucosal immune system remains naive to vaccinia and therefore amenable to immunization with recombinant vaccinia vectors despite earlier vaccinia exposure. We show that mucosal immunization of vaccinia-immune BALB/c mice with recombinant vaccinia expressing HIV gp160 induced specific serum antibody and strong HIV-specific cytotoxic T lymphocyte responses. These responses occurred not only in mucosal but also in systemic lymphoid tissue, whereas systemic immunization was ineffective under these circumstances. In this context, intrarectal immunization was more effective than intranasal immunization. Boosting with a second dose of recombinant vaccinia was also more effective via the mucosal route. The systemic HIV-specific cytotoxic T lymphocyte response was enhanced by coadministration of IL-12 at the mucosal site. These results also demonstrate the independent compartmentalization of the mucosal versus systemic immune systems and the asymmetric trafficking of lymphocytes between them. This approach to circumvent previous vaccinia immunity may be useful for induction of protective immunity against infectious diseases and cancer in the sizable populations with preexisting immunity to vaccinia from smallpox vaccination.

  16. Overcoming the limitations of directed C-H functionalizations of heterocycles. (United States)

    Liu, Yue-Jin; Xu, Hui; Kong, Wei-Jun; Shang, Ming; Dai, Hui-Xiong; Yu, Jin-Quan


    In directed C-H activation reactions, any nitrogen or sulphur atoms present in heterocyclic substrates will coordinate strongly with metal catalysts. This coordination, which can lead to catalyst poisoning or C-H functionalization at an undesired position, limits the application of C-H activation reactions in heterocycle-based drug discovery, in which regard they have attracted much interest from pharmaceutical companies. Here we report a robust and synthetically useful method that overcomes the complications associated with performing C-H functionalization reactions on heterocycles. Our approach employs a simple N-methoxy amide group, which serves as both a directing group and an anionic ligand that promotes the in situ generation of the reactive PdX2 (X = ArCONOMe) species from a Pd(0) source using air as the sole oxidant. In this way, the PdX2 species is localized near the target C-H bond, avoiding interference from any nitrogen or sulphur atoms present in the heterocyclic substrates. This reaction overrides the conventional positional selectivity patterns observed with substrates containing strongly coordinating heteroatoms, including nitrogen, sulphur and phosphorus. Thus, this operationally simple aerobic reaction demonstrates that it is possible to bypass a fundamental limitation that has long plagued applications of directed C-H activation in medicinal chemistry.

  17. Overcome side identification in PPOP by making orifices on both layers. (United States)

    Zhang, Zhi-hong; Li, Wei; Nie, Shu-fang; Tang, Xin; Peng, Bo; Tian, Lei; Pan, Wei-san


    The original purpose of this research was to build a database for an expert system. Unexpectedly, it was found that the color-identifying device in push-pull osmotic pump (PPOP) manufacturing process could be unnecessary. Water-insoluble drug indapamide, gliclazide and dipyridamole were employed as model drugs. Bunches of conventional formulations were designed; and traditional preparation procedures were used. In vitro drug release was studied; and the similarity between the conditions of orifice only on the side of the drug layer and orifices of the same diameter on both sides was evaluated. It was found that the drug release from PPOP could be influenced by formulation and core hardness while it could hardly be influenced by orifice size. No significant difference was observed between the dissolution profiles of orifice only on the side of the drug layer and orifices of the same diameter on both sides. Mechanism of drug release was discussed. The conclusion was that the disadvantage of side identification in PPOP manufacturing process could be overcome by drilling orifices on both sides.

  18. A Novel Methodology to Overcome Routing Misbehavior in Manet using Retaliation Model

    Directory of Open Access Journals (Sweden)

    Md. Amir Khusru Akhtar


    Full Text Available MANET is a cooperative network in which nodes are responsible for forwarding as well as routing.Noncooperation is still a big challenge that certainly degrades the performance and reliability of aMANET. This paper presents a novel methodology to overcome routing misbehavior in MANET usingRetaliation Model. In this model node misbehavior is watched and an equivalent misbehavior is given inreturn. This model employs several parameters such as number of packets forwarded, number of packetsreceived for forwarding, packet forwarding ratio etc. to calculate Grade and Bonus Points. The Grade isused to isolate selfish nodes from the routing paths and the Bonus Points defines the number of packetsdropped by an honest node in retaliation over its misconducts. The implementation is done in “GloMoSim”on top of the DSR protocol. We obtained up to 40% packet delivery ratio with a cost of a minimum of 7.5%overhead compared to DSR. To minimize total control traffic overhead we have included the FG Modelwith our model and it reduces the overhead up to 75%. This model enforces cooperation due to its stricterpunishment strategy and justifies its name.

  19. Multimodal biometrics approach using face and ear recognition to overcome adverse effects of pose changes (United States)

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


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

  20. Overcoming inter-subspecific hybrid sterility in rice by developing indica-compatible japonica lines. (United States)

    Guo, Jie; Xu, Xiaomei; Li, Wentao; Zhu, Wenyin; Zhu, Haitao; Liu, Ziqiang; Luan, Xin; Dai, Ziju; Liu, Guifu; Zhang, Zemin; Zeng, Ruizhen; Tang, Guang; Fu, Xuelin; Wang, Shaokui; Zhang, Guiquan


    Rice (Oryza sativa L.) is an important staple crop. The exploitation of the great heterosis that exists in the inter-subspecific crosses between the indica and japonica rice has long been considered as a promising way to increase the yield potential. However, the male and female sterility frequently occurred in the inter-subspecific hybrids hampered the utilization of the heterosis. Here we report that the inter-subspecific hybrid sterility in rice is mainly affected by the genes at Sb, Sc, Sd and Se loci for F1 male sterility and the gene at S5 locus for F1 female sterility. The indica-compatible japonica lines (ICJLs) developed by pyramiding the indica allele (S-i) at Sb, Sc, Sd and Se loci and the neutral allele (S-n) at S5 locus in japonica genetic background through marker-assisted selection are compatible with indica rice in pollen fertility and in spikelet fertility. These results showed a great promise of overcoming the inter-subspecific hybrid sterility and exploiting the heterosis by developing ICJLs.

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

    Directory of Open Access Journals (Sweden)

    Verónica Montes de Oca Zavala


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

  2. Animal models in idiopathic inflammatory myopathies: How to overcome a translational roadblock? (United States)

    Afzali, Ali Maisam; Ruck, Tobias; Wiendl, Heinz; Meuth, Sven G


    Idiopathic inflammatory myopathies (IIMs) encompass a heterogenic group of rare muscle diseases with common symptoms including muscle weakness and the presence of certain histological features. Since the pathogenesis remains unclear, therapeutic approaches in general comprise unspecific immunosuppression strategies that have been met with limited success. Therefore, a deeper understanding of the underlying pathophysiological mechanisms is critically required to assist in development of targeted therapies. Animal models have proven to be tremendously helpful in mechanistic studies and allow researchers to overcome the inevitable restrictions of human research. Although the number of different IIM models has drastically increased over the last few decades, a model that exhibits the phenotypical and histopathological hallmarks of IIM is still missing. Recent publications have shown promising results addressing different pathophysiological issues like mechanisms of onset, chronification or relapse in IIM. However, a standardization of the methodology is critically required in order to improve comparability and transferability among different groups. Here we provide an overview of the currently available IIM models including our own C-peptide based small-peptide model, critically discuss their advantages and disadvantages and give perspectives to their future use.

  3. Sustainable fuel, food, fertilizer and ecosystems through a global artificial photosynthetic system: overcoming anticompetitive barriers (United States)

    Bruce, Alex; Faunce, Thomas


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

  4. Overcoming disparities in organized physical activity: findings from Australian community strategies. (United States)

    Smith, Ben J; Thomas, Margaret; Batras, Dimitri


    Organized physical activity through sport and recreational activities is beneficial for physical and psychosocial well-being and community connectedness. However, many who could gain significantly from this have lower participation, especially the socioeconomically disadvantaged, Indigenous people, culturally diverse communities and people with a disability. This study examined barriers to participation by these underserved groups and the success of strategies for overcoming these used in 22 community projects over 3 years in the VicHealth Participation in Community Sport and Recreation Program, in Victoria, Australia. Each year, in-depth interviews were undertaken with 50-60 activity providers and 30-40 project partners. Major barriers to participation were cost, lack of transport, cultural differences, the environment of sporting groups and inaccessible facilities for people with disabilities. Projects that overcame these selected one or two priority groups, put significant effort into communication and building partnerships with community organizations, provided training to staff and volunteers and created new or modified forms of activity. Strategies were put in place to reduce cost and provide transport, but these did not appear to be sustainable. Many organizations found engaging the underserved was more difficult than anticipated and require information and support about how to develop acceptable, accessible and flexible opportunities for disadvantaged groups. Cost and lack of transport are persistent barriers to participation that need to be addressed by the sport and recreation sector and policy-makers.

  5. Overcoming Information Aesthetics: In Defense of a Non-Quantitative Informational Understanding of Artworks

    Directory of Open Access Journals (Sweden)

    Rodrigo Hernández-Ramírez


    Full Text Available Attempts to describe aesthetic artefacts through informational models have existed at least since the late 1950s; but they have not been as successful as their proponents expected nor are they popular among art scholars because of their (mostly quantitative nature. However, given how information technology has deeply shifted every aspect of our world, it is fair to ask whether aesthetic value continues to be immune to informational interpretations. This paper discusses the ideas of the late Russian biophysicist, Mikhail Volkenstein concerning art and aesthetic value. It contrasts them with Max Bense’s ‘information aesthetics’, and with contemporary philosophical understandings of information. Overall, this paper shows that an informational but not necessarily quantitative approach serves not only as an effective means to describe our interaction with artworks, but also contributes to explain why purely quantitative models struggle to formalise aesthetic value. Finally, it makes the case that adopting an informational outlook helps overcome the ‘analogue vs digital’ dichotomy by arguing the distinction is epistemological rather than ontological, and therefore the two notions need not be incompatible.

  6. Overcoming challenges to initiating cell therapy clinical trials in rapidly developing countries: India as a model. (United States)

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


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

  7. Overcoming liability of outsidership in China: The experience of Brazilian companies in developing Guanxi

    Directory of Open Access Journals (Sweden)

    Janaina Mortari Schiavini


    Full Text Available In light of discussions on corporate internationalization, a theoretical approach advocates that the main barriers to internationalization are related to the burden of being outside international relationship networks, that is, so-called liability of outsidership. Given China’s relevance to Brazil and the complexity of that country’s business relations (guanxi, this study aims to investigate how Brazilian companies operating in China develop guanxi as a means of overcoming liability of outsidership, based on Chen and Chen’s theoretical framework (2004. A descriptive and qualitative study was conducted analyzing multiple cases in four Brazilian companies from the services sector with offices in China. Data were collected through semi-structured interviews. Data were treated by content analysis using NVivo 8.0 software. The results identified the motives behind internationalization to China, the difficulties encountered due to the liability of outsidership, the significant benefits of guanxi, and activities carried out in order to develop it. This study is expected to contribute to generating knowledge on the internationalization of companies to China.

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

    Directory of Open Access Journals (Sweden)

    Haroon Jamshaid Qazi


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

  9. Harnessing Noxa demethylation to overcome Bortezomib resistance in mantle cell lymphoma. (United States)

    Leshchenko, Violetta V; Kuo, Pei-Yu; Jiang, Zewei; Weniger, Marc A; Overbey, Jessica; Dunleavy, Kieron; Wilson, Wyndham H; Wiestner, Adrian; Parekh, Samir


    Bortezomib (BZM) is the first proteasome inhibitor approved for relapsed Mantle Cell Lymphoma (MCL) with durable responses seen in 30%-50% of patients. Given that a large proportion of patients will not respond, BZM resistance is a significant barrier to use this agent in MCL. We hypothesized that a subset of aberrantly methylated genes may be modulating BZM response in MCL patients. Genome-wide DNA methylation analysis using a NimbleGen array platform revealed a striking promoter hypomethylation in MCL patient samples following BZM treatment. Pathway analysis of differentially methylated genes identified molecular mechanisms of cancer as a top canonical pathway enriched among hypomethylated genes in BZM treated samples. Noxa, a pro-apoptotic Bcl-2 family member essential for the cytotoxicity of BZM, was significantly hypomethylated and induced following BZM treatment. Therapeutically, we could demethylate Noxa and induce anti-lymphoma activity using BZM and the DNA methytransferase inhibitor Decitabine (DAC) and their combination in vitro and in vivo in BZM resistant MCL cells. These findings suggest a role for dynamic Noxa methylation for the therapeutic benefit of BZM. Potent and synergistic cytotoxicity between BZM and DAC in vitro and in vivo supports a strategy for using epigenetic priming to overcome BZM resistance in relapsed MCL patients.

  10. Teams, tribes and patient safety: overcoming barriers to effective teamwork in healthcare. (United States)

    Weller, Jennifer; Boyd, Matt; Cumin, David


    Modern healthcare is delivered by multidisciplinary, distributed healthcare teams who rely on effective teamwork and communication to ensure effective and safe patient care. However, we know that there is an unacceptable rate of unintended patient harm, and much of this is attributed to failures in communication between health professionals. The extensive literature on teams has identified shared mental models, mutual respect and trust and closed-loop communication as the underpinning conditions required for effective teams. However, a number of challenges exist in the healthcare environment. We explore these in a framework of educational, psychological and organisational challenges to the development of effective healthcare teams. Educational interventions can promote a better understanding of the principles of teamwork, help staff understand each other's roles and perspectives, and help develop specific communication strategies, but may not be sufficient on their own. Psychological barriers, such as professional silos and hierarchies, and organisational barriers such as geographically distributed teams, can increase the chance of communication failures with the potential for patient harm. We propose a seven-step plan to overcome the barriers to effective team communication that incorporates education, psychological and organisational strategies. Recent evidence suggests that improvement in teamwork in healthcare can lead to significant gains in patient safety, measured against efficiency of care, complication rate and mortality. Interventions to improve teamwork in healthcare may be the next major advance in patient outcomes.

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


    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.

  12. Strategies used by nurses, academics and students to overcome intercultural communication challenges. (United States)

    Henderson, Saras; Barker, Michelle; Mak, Anita


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

  13. A generic concept to overcome bandgap limitations for designing highly efficient multi-junction photovoltaic cells (United States)

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


    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. PMID:26177808

  14. Overcoming obstacles to implementation: addressing political,institutional and behavioral problems in earthquake hazard mitigationpolicies

    Institute of Scientific and Technical Information of China (English)


    This project is aimed at bridging the three planes, from basic research, through enabling processes, toengineered systems. At the basic research plane, we have been working to improve our collective understanding aboutobstacles to implementing mitigation practices, owner decision processes (in connection with other MCEER projects), andpublic policy processes. At the level of enabling processes, we have been seeking to develop an understanding of howobstacles to greater mitigation can be overcome by improved policy design and processes. At the engineered systems plane,our work is intended to result in practical guidelines for devising policies and programs with appropriate motivation andincentives for implementing policies and programs once adopted. This phase of the research has been aimed, first, at athorough, multidisciplinary review of the literature concerning obstacles to implementation. Second, the research has focusedon advancing the state of the art by developing means for integrating the insights offered by diverse perspectives on theimplementation process from the several social, behavioral, and decision sciences. The research establishes a basis for testingour understanding of these processes in the case of hospital retrofit decisions.

  15. Qualifying stem cell sources: how to overcome potential pitfalls in regenerative medicine? (United States)

    Reinke, Simon; Dienelt, Anke; Blankenstein, Antje; Duda, Georg N; Geissler, Sven


    Regenerative medicine aims to replace lost cells and to restore damaged tissues and organs by either tissue-engineering approaches or stimulation of endogenous processes. Due to their biological properties, stem cells promise to be an effective source for such strategies. Especially adult multipotent stem cells (ASCs) are believed to be applicable in a broad range of therapies for the treatment of multifactorial diseases or age-related degeneration, although the molecular and cellular mechanisms underlying their regenerative function are often hardly described. Moreover, in some demanding clinical situations their efficiency remains limited. Thus, a basic understanding of ASCs regenerative function, their complex interplay with their microenvironment and how compromising conditions interfere with their efficiency is mandatory for any regenerative strategy. Concerning this matter, the impact of patient-specific constraints are often underestimated in research projects and their influence on the study results disregarded. Thus, researchers are urgently depending on well-characterized tissue samples or cells that are connected with corresponding donor information, such as secondary diseases, medication. Here, we outline principle pitfalls during experimental studies using human samples, and describe a potential strategy to overcome these challenges by establishing a core unit for cell and tissue harvesting. This facility aims to bridge the gap between clinic and research laboratories by the provision of a direct link to the clinical operating theatres. Such a strategy clearly supports basic and clinical research in the conduct of their studies and supplies highly characterized human samples together with the corresponding donor information.

  16. Identifying and Overcoming Obstacles to Point-of-Care Data Collection for Eye Care Professionals (United States)

    Lobach, David F.; Silvey, Garry M.; Macri, Jennifer M.; Hunt, Megan; Kacmaz, Roje O.; Lee, Paul P.


    Supporting data entry by clinicians is considered one of the greatest challenges in implementing electronic health records. In this paper we describe a formative evaluation study using three different methodologies through which we identified obstacles to point-of-care data entry for eye care and then used the formative process to develop and test solutions to overcome these obstacles. The greatest obstacles were supporting free text annotation of clinical observations and accommodating the creation of detailed diagrams in multiple colors. To support free text entry, we arrived at an approach that captures an image of a free text note and associates this image with related data elements in an encounter note. The detailed diagrams included a color pallet that allowed changing pen color with a single stroke and also captured the diagrams as an image associated with related data elements. During observed sessions with simulated patients, these approaches satisfied the clinicians’ documentation needs by capturing the full range of clinical complexity that arises in practice. PMID:16779083

  17. Educational pathways of Black women physicists: Stories of experiencing and overcoming obstacles in life (United States)

    Rosa, Katemari


    This talk presents an empirical study on the underrepresentation of people of color in scientific careers. Grounded in Critical Race Theory, the presentation examines the lived experiences of six Black women physicists in the United States, addresses obstacles faced in their career paths, and strategies used to overcome these obstacles. Data for this study were collected through semi-structured interviews and coded for emergent themes, which are invitation to engage in science, communities of science practices, and isolation in the academy. The findings reveal that college recruitment and funding were fundamental for these women to choose Physics over other STEM fields. The analysis shows Physics can be a hostile environment for these women. In addition, Black women experience unique challenges of socialization in Physics, particularly by exclusion of study groups. In this talk, suggestions will be presented to make Physics departments a more inclusive space to support Black women in science. This presentation is based on work supported by the Brazilian government through CAPES (BEX1907-07-7), the Fulbright Program, Comissño Fulbright Brasil, and the Office of Diversity at Teachers College, Columbia University.

  18. Super-aperture metrology: overcoming a fundamental limit in imaging smooth highly curved surfaces. (United States)

    Liu, J; Liu, C; Tan, J; Yang, B; Wilson, T


    The imaging of smooth, highly curved or tilted surfaces is widely recognized as one of the most challenging and unsolved problems in optical imaging and metrology today. The reason is that even when such surfaces are imaged using high aperture microscope objectives the steepness of the features causes the light to be reflected in such a way that it is not captured by the lens. This is true even in the limiting case of unity numerical aperture since the illuminating light may also be reflected in the forward direction. In order to overcome this fundamental problem we have developed a method whereby such specimens are covered with a readily removable organic fluorescent film thereby creating an isotropic scattering surface. We show that we are readily able to detect slopes with angles close 90° using a 0.75 NA objective--an 82% improvement over the theoretical aperture limit. Issues of variation in film thickness deposition are shown to be readily accommodated. This approach may be used with other fluorophore materials, organic or inorganic, since there is no need for biocompatibility in this application.


    Directory of Open Access Journals (Sweden)


    Full Text Available ABSTRACT Some Annonaceae seeds are known to exhibit dormancy mechanisms ranging from possible seed coat impermeability to physiological dormancy. Thus, the aim of this study was to evaluate the effects of gibberellin (GA GA3 and GA4+7 + benzyladenine (GA4+7 + BA application in seeds of Annona macroprophyllata Donn. Sm (papausa and Annona purpurea Moc. & Sessé ex Dunal (chincuya. The experiment was performed by the application of GA3 and GA4+7 + BA on seeds in concentrations of 0, 200, 400, 500, 600, 800 and 1000 mg L-1. The regulators broke the dormancy of both species. However, application of the GA4+7 + BA mixture had more significant results, with greater increases in germination in A. macroprophyllata than in A. purpurea. Treatments that promoted the highest germinations were GA4+7 + BA at a concentration of 200 mg L-1 for A. macroprophyllata (77% and 200 mg L-1 of GA4+7 + BA and 500 mg L-1 of GA3 for A. purpurea (30% and 29%, respectively. Rate index, mean time and frequency of germination were distinct for both species and both treatments. Although both GA3 and GA4+7 + BA promote germination, the GA4+7 + BA mixture was more effective than GA3 to overcoming seed dormancy of both species, A. purpurea has a harder dormancy than A. macroprophyllata

  20. [Future Regulatory Science through a Global Product Development Strategy to Overcome the Device Lag]. (United States)

    Tsuchii, Isao


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

  1. Incorporation of a tag helps to overcome expression variability in a recombinant host

    Directory of Open Access Journals (Sweden)

    Saikat Bhattacharya


    Full Text Available Epigenetics have witnessed a renewed interest over the past decade and assays with recombinant histones has become an important tool for uncovering various aspects of histone biology. However, at times absence of recombinant histone accumulation in bacteria is encountered which is also commonly observed for many eukaryotic proteins in general. In this study, we have investigated the effect of multiple parameters on heterologous expression of proteins. We show that there is marked variability in the accumulation of H2A.2, H2B.1, H3.2 and H4 in the recombinant host, possibly owing to translational variability and degradation by the host proteases. We found that the variability could be overcome by incorporation of the commonly used purification tags, like GST or MBP, of appropriate size and position. Our results provide compelling evidence that transcript parameters like rare codon and GC content, mRNA secondary structure etc. together modulate translation kinetics and govern recombinant protein accumulation.

  2. Conceptual Difficulties of Standard Quantum Mechanics and the Role of Noise in Overcoming Them (United States)

    Ghirardi, Giancarlo


    We briefly review the difficulties of the standard version of quantum mechanics in accounting for all kinds of physical processes (in particular both the micro and the macroscopic ones) and we argue that to overcome such difficulties one has to give up the superposition principle, i.e., to break the linear nature of the theory. We then show that the simple introduction of terms violating the linearity of the deterministic evolution of the standard theory has physically unacceptable consequences. Taking this into account we are led to modify the quantum dynamics by adding to Schrödinger’s equation, besides nonlinear terms, a coupling with an appropriate noise. We show that, with such a move, one can work out a theory which is internally consistent and it allows to account, in a quite simple and physically appealing way, for natural processes including the measurements and the classical behavior of macroscopic bodies. On the basis of our analysis, we are led to conclude that the consideration of the noise represents a crucial element for understanding the laws of nature.

  3. Optimizing Physical Activity Among Older Adults Post Trauma: Overcoming System and Patient Challenges (United States)

    Resnick, Barbara; Galik, Elizabeth; Wells PT, Chris L.; Boltz, Marie; Holtzman, Lauren


    By 2050 it is anticipated that close to half (40%) of all trauma patients will be over the age of 65. Recovery post trauma for these individuals is more complicated than among younger individuals. Specifically there is an increased risk for: (1) functional decline; (2) higher mortality rates; (3) longer length of stay; (4) greater resource consumption; (5) nursing home placement; (6) adverse events such as infections, pressure ulcers and falls; and (7) rehospitalization post discharge. Early mobilization has been shown to improve outcomes. Unfortunately, there are many challenges to early mobilization. The Function Focused Care Intervention was developed to overcome these challenges. The purpose of this paper was to describe the initial recruitment of the first 25 participants and delineate the challenges and successes associated with implementation of this intervention. Overall the intervention was implemented as intended and recruitment rates were consistent with other studies. Most patients were female, white and on average 79 years of age. Optimizing physical activity of patients was a low priority for the nurses with patient safety taking precedence. Patients spent most of the time in bed. Age, depression and tethering were the only factors that were associated with physical activity and functional outcomes of patients. Ongoing work is needed to keep patients physically active in the immediate post trauma recovery period. PMID:26547682

  4. Amphibians acquire resistance to live and dead fungus overcoming fungal immunosuppression. (United States)

    McMahon, Taegan A; Sears, Brittany F; Venesky, Matthew D; Bessler, Scott M; Brown, Jenise M; Deutsch, Kaitlin; Halstead, Neal T; Lentz, Garrett; Tenouri, Nadia; Young, Suzanne; Civitello, David J; Ortega, Nicole; Fites, J Scott; Reinert, Laura K; Rollins-Smith, Louise A; Raffel, Thomas R; Rohr, Jason R


    Emerging fungal pathogens pose a greater threat to biodiversity than any other parasitic group, causing declines of many taxa, including bats, corals, bees, snakes and amphibians. Currently, there is little evidence that wild animals can acquire resistance to these pathogens. Batrachochytrium dendrobatidis is a pathogenic fungus implicated in the recent global decline of amphibians. Here we demonstrate that three species of amphibians can acquire behavioural or immunological resistance to B. dendrobatidis. Frogs learned to avoid the fungus after just one B. dendrobatidis exposure and temperature-induced clearance. In subsequent experiments in which B. dendrobatidis avoidance was prevented, the number of previous exposures was a negative predictor of B. dendrobatidis burden on frogs and B. dendrobatidis-induced mortality, and was a positive predictor of lymphocyte abundance and proliferation. These results suggest that amphibians can acquire immunity to B. dendrobatidis that overcomes pathogen-induced immunosuppression and increases their survival. Importantly, exposure to dead fungus induced a similar magnitude of acquired resistance as exposure to live fungus. Exposure of frogs to B. dendrobatidis antigens might offer a practical way to protect pathogen-naive amphibians and facilitate the reintroduction of amphibians to locations in the wild where B. dendrobatidis persists. Moreover, given the conserved nature of vertebrate immune responses to fungi and the fact that many animals are capable of learning to avoid natural enemies, these results offer hope that other wild animal taxa threatened by invasive fungi might be rescued by management approaches based on herd immunity.

  5. Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy. (United States)

    Mastorakos, Panagiotis; da Silva, Adriana L; Chisholm, Jane; Song, Eric; Choi, Won Kyu; Boyle, Michael P; Morales, Marcelo M; Hanes, Justin; Suk, Jung Soo


    Gene therapy has emerged as an alternative for the treatment of diseases refractory to conventional therapeutics. Synthetic nanoparticle-based gene delivery systems offer highly tunable platforms for the delivery of therapeutic genes. However, the inability to achieve sustained, high-level transgene expression in vivo presents a significant hurdle. The respiratory system, although readily accessible, remains a challenging target, as effective gene therapy mandates colloidal stability in physiological fluids and the ability to overcome biological barriers found in the lung. We formulated highly stable DNA nanoparticles based on state-of-the-art biodegradable polymers, poly(β-amino esters) (PBAEs), possessing a dense corona of polyethylene glycol. We found that these nanoparticles efficiently penetrated the nanoporous and highly adhesive human mucus gel layer that constitutes a primary barrier to reaching the underlying epithelium. We also discovered that these PBAE-based mucus-penetrating DNA nanoparticles (PBAE-MPPs) provided uniform and high-level transgene expression throughout the mouse lungs, superior to several gold standard gene delivery systems. PBAE-MPPs achieved robust transgene expression over at least 4 mo following a single administration, and their transfection efficiency was not attenuated by repeated administrations, underscoring their clinical relevance. Importantly, PBAE-MPPs demonstrated a favorable safety profile with no signs of toxicity following intratracheal administration.

  6. Overcoming the difficulties of inquiry-based teaching through the use of coaching (United States)

    Kraus, Rudolf

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

  7. Making Games Not Work: Paradoxes Embedded in Game-Based Training and Concepts for Overcoming Them (United States)

    Jones, Phillip N.; Cuper, Taryn


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

  8. Pixelated CdTe detectors to overcome intrinsic limitations of crystal based positron emission mammographs (United States)

    De Lorenzo, G.; Chmeissani, M.; Uzun, D.; Kolstein, M.; Ozsahin, I.; Mikhaylova, E.; Arce, P.; Cañadas, M.; Ariño, G.; Calderón, Y.


    A positron emission mammograph (PEM) is an organ dedicated positron emission tomography (PET) scanner for breast cancer detection. State-of-the-art PEMs employing scintillating crystals as detection medium can provide metabolic images of the breast with significantly higher sensitivity and specificity with respect to standard whole body PET scanners. Over the past few years, crystal PEMs have dramatically increased their importance in the diagnosis and treatment of early stage breast cancer. Nevertheless, designs based on scintillators are characterized by an intrinsic deficiency of the depth of interaction (DOI) information from relatively thick crystals constraining the size of the smallest detectable tumor. This work shows how to overcome such intrinsic limitation by substituting scintillating crystals with pixelated CdTe detectors. The proposed novel design is developed within the Voxel Imaging PET (VIP) Pathfinder project and evaluated via Monte Carlo simulation. The volumetric spatial resolution of the VIP-PEM is expected to be up to 6 times better than standard commercial devices with a point spread function of 1 mm full width at half maximum (FWHM) in all directions. Pixelated CdTe detectors can also provide an energy resolution as low as 1.5% FWHM at 511 keV for a virtually pure signal with negligible contribution from scattered events.

  9. Sustainable fuel, food, fertilizer and ecosystems through a global artificial photosynthetic system: overcoming anticompetitive barriers. (United States)

    Bruce, Alex; Faunce, Thomas


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

  10. Identification of Genes in Saccharomyces cerevisiae that Are Haploinsufficient for Overcoming Amino Acid Starvation

    Directory of Open Access Journals (Sweden)

    Nancy S. Bae


    Full Text Available The yeast Saccharomyces cerevisiae responds to amino acid deprivation by activating a pathway conserved in eukaryotes to overcome the starvation stress. We have screened the entire yeast heterozygous deletion collection to identify strains haploinsufficient for growth in the presence of sulfometuron methyl, which causes starvation for isoleucine and valine. We have discovered that cells devoid of MET15 are sensitive to sulfometuron methyl, and loss of heterozygosity at the MET15 locus can complicate screening the heterozygous deletion collection. We identified 138 cases of loss of heterozygosity in this screen. After eliminating the issues of the MET15 loss of heterozygosity, strains isolated from the collection were retested on sulfometuron methyl. To determine the general effect of the mutations for a starvation response, SMM-sensitive strains were tested for the ability to grow in the presence of canavanine, which induces arginine starvation, and strains that were MET15 were also tested for growth in the presence of ethionine, which causes methionine starvation. Many of the genes identified in our study were not previously identified as starvation-responsive genes, including a number of essential genes that are not easily screened in a systematic way. The genes identified span a broad range of biological functions, including many involved in some level of gene expression. Several unnamed proteins have also been identified, giving a clue as to possible functions of the encoded proteins.

  11. New approaches to overcome transport related drug resistance in trypanosomatid parasites

    Directory of Open Access Journals (Sweden)

    Jose A Garcia-Salcedo


    Full Text Available Leishmania and Trypanosoma are members of the Trypanosomatidae family that cause severe human infections such as leishmaniasis, Chagas disease, and sleeping sickness affecting millions of people worldwide. Despite efforts to eradicate them, migrations are expanding these infections to developing countries. There are no vaccines available and current treatments depend only on chemotherapy. Drug resistance is a major obstacle for the treatment of these diseases given that existing drugs are old and limited, with some having severe side effects. Most resistance mechanisms developed by these parasites are related with a decreased uptake or increased efflux of the drug due to mutations or altered expression of membrane transporters. Different new approaches have been elaborated that can overcome these mechanisms of resistance including the use of inhibitors of efflux pumps and drug carriers for both active and passive targeting. Here we review new formulations that have been successfully applied to circumvent resistance related to drug transporters, opening alternative ways to solve drug resistance in protozoan parasitic diseases.

  12. Overcoming the Problems of Inconsistent International Migration data: A New Method Applied to Flows in Europe. (United States)

    de Beer, Joop; Raymer, James; van der Erf, Rob; van Wissen, Leo


    Due to differences in definitions and measurement methods, cross-country comparisons of international migration patterns are difficult and confusing. Emigration numbers reported by sending countries tend to differ from the corresponding immigration numbers reported by receiving countries. In this paper, a methodology is presented to achieve harmonised estimates of migration flows benchmarked to a specific definition of duration. This methodology accounts for both differences in definitions and the effects of measurement error due to, for example, under reporting and sampling fluctuations. More specifically, the differences between the two sets of reported data are overcome by estimating a set of adjustment factors for each country's immigration and emigration data. The adjusted data take into account any special cases where the origin-destination patterns do not match the overall patterns. The new method for harmonising migration flows that we present is based on earlier efforts by Poulain (European Journal of Population, 9(4): 353-381 1993, Working Paper 12, joint ECE-Eurostat Work Session on Migration Statistics, Geneva, Switzerland 1999) and is illustrated for movements between 19 European countries from 2002 to 2007. The results represent a reliable and consistent set of international migration flows that can be used for understanding recent changes in migration patterns, as inputs into population projections and for developing evidence-based migration policies.

  13. Topological robustness analysis of protein interaction networks reveals key targets for overcoming chemotherapy resistance in glioma (United States)

    Azevedo, Hátylas; Moreira-Filho, Carlos Alberto


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

  14. New Approaches to Overcome Transport Related Drug Resistance in Trypanosomatid Parasites (United States)

    Garcia-Salcedo, Jose A.; Unciti-Broceta, Juan D.; Valverde-Pozo, Javier; Soriano, Miguel


    Leishmania and Trypanosoma are members of the Trypanosomatidae family that cause severe human infections such as leishmaniasis, Chagas disease, and sleeping sickness affecting millions of people worldwide. Despite efforts to eradicate them, migrations are expanding these infections to developing countries. There are no vaccines available and current treatments depend only on chemotherapy. Drug resistance is a major obstacle for the treatment of these diseases given that existing drugs are old and limited, with some having severe side effects. Most resistance mechanisms developed by these parasites are related with a decreased uptake or increased efflux of the drug due to mutations or altered expression of membrane transporters. Different new approaches have been elaborated that can overcome these mechanisms of resistance including the use of inhibitors of efflux pumps and drug carriers for both active and passive targeting. Here we review new formulations that have been successfully applied to circumvent resistance related to drug transporters, opening alternative ways to solve drug resistance in protozoan parasitic diseases. PMID:27733833

  15. Creating sustainable local health information exchanges: can barriers to stakeholder participation be overcome? (United States)

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


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

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

    Energy Technology Data Exchange (ETDEWEB)

    Cole, Pamala C.; Gilbride, Theresa L.


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

  17. [Cytological Study in vitro on Co-delivery of siRNA and Paclitaxel within Solid Lipid Nanoparticles to Overcome Multidrug Resistance in Tumors]. (United States)

    Huang, Rui; Yao, Xinyu; Chen, Yuan; Sun, Xun; Lin, Yunzhu


    Multidrug resistance (MDR) remains the major obstacle to the success of clinical cancer chemotherapy. P-glycoprotein (P-gp), encoded by the MDR1, is an important part with complex mechanisms associated with the MDR. In order to overcome the MDR of tumors, we in the present experimental design incorporated small interfering RNA (siRNA) targeting MDR1 gene and anticancer drug paclitaxel (PTX) into the solid lipid nanoparticles (SLNs) to achieve the combinational therapeutic effects of genetherapy and chemotherapy. In this study, siRNA-PTX-SLNs were successfully prepared. The cytotoxicity of blank SLNs and siRNA-PTX-SLNs in MCF-7 cells and MCF-7/ADR cells were detected by MTT; and the uptake efficiency of PTX in MCF-7/ADR cells were detected via HPLC method; quantitative real-time PCR and flow cytometry were performed to investigate the silencing effect of siRNA-PTX- SLNs on MDR1 gene in MCF-7/ADR cells. The results showed that PTX loaded SLNs could significantly inhibit the growth of tumor cells, and more importantly, the MDR tumor cells treated with siRNA-PTX-SLNs showed the lowest viability. HPLC study showed that SLNs could enhance the cellular uptake for PTX. Meanwhile, siRNA delivered by SLNs significantly decreased the P-gp expression in MDR tumor cells, thus increased the cellular accumulation of rhodamine123 as a P-gp substrate. In conclusion, the MDR1 gene could be silenced by siRNA-PTX-SLNs, which could promote the growth inhibition efficiency of PTX on tumor cells, leading to synergetic effect on MDR tumor therapy.

  18. When the patient and family just do not get it: overcoming low health literacy in critical care. (United States)

    Ingram, Racquel; Kautz, Donald D


    Low health literacy in patients and families has been called a silent epidemic. Although there is a great deal of literature to assist nurses to address health literacy problems, little has focused on overcoming low health literacy in critical care. This article provides a definition of health literacy, explores how Baker's health literacy model can be applied to the critical care environment using Osborne's practical strategies, and presents 2 patient scenarios in which addressing low health literacy changed the outcomes for the patient and family. The article concludes with recommendations for critical care nurses to overcome low health literacy of patients and their families.

  19. 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


    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.

  20. Cancer-targeted MDR-1 siRNA delivery using self-cross-linked glycol chitosan nanoparticles to overcome drug resistance. (United States)

    Yhee, Ji Young; Song, Seungyong; Lee, So Jin; Park, Sung-Gurl; Kim, Ki-Suk; Kim, Myung Goo; Son, Sejin; Koo, Heebeom; Kwon, Ick Chan; Jeong, Ji Hoon; Jeong, Seo Young; Kim, Sun Hwa; Kim, Kwangmeyung


    P-glycoprotein (Pgp) mediated multi-drug resistance (MDR) is a major cause of failure in chemotherapy. In this study, small interfering RNA (siRNA) for Pgp down-regulation was delivered to tumors to overcome MDR in cancer. To achieve an efficient siRNA delivery in vivo, self-polymerized 5'-end thiol-modified siRNA (poly-siRNA) was incorporated in tumor targeting glycol chitosan nanoparticles. Pgp-targeted poly-siRNA (psi-Pgp) and thiolated glycol chitosan polymers (tGC) formed stable nanoparticles (psi-Pgp-tGC NPs), and the resulting nanoparticles protected siRNA molecules from enzymatic degradation. The psi-Pgp-tGC NPs could release functional siRNA molecules after cellular delivery, and they were able to facilitate siRNA delivery to Adriamycin-resistant breast cancer cells (MCF-7/ADR). After intravenous administration, the psi-Pgp-tGC NPs accumulated in MCF-7/ADR tumors and down-regulated P-gp expression to sensitize cancer cells. Consequently, chemo-siRNA combination therapy significantly inhibited tumor growth without systemic toxicity. These psi-Pgp-tGC NPs showed great potential as a supplementary therapeutic agent for drug-resistant cancer.

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

    Energy Technology Data Exchange (ETDEWEB)

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


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

  2. 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.

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

    Directory of Open Access Journals (Sweden)

    You-Jin Lee


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

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

    Directory of Open Access Journals (Sweden)

    Albert Weideman


    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

  5. Overcoming potential energy distortions in constrained internal coordinate molecular dynamics simulations. (United States)

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


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

  6. Cardiac Arrhythmia: In vivo screening in the zebrafish to overcome complexity in drug discovery (United States)

    MacRae, Calum A.


    Importance of the field Cardiac arrhythmias remain a major challenge for modern drug discovery. Clinical events are paroxysmal, often rare and may be asymptomatic until a highly morbid complication. Target selection is often based on limited information and though highly specific agents are identified in screening, the final efficacy is often compromised by unanticipated systemic responses, a narrow therapeutic index and substantial toxicities. Areas covered in this review Our understanding of complexity of arrhythmogenesis has grown dramatically over the last two decades, and the range of potential disease mechanisms now includes pathways previously thought only tangentially involved in arrhythmia. This review surveys the literature on arrhythmia mechanisms from 1965 to the present day, outlines the complex biology underlying potentially each and every rhythm disturbance, and highlights the problems for rational target identification. The rationale for in vivo screening is described and the utility of the zebrafish for this approach and for complementary work in functional genomics is discussed. Current limitations of the model in this setting and the need for careful validation in new disease areas are also described. What the reader will gain An overview of the complex mechanisms underlying most clinical arrhythmias, and insight into the limits of ion channel conductances as drug targets. An introduction to the zebrafish as a model organism, in particular for cardiovascular biology. Potential approaches to overcoming the hurdles to drug discovery in the face of complex biology including in vivo screening of zebrafish genetic disease models. Take home message In vivo screening in faithful disease models allows the effects of drugs on integrative physiology and disease biology to be captured during the screening process, in a manner agnostic to potential drug target or targets. This systematic strategy bypasses current gaps in our understanding of disease biology

  7. Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance in vitro. (United States)

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


    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.

  8. Molecular and Material Approaches to Overcome Kinetic and Energetic Constraints in Dye-Sensitized Solar Cells

    Energy Technology Data Exchange (ETDEWEB)

    Hamann, Thomas [Michigan State Univ., East Lansing, MI (United States)


    Dye-sensitized solar cells (DSSCs) have attracted a lot of interest as they proffer the possibility of extremely inexpensive and efficient solar energy conversion. The excellent performance of the most efficient DSSCs relies on two main features: 1) a high surface area nanoparticle semiconductor photoanode to allow for excellent light absorption with moderate extinction molecular dyes and 2) slow recombination rates from the photoanode to I3- allowing good charge collection. The I3-/I- couple, however, has some disadvantages, notably the redox potential limits the maximum open-circuit voltage, and the dye regeneration requires a large driving force which constrains the light harvesting ability. Thus, the design features that allow DSSCs to perform as well as they do also prevent further significant improvements in performance. As a consequence, the most efficient device configuration, and the maximum efficiency, has remained essentially unchanged over the last 16 years. Significant gains in performance are possible; however it will likely require a substantial paradigm shift. The general goal of this project is to understand the fundamental role of dye-sensitized solar cell, DSSC, components (sensitizer, redox shuttle, and photoanode) involved in key processes in order to overcome the kinetic and energetic constraints of current generation DSSCs. For example, the key to achieving high energy conversion efficiency DSSCs is the realization of a redox shuttle which fulfills the dual requirements of 1) efficient dye regeneration with a minimal driving force and 2) efficient charge collection. In current generation DSSCs, however, only one or the other of these requirements is met. We are currently primarily interested in understanding the physical underpinnings of the regeneration and recombination reactions. Our approach is to systematically vary the components involved in reactions and interrogate them with a

  9. Differential gene expression by Moniliophthora roreri while overcoming cacao tolerance in the field. (United States)

    Bailey, Bryan A; Melnick, Rachel L; Strem, Mary D; Crozier, Jayne; Shao, Jonathan; Sicher, Richard; Phillips-Mora, Wilberth; Ali, Shahin S; Zhang, Dapeng; Meinhardt, Lyndel


    Frosty pod rot (FPR) of Theobroma cacao (cacao) is caused by the hemibiotrophic fungus Moniliophthora roreri. Cacao clones tolerant to FPR are being planted throughout Central America. To determine whether M. roreri shows a differential molecular response during successful infections of tolerant clones, we collected field-infected pods at all stages of symptomatology for two highly susceptible clones (Pound-7 and CATIE-1000) and three tolerant clones (UF-273, CATIE-R7 and CATIE-R4). Metabolite analysis was carried out on clones Pound-7, CATIE-1000, CATIE-R7 and CATIE-R4. As FPR progressed, the concentrations of sugars in pods dropped, whereas the levels of trehalose and mannitol increased. Associations between symptoms and fungal loads and some organic and amino acid concentrations varied depending on the clone. RNA-Seq analysis identified 873 M. roreri genes that were differentially expressed between clones, with the primary difference being whether the clone was susceptible or tolerant. Genes encoding transcription factors, heat shock proteins, transporters, enzymes modifying membranes or cell walls and metabolic enzymes, such as malate synthase and alternative oxidase, were differentially expressed. The differential expression between clones of 43 M. roreri genes was validated by real-time quantitative reverse transcription polymerase chain reaction. The expression profiles of some genes were similar in susceptible and tolerant clones (other than CATIE-R4) and varied with the biotrophic/necrotropic shift. Moniliophthora roreri genes associated with stress metabolism and responses to heat shock and anoxia were induced early in tolerant clones, their expression profiles resembling that of the necrotrophic phase. Moniliophthora roreri stress response genes, induced during the infection of tolerant clones, may benefit the fungus in overcoming cacao defense mechanisms.

  10. An Improved Methodology to Overcome Key Issues in Human Fecal Metagenomic DNA Extraction

    Directory of Open Access Journals (Sweden)

    Jitendra Kumar


    Full Text Available Microbes are ubiquitously distributed in nature, and recent culture-independent studies have highlighted the significance of gut microbiota in human health and disease. Fecal DNA is the primary source for the majority of human gut microbiome studies. However, further improvement is needed to obtain fecal metagenomic DNA with sufficient amount and good quality but low host genomic DNA contamination. In the current study, we demonstrate a quick, robust, unbiased, and cost-effective method for the isolation of high molecular weight (>23 kb metagenomic DNA (260/280 ratio >1.8 with a good yield (55.8 ± 3.8 ng/mg of feces. We also confirm that there is very low human genomic DNA contamination (eubacterial: human genomic DNA marker genes = 227.9:1 in the human feces. The newly-developed method robustly performs for fresh as well as stored fecal samples as demonstrated by 16S rRNA gene sequencing using 454 FLX+. Moreover, 16S rRNA gene analysis indicated that compared to other DNA extraction methods tested, the fecal metagenomic DNA isolated with current methodology retains species richness and does not show microbial diversity biases, which is further confirmed by qPCR with a known quantity of spike-in genomes. Overall, our data highlight a protocol with a balance between quality, amount, user-friendliness, and cost effectiveness for its suitability toward usage for culture-independent analysis of the human gut microbiome, which provides a robust solution to overcome key issues associated with fecal metagenomic DNA isolation in human gut microbiome studies.

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

    Energy Technology Data Exchange (ETDEWEB)

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


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

  12. Targeted therapeutic nanotubes influence the viscoelasticity of cancer cells to overcome drug resistance. (United States)

    Bhirde, Ashwinkumar A; Chikkaveeraiah, Bhaskara V; Srivatsan, Avinash; Niu, Gang; Jin, Albert J; Kapoor, Ankur; Wang, Zhe; Patel, Sachin; Patel, Vyomesh; Gorbach, Alexander M; Leapman, Richard D; Gutkind, J Silvio; Hight Walker, Angela R; Chen, Xiaoyuan


    Resistance to chemotherapy is the primary cause of treatment failure in over 90% of cancer patients in the clinic. Research in nanotechnology-based therapeutic alternatives has helped provide innovative and promising strategies to overcome multidrug resistance (MDR). By targeting CD44-overexpressing MDR cancer cells, we have developed in a single-step a self-assembled, self-targetable, therapeutic semiconducting single-walled carbon nanotube (sSWCNT) drug delivery system that can deliver chemotherapeutic agents to both drug-sensitive OVCAR8 and resistant OVCAR8/ADR cancer cells. The novel nanoformula with a cholanic acid-derivatized hyaluronic acid (CAHA) biopolymer wrapped around a sSWCNT and loaded with doxorubicin (DOX), CAHA-sSWCNT-DOX, is much more effective in killing drug-resistant cancer cells compared to the free DOX and phospholipid PEG (PL-PEG)-modified sSWCNT formula, PEG-sSWCNT-DOX. The CAHA-sSWCNT-DOX affects the viscoelastic property more than free DOX and PL-PEG-sSWCNT-DOX, which in turn allows more drug molecules to be internalized. Intravenous injection of CAHA-sSWCNT-DOX (12 mg/kg DOX equivalent) followed by 808 nm laser irradiation (1 W/cm(2), 90 s) led to complete tumor eradication in a subcutaneous OVCAR8/ADR drug-resistant xenograft model, while free DOX alone failed to delay tumor growth. Our newly developed CAHA-sSWCNT-DOX nanoformula, which delivers therapeutics and acts as a sensitizer to influence drug uptake and induce apoptosis with minimal resistance factor, provides a novel effective means of counteracting the phenomenon of multidrug resistance.

  13. Overcoming problems of density and thickness measurements in FTIR volatile determinations: a spectroscopic approach (United States)

    Agrinier, Pierre; Jendrzejewski, Nathalie

    The Beer-Lambert law is traditionally used to determine water and carbon concentrations in glasses from their infrared (IR) spectra. In practice, this method requires estimation of the thickness and density of the glass as well as the calibration of the molecular absorptivities of the species concerned. All of these parameters can be sources of practical difficulties and analytical uncertainty. These weaknesses in the application of the Beer-Lambert law have been overcome by an empirical analysis of the infrared spectra. Using a set of 292 spectra obtained on 113 natural and experimental tholeiitic glasses (SiO2 48.5-51wt% water contents 0-4000ppm H2O), it can be shown that the thickness-density (ρd) product of a glass sample can be directly and reliably inferred from its IR spectrum. This allows the Beer-Lambert law to be rewritten. The new form no longer requires thickness or density estimations to determine volatile contents. Moreover, if needed, the thickness of the glass slab can also be accurately determined from the IR spectra. This new method is developed for quantitative determination of water concentrations in MORB glasses but can also be applied to any minor species (carbon, sulfur, etc.) provided it is active in the IR domain and that a suitable independent frequency of IR absorption can be identified. Precision is about 60ppm H2O on O-H- contents. This method, tested on natural and experimental MORB-type glasses, can be applied to any chemical composition provided a set of reference spectra is available.

  14. Strategies to overcome clinical, regulatory, and financial challenges in the implementation of personalized medicine. (United States)

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


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

  15. Central leptin gene therapy fails to overcome leptin resistance associated with diet-induced obesity. (United States)

    Wilsey, Jared; Zolotukhin, Sergei; Prima, Victor; Scarpace, Philip J


    The objective of this study was to determine if central overexpression of leptin could overcome the leptin resistance caused by 100 days of high-fat feeding. Three-month old-F344XBN male rats were fed either control low fat chow (Chow), which provides 15% of energy as fat, or a high-fat/high-sucrose diet (HF), which provides 59% of energy as fat. Over several weeks, the HF-fed animals spontaneously split into two groups of animals: those that became obese on the HF diet (DIO) and those that did not gain extra weight on the HF diet [diet resistant (DR)]. After 100 days of HF feeding, animals were given a single intracerebroventricular injection containing 5.75E10 particles of rAAV encoding leptin (rAAV-leptin) or control virus (rAAV-con). Chow animals responded robustly to rAAV-leptin, including significant anorexia, weight loss, and lipopenia. In contrast, DIO were completely unresponsive to rAAV-leptin. DR rats responded to rAAV-leptin, but in a more variable fashion than Chow. Unlike what was observed in Chow, the anorectic response to rAAV-leptin rapidly attenuated and was no longer significant by day 14 postvector delivery. Both DIO and DR animals were found to have reduced long-form leptin receptor expression and enhanced basal P-STAT-3 in the hypothalamus with respect to Chow. rAAV-leptin caused an increase in STAT3 phosphorylation and proopiomelanocortin expression in the hypothalamus and an increase in uncoupling protein-1 in brown adipose tissue in both Chow and DR animals, but failed to do so in DIO. This suggests that central overexpression of leptin is not a viable strategy to reverse diet-induced obesity.

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

    Directory of Open Access Journals (Sweden)

    Koji eYoshimoto


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

  17. Soviet “Life Canon” in scientist’s biography and problem of its overcoming

    Directory of Open Access Journals (Sweden)

    Khazagerov Georgii Georgievich


    Full Text Available This article is dedicated to one of the fragments of modern textual culture, namely the presentation of the image of the scientist, usually presented in the book, devoted to anniversaries. Often it is the memories of students. Scientific pathos of the article is due to the fact that these memories do not always create a life image of the scientist, not realizing his appointment. Often different publications not only smooth personal traits of individuals, but also smooth individual features of the style of the authors and individual differences of their texts. The article identifies the causes of these phenomena. One of them is blind, non-functional copy of topos characteristic of Soviet biographies. It is, for example, a topos of poverty and democratic origin of the scientist who during the Soviet biographies was intended to carry out agitation and didactic function. Combining topos with biographical frame results in a maximum leveling in the representation of a person. Thus it appears what the article calls “Soviet life canon.” Another reason for the smoothing of individual style and create a speculative form of teaching is the penetration in the biographical genre of officialese expressing indifferent attitude to people. Concerning modern biographies of scientists officialese involves business style, that serves genres of reviews, i.e. all that is related to business decision-making relating to the work of the scientist. The article pointed out ways to overcome these negative trends in modern publications related to the demand for intimization category, which primarily should be shown in the plot structure of the narration.

  18. Redox active copper chelate overcomes multidrug resistance in T-lymphoblastic leukemia cell by triggering apoptosis. (United States)

    Ganguly, Avishek; Basu, Soumya; Banerjee, Kaushik; Chakraborty, Paramita; Sarkar, Avijit; Chatterjee, Mitali; Chaudhuri, Soumitra Kumar


    Multidrug resistance (MDR) mediated by the over expression of drug efflux protein P-glycoprotein (P-gp) is one of the major impediments to successful treatment of cancer. P-gp acts as an energy-dependent drug efflux pump and reduces the intracellular concentration of structurally unrelated drugs inside the cells. Therefore, there is an urgent need for development of new molecules that are less toxic to normal cell and preferentially effective against drug resistant malignant cells. In this preclinical study we report the apoptotic potential of copper N-(2-hydroxyacetophenone) glycinate (CuNG) on doxorubicin resistant T lymphoblastic leukaemia cells (CEM/ADR5000). To evaluate the cytotoxic effect of CuNG, we used different normal cell lines (NIH 3T3, Chang liver and human PBMC) and cancerous cell lines (CEM/ADR5000, parental sensitive CCRF-CEM, SiHa and 3LL) and conclude that CuNG preferentially kills cancerous cells, especially both leukemic cell types irrespective of their MDR status, while leaving normal cell totally unaffected. Moreover, CuNG involves reactive oxygen species (ROS) for induction of apoptosis in CEM/ADR5000 cells through the intrinsic apoptotic pathway. This is substantiated by our observation that antioxidant N-acetyle-cysteine (NAC) and PEG catalase could completely block ROS generation and, subsequently, abrogates CuNG induced apoptosis. On the other hand, uncomplexed ligand N-(2-hydroxyacetophenone) glycinate (NG) fails to generate a significant amount of ROS and concomitant induction of apoptosis in CEM/ADR5000 cells. Therefore, CuNG induces drug resistant leukemia cells to undergo apoptosis and proves to be a molecule having therapeutic potential to overcome MDR in cancer.

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

    Energy Technology Data Exchange (ETDEWEB)

    Osso, J.A. Jr.; Teodoro, R.; Dias, C.R.B.R.; Bezerra, R.R.L.; Villela, L.A.; Correia, J.L.; Perrotta, J.A.; Pereira, G.A.; Zapparoli, C.L. Jr.; Mengatti, J. [Diretoria de Radiofarmacia, Instituto de Pesquisas Energeticas e Nucleares (DIRF-IPEN), Avenida Prof. Lineu Prestes 2242, 05508-000, Sao Paulo, SP (Brazil)


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

  20. 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


    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.

  1. Overcoming catastrophic interference in connectionist networks using Gram-Schmidt orthogonalization.

    Directory of Open Access Journals (Sweden)

    Vipin Srivastava

    Full Text Available Connectionist models of memory storage have been studied for many years, and aim to provide insight into potential mechanisms of memory storage by the brain. A problem faced by these systems is that as the number of items to be stored increases across a finite set of neurons/synapses, the cumulative changes in synaptic weight eventually lead to a sudden and dramatic loss of the stored information (catastrophic interference, CI as the previous changes in synaptic weight are effectively lost. This effect does not occur in the brain, where information loss is gradual. Various attempts have been made to overcome the effects of CI, but these generally use schemes that impose restrictions on the system or its inputs rather than allowing the system to intrinsically cope with increasing storage demands. We show here that catastrophic interference occurs as a result of interference among patterns that lead to catastrophic effects when the number of patterns stored exceeds a critical limit. However, when Gram-Schmidt orthogonalization is combined with the Hebb-Hopfield model, the model attains the ability to eliminate CI. This approach differs from previous orthogonalisation schemes used in connectionist networks which essentially reflect sparse coding of the input. Here CI is avoided in a network of a fixed size without setting limits on the rate or number of patterns encoded, and without separating encoding and retrieval, thus offering the advantage of allowing associations between incoming and stored patterns. PACS Nos.: 87.10.+e, 87.18.Bb, 87.18.Sn, 87.19.La.

  2. Genome network medicine: innovation to overcome huge challenges in cancer therapy. (United States)

    Roukos, Dimitrios H


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

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

    Directory of Open Access Journals (Sweden)

    Fanus Nagimovich Garipov


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

  4. Malthusian overfishing and efforts to overcome it on Kenyan coral reefs. (United States)

    McClanahan, Tim R; Hicks, Christina C; Darling, Emily S


    This study examined trends along a gradient of fishing intensity in an artisanal coral reef fishery over a 10-year period along 75 km of Kenya's most populated coastline. As predicted by Malthusian scenarios, catch per unit effort (CPUE), mean trophic level, the functional diversity of fished taxa, and the diversity of gear declined, while total annual catch and catch variability increased along the fishing pressure gradient. The fishery was able to sustain high (approximately 16 Mg x km(-2) x yr(-1)) but variable yields at high fishing pressure due to the dominance of a few productive herbivorous fish species in the catch. The effect of two separate management strategies to overcome this Malthusian pattern was investigated: fisheries area closure and elimination of the dominant and most "competitive" gear. We found that sites within 5 km of the enforced closure showed significantly lower total catch and CPUE, but increased yield stability and trophic level of catch than predicted by regression models normalized for fishing effort. Sites that had excluded illegal beach seine use through active gear management exhibited increased total catch and CPUE. There was a strong interaction between closure and gear management, which indicates that, for closures to be effective at increasing catch, there must be simultaneous efforts at gear management around the periphery of the closures. We propose that Malthusian effects are responsible for the variation in gear and catch and that active management through reduced effort and reductions in the most competitive gear have the greatest potential to increase the functional and trophic diversity and per-person productivity.

  5. What Works to Overcome Indigenous Disadvantage: Key Learnings and Gaps in the Evidence. Closing the Gap Clearinghouse. 2009-10 (United States)

    Al-Yaman, Fadwa; Higgins, Daryl


    The Closing the Gap Clearinghouse was established by the Council of Australian Governments (COAG) to bring together evidence-based research on overcoming disadvantage for Indigenous Australians. The Clearinghouse provides access to a collection of information on what works to improve Indigenous people's lives across the building blocks identified…

  6. Practical Teaching Programme Online: Overcoming Communication Issues (Learning from the Experience of PKPG Teaching Practice Website in UNIMAS). (United States)

    NoorShah, Mohd Salleh


    Describes the use of a Web-based learning environment for practice teaching at the Universiti Malaysia Sarawak (UNIMAS). Topics include overcoming communication problems between student teachers and between students and instructors; participation rates; and the Program Khas Pensiswazahan Guru (PKPG) program, an inservice course for nongraduate…

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

    DEFF Research Database (Denmark)

    Viala, Eva Silberschmidt


    Despite extensive research on the causes of bullying and how it can be stopped, little is known about how or why some children overcome or transgress their position as victim of bullying. Based on analyses of three “extreme cases” in which peer victimization have been stopped or prevented, the pa...

  8. Overcoming Students' Misconceptions Concerning Thermal Physics with the Aid of Hints and Peer Interaction during a Lecture Course (United States)

    Leinonen, Risto; Asikainen, Mervi A.; Hirvonen, Pekka E.


    As has been shown by previous research, students may possess various misconceptions in the area of thermal physics. In order to help them overcome misconceptions observed prior to instruction, we implemented a one-hour lecture-based intervention in their introductory thermal physics course. The intervention was held after the conventional lectures…

  9. Cut It Up and Put It Back Together: Cut-up and Collage as Tools to Overcome Academic Deadlock

    DEFF Research Database (Denmark)

    Bager-Elsborg, Anna; Loads, Daphne


    This ‘On the Horizon’ paper concerns creativity in the research process as a way to overcome unhelpful pre-understandings and ‘false clarity’. This paper gives an idea of how we can allow research to be as complex and messy as reality. Cut-up and collage are introduced and suggested as a way of l...

  10. Strategies to Inhibit Myc and Their Clinical Applicability (United States)

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


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

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

    Institute of Scientific and Technical Information of China (English)

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


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

  12. Aerosol administration of phospho-sulindac inhibits lung tumorigenesis. (United States)

    Cheng, Ka Wing; Wong, Chi C; Alston, Ninche; Mackenzie, Gerardo G; Huang, Liqun; Ouyang, Nengtai; Xie, Gang; Wiedmann, Timothy; Rigas, Basil


    Phospho-sulindac is a sulindac derivative with promising anticancer activity in lung cancer, but its limited metabolic stability presents a major challenge for systemic therapy. We reasoned that inhalation delivery of phospho-sulindac might overcome first-pass metabolism and produce high levels of intact drug in lung tumors. Here, we developed a system for aerosolization of phospho-sulindac and evaluated the antitumor efficacy of inhaled phospho-sulindac in an orthotopic model of human non-small cell lung cancer (A549 cells). We found that administration by inhalation delivered high levels of phospho-sulindac to the lungs and minimized its hydrolysis to less active metabolites. Consequently, inhaled phospho-sulindac (6.5 mg/kg) was highly effective in inhibiting lung tumorigenesis (75%; P sulindac suppressed lung tumorigenesis by (i) inhibiting EGF receptor (EGFR) activation, leading to profound inhibition of Raf/MEK/ERK and PI3K/AKT/mTOR survival cascades; (ii) inducing oxidative stress, which provokes the collapse of mitochondrial membrane potential and mitochondria-dependent cell death; and (iii) inducing autophagic cell death. Our data establish that inhalation delivery of phospho-sulindac is an efficacious approach to the control of lung cancer, which merits further evaluation.

  13. Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases. (United States)

    Niessner, Heike; Forschner, Andrea; Klumpp, Bernhard; Honegger, Jürgen B; Witte, Maria; Bornemann, Antje; Dummer, Reinhard; Adam, Annemarie; Bauer, Jürgen; Tabatabai, Ghazaleh; Flaherty, Keith; Sinnberg, Tobias; Beck, Daniela; Leiter, Ulrike; Mauch, Cornelia; Roesch, Alexander; Weide, Benjamin; Eigentler, Thomas; Schadendorf, Dirk; Garbe, Claus; Kulms, Dagmar; Quintanilla-Martinez, Leticia; Meier, Friedegund


    Brain metastases are the most common cause of death in patients with metastatic melanoma, and the RAF-MEK-ERK and PI3K-AKT signaling pathways are key players in melanoma progression and drug resistance. The BRAF inhibitor vemurafenib significantly improved overall survival. However, brain metastases still limit the effectiveness of this therapy. In a series of patients, we observed that treatment with vemurafenib resulted in substantial regression of extracerebral metastases, but brain metastases developed. This study aimed to identify factors that contribute to treatment resistance in brain metastases. Matched brain and extracerebral metastases from melanoma patients had identical ERK, p-ERK, and AKT immunohistochemistry staining patterns, but there was hyperactivation of AKT (p-AKT) and loss of PTEN expression in the brain metastases. Mutation analysis revealed no differences in BRAF, NRAS, or KIT mutation status in matched brain and extracerebral metastases. In contrast, AKT, p-AKT, and PTEN expression was identical in monolayer cultures derived from melanoma brain and extracerebral metastases. Furthermore, melanoma cells stimulated by astrocyte-conditioned medium showed higher AKT activation and invasiveness than melanoma cells stimulated by fibroblast-conditioned medium. Inhibition of PI3K-AKT signaling resensitized melanoma cells isolated from a vemurafenib-resistant brain metastasis to vemurafenib. Brain-derived factors appear to induce hyperactivation of the AKT survival pathway and to promote the survival and drug resistance of melanoma cells in the brain. Thus, inhibition of PI3K-AKT signaling shows potential for enhancing and/or prolonging the antitumor effect of BRAF inhibitors or other anticancer agents in melanoma brain metastases.

  14. Multifaceted mechanisms of HIV inhibition and resistance to CCR5 inhibitors PSC-RANTES and Maraviroc. (United States)

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


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

  15. Lateral inhibition during nociceptive processing

    DEFF Research Database (Denmark)

    Quevedo, Alexandre S.; Mørch, Carsten Dahl; Andersen, Ole Kæseler


    of skin. Thus, the stimulation of the skin region between the endpoints of the lines appears to produce inhibition. These findings indicate that lateral inhibition limits spatial summation of pain and is an intrinsic component of nociceptive information processing. Disruption of such lateral inhibition......Spatial summation of pain is the increase of perceived intensity that occurs as the stimulated area increases. Spatial summation of pain is sub-additive in that increasing the stimulus area produces a disproportionately small increase in the perceived intensity of pain. A possible explanation...... for sub-additive summation may be that convergent excitatory information is modulated by lateral inhibition. To test the hypothesis that lateral inhibition may limit spatial summation of pain, we delivered different patterns of noxious thermal stimuli to the abdomens of 15 subjects using a computer...

  16. Adaptation of bacteriophages to new hosts through overcoming the interspecific barrier

    Directory of Open Access Journals (Sweden)

    Е. N. Andriychuk


    Full Text Available Four wild type phage isolates were tested on P. syringae isolated from potato tuber samples collected in the Kiev and Cherkasy regions of Ukraine. The isolated phages formed clear plaques and had a virion size of 2 to 12 nm. Electron microscopy showed that the phages were of similar size and structure and consisted of isometric particles with long tails characteristic of the Podoviridae family. The effectiveness of phage culturing on bacteria different from the original host was also studied on two phytopathogenic strains of Pseudomonas savastanoi pv. рhaseolicola 4013 and P. syringae pv. tabaci 223. However, no stable isolates could be extracted from P. savastanoi pv. phaseolicola as the plages became inactive after a few passages on the bacterial culture. In order to overcome this, the phages were first cultured on P. syringae pv. tabaci before being transferred to P. savastanoi pv. рhaseolicola. The titers obtained were compared with phage titers from the original host bacteria. Thus, it was determined that the changes occuring in phages after their transfer to the Pseudomonas strain 4013 were irreversible. The changes were evaluated by comparing the effectiveness of phage culturing after a cycle of passages on strains 4013 and 223 where the phages were adapted to strain 4013 after being cultured on strain 223. Additionally, the effectiveness of phage culturing on strain 223 was also determined. The change in the effectiveness of phage culturing for the entire phage range suggests the presence of a defensive system in bacteria when the phages were transferred from strain 223 to strain 4013. The irreversibility of the changes occuring in phages was also tested and it was determined that phages 223/4 and 7591/2 adapt to original hosts and swiftly restore their original titers. Phage 7591/1, however, showed titers that were lower than the ones obtained from the original host culture. The testing of the irreversibility of changes in phages

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

    Directory of Open Access Journals (Sweden)

    Choi J


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

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

    Directory of Open Access Journals (Sweden)

    Dedeepiya V


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

  19. Overcoming paclitaxel resistance in uterine endometrial cancer using a COX-2 inhibitor. (United States)

    Hasegawa, Kiyoshi; Ishikawa, Kunimi; Kawai, Satoshi; Torii, Yutaka; Kawamura, Kyoko; Kato, Rina; Tsukada, Kazuhiko; Udagawa, Yasuhiro


    treatment. Co-administration of paclitaxel and etodolac in both cell lines resulted in decreased rhodamine 123 efflux. The actual concentration of intracellular paclitaxel in OMC-2P cells was significantly lower than that in OMC-2 cells treated with paclitaxel alone and was significantly increased after co-administration of paclitaxel and etodolac. These findings suggest that paclitaxel resistance may be associated with COX-2 and MDR1 expression in cancer cells. Co-administration of COX-2 inhibitors and paclitaxel may have a key role in modulating or overcoming paclitaxel resistance in endometrial cancers.

  20. Angiogenesis Inhibition in Prostate Cancer: Current Uses and Future Promises

    Directory of Open Access Journals (Sweden)

    Jeanny B. Aragon-Ching


    Full Text Available Angiogenesis has been well recognized as a fundamental part of a multistep process in the evolution of cancer progression, invasion, and metastasis. Strategies for inhibiting angiogenesis have been one of the most robust fields of cancer investigation, focusing on the vascular endothelial growth factor (VEGF family and its receptors. There are numerous regulatory drug approvals to date for the use of these agents in treating a variety of solid tumors. While therapeutic efficacy has been established, challenges remain with regards to overcoming resistance and assessing response to antiangiogenic therapies. Prostate cancer is the most common noncutaneous malignancy among American men and angiogenesis plays a role in disease progression. The use of antiangiogenesis agents in prostate cancer has been promising and is hereby explored.

  1. Inhibitory Effects of Biomass Degradation Products on Ethanol Fermentation and a Strategy to Overcome Them

    Directory of Open Access Journals (Sweden)

    Shiyu Fu


    Full Text Available The influence of buffers, as well as inhibitors such as formic acid, furfural, HMF, guaiacol, and vanillin, on ethanol formation was investigated. Compared to phosphoric buffer, the acetic and citric buffers were less inhibitory on ethanol fermentation. The addition of formic acid (2.5 g/L to the buffer reduced the ethanol yield by 8%. Guaiacol (3 g/L and vanillin (2.5 g/L decreased ethanol production by 50% and 20%, respectively. Furfural and HMF delayed the yeast fermentation without reducing the total yield. The fermentation was seriously inhibited by the mixture of furfural (1 g/L, HMF (1 g/L, formic acid (1 g/L, vanillin (1 g/L, and guaiacol (1 g/L. The ethanol yield of the fermentation based on enzymatic hydrolyzate from treated biomass was 82%. The addition of 1 g/L MgSO4 as a shielding protector rehabilitated nearly 100% of the total yield.

  2. Amnesia of inhibitory avoidance by scopolamine is overcome by previous open-field exposure (United States)

    Colettis, Natalia C.; Snitcofsky, Marina; Kornisiuk, Edgar E.; Gonzalez, Emilio N.; Quillfeldt, Jorge A.


    The muscarinic cholinergic receptor (MAChR) blockade with scopolamine either extended or restricted to the hippocampus, before or after training in inhibitory avoidance (IA) caused anterograde or retrograde amnesia, respectively, in the rat, because there was no long-term memory (LTM) expression. Adult Wistar rats previously exposed to one or two open-field (OF) sessions of 3 min each (habituated), behaved as control animals after a weak though over-threshold training in IA. However, after OF exposure, IA LTM was formed and expressed in spite of an extensive or restricted to the hippocampus MAChR blockade. It was reported that during and after OF exposure and reexposure there was an increase in both hippocampal and cortical ACh release that would contribute to “prime the substrate,” e.g., by lowering the synaptic threshold for plasticity, leading to LTM consolidation. In the frame of the “synaptic tagging and capture” hypothesis, plasticity-related proteins synthesized during/after the previous OF could facilitate synaptic plasticity for IA in the same structure. However, IA anterograde amnesia by hippocampal protein synthesis inhibition with anisomycin was also prevented by two OF exposures, strongly suggesting that there would be alternative interpretations for the role of protein synthesis in memory formation and that another structure could also be involved in this “OF effect.” PMID:25322799

  3. Levistolide A overcomes P-glycoprotein-mediated drug resistance in human breast carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    Fei CHEN; Tao WANG; Jia WANG; Zi-qiang WANG; Ming QIAN


    Aim:The aim of the present study was to investigate the reversing effect of levistolide A (LA) on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in human breast carcinoma Bcap37/MDR1 cells. Methods:After chemotherapeu-tic drugs (adriamycin or vincristine) used alone or in combination with LA, cell proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazo-lium bromide assay and cell cycle distribution by flow cytometry. RT-PCR was used to detect MDR1 gene transcription and the Western blot assay was used to assess P-gp expression and the cleavages of poly(ADP-ribose) polymerase and caspase-3. Apoptosis was detected by terminal transferase-mediated dUTP nick end-labeling assay. Moreover, the P-gp function was evaluated by the intracellu-lar accumulation of the P-gp substrate detected by flow cytometry. Results:We found the subcytotoxic doses of LA significantly enhanced adriamycin- or vinc-ristine-induced G2/M arrest and apoptosis. These effects were consistent with the ability of LA to inhibit P-gp function. Moreover, LA dramatically enhanced the verapamil (VER) ability to reverse drug resistance. Conclusion:LA has the poten-tial to be developed as a novel P-gp modulator. Furthermore, the combination of LA and VER might represent a more sufficient but less toxic anti-MDR regimen.

  4. Overcoming the bottlenecks of anaerobic digestion of olive mill solid waste by two-stage fermentation. (United States)

    Stoyanova, Elitza; Lundaa, Tserennyam; Bochmann, Günther; Fuchs, Werner


    Two-stage anaerobic digestion (AD) of two-phase olive mill solid waste (OMSW) was applied for reducing the inhibiting factors by optimizing the acidification stage. Single-stage AD and co-fermentation with chicken manure were conducted coinstantaneous for direct comparison. Degradation of the polyphenols up to 61% was observed during the methanogenic stage. Nevertheless the concentration of phenolic substances was still high; the two-stage fermentation remained stable at OLR 1.5 kgVS/m³day. The buffer capacity of the system was twice as high, compared to the one-stage fermentation, without additives. The two-stage AD was a combined process - thermophilic first stage and mesophilic second stage, which pointed out to be the most profitable for AD of OMSW for the reduced hydraulic retention time (HRT) from 230 to 150 days, and three times faster than the single-stage and the co-fermentation start-up of the fermentation. The optimal HRT and incubation temperature for the first stage were determined to four days and 55°C. The performance of the two-stage AD concerning the stability of the process was followed by the co-digestion of OMSW with chicken manure as a nitrogen-rich co-substrate, which makes them viable options for waste disposal with concomitant energy recovery.

  5. Trials to overcome drug resistance to EGFR and ALK targeted therapies - past, present and future

    Directory of Open Access Journals (Sweden)

    Glenwood Dillon Goss


    Full Text Available Molecularly targeted agents (MTAs are changing the therapeutic landscape in advanced non-small cell lung cancer (NSCLC. Since the discovery of sensitizing mutations in the epidermal growth factor receptor (EGFR and anaplastic lymphoma kinase (ALK domain, clinical investigations have focused on optimizing the efficacy of EGFR and ALK tyrosine kinase inhibitors by addressing therapeutic resistance that commonly develops within a year of treatment initiation. Here, we review the clinical trials of novel therapies and combination regimens that have been undertaken in response to our evolving understanding of the mechanisms of resistance to therapy. The aim of these trials was to enhance the therapeutic efficacy of targeted therapies by improving targeted blockade and/or inhibiting parallel or compensatory signalling pathways. We have documented the sequential conduct of EGFR an ALK biomarker driven trials in order to highlight particular pitfalls and successes which should be considered in the design of future trials. Although there remain significant challenges, substantial gains have been made in our understanding of cellular resistance. This knowledge will drive the design of future trials, to the benefit of lung cancer patients.


    Directory of Open Access Journals (Sweden)

    S. N. Bel'diev


    Full Text Available According to a recent study, Russian physicians often and sometimes unreasonably find it impossible to use statins in patients with cardiovascular diseases and concomitant chronic liver diseases. Analysis of domestic publications of recent years reveals the following factors which can impede overcoming statinophobia: 1 fragmentary and contradictory statement of the problem "Statins and liver" in Russian clinical guidelines for management of patients with high cardiovascular risk; 2 common perception that isolated transaminase increase in response to statin therapy is an indicator of "cytolysis" or "cytolytic syndrome"; 3 unreasonably overestimated lipid-lowering activity of combination therapy with low doses of statins and ursodeoxycholic acid; 4 view of the inadmissibility of statin use in patients with transaminase levels more than three upper limit of normal. To overcome these shortcomings and mistakes it seems appropriate to issue national clinical guidelines on statin use in high cardiovascular risk patients with underlying liver disease and/or with elevated transaminases.

  7. Let's not contribute to disparities: the best methods for teaching clinicians how to overcome language barriers to health care. (United States)

    Diamond, Lisa C; Jacobs, Elizabeth A


    Clinicians should be educated about how language barriers contribute to disparities for patients with limited English proficiency (LEP). However, educators must avoid developing educational interventions that increase health disparities for LEP patients. For example, studies suggest that teaching "Medical Spanish" or related courses may actually contribute to health care disparities if clinicians begin using these non-English language skills inappropriately with patients. We discuss the risks and benefits of teaching specific cultural competence skills and make evidence-based recommendations for the teaching content and methods for educational interventions focused on overcoming language barriers in health care. At minimum, we suggest such interventions include: (1) the role of language barriers in health disparities, (2) means of overcoming language barriers, (3) how to work with interpreters, (4) identifying and fixing problems in interpreted encounters, and (5) appropriate and safe use of one's own limited non-English language skills.

  8. Migration of tumor cells and leukocytes in extracellular matrix : proteolytic and nonproteolytic strategies for overcoming tissue barriers


    Wolf, Katarina


    The extracellular matrix within connective tissues represents a structural scaffold as well as a barrier for motile cells, such as invading tumor cells or passenger leukocytes. It remains unclear how different cell types utilize matrix-degrading enzymes for proteolytic migration strategies and, on the other hand, non-proteolytic strategies to overcome 3D fibrillar matrix networks. To monitor cell migration, a 3D collagen model in vitro or the mouse dermis in vivo were used, in combination wit...



    Ossy Firstanti Wardany; Abdul Salim Choiri


    This research aims to determine the effectiveness of Differential Reinforcement of Incompatible Behaviour (DRI) to overcome the disruptive behaviour of intellectual disability students in the classroom during lesson. The type of disruptive behaviour, which becomes the target behaviour in this research, is physical aggression against classmates. This research used quantitative approach with experimental research design. The approach for this experimental research is Single Subject Research (SS...

  10. Interferon-γ-induced upregulation of immunoproteasome subunit assembly overcomes bortezomib resistance in human hematological cell lines



    Background Despite encouraging results with the proteasome inhibitor bortezomib in the treatment of hematologic malignancies, emergence of resistance can limit its efficacy, hence calling for novel strategies to overcome bortezomib-resistance. We previously showed that bortezomib-resistant human leukemia cell lines expressed significantly lower levels of immunoproteasome at the expense of constitutive proteasomes, which harbored point mutations in exon 2 of the PSMB5 gene encoding the β5 subu...

  11. Drug delivery by a self-assembled DNA tetrahedron for overcoming drug resistance in breast cancer cells. (United States)

    Kim, Kyoung-Ran; Kim, Da-Rae; Lee, Taemin; Yhee, Ji Young; Kim, Byeong-Su; Kwon, Ick Chan; Ahn, Dae-Ro


    A DNA tetrahedron is employed for efficient delivery of doxorubicin into drug-resistant breast cancer cells. The drug delivered with the DNA nanoconstruct is considerably cytotoxic, whereas free doxorubicin is virtually non-cytotoxic for the drug-resistant cells. Thus, the DNA tetrahedron, made of the inherently natural and biocompatible material, can be a good candidate for the drug carrier to overcome MDR in cancer cells.

  12. Induction of type I IFN is required for overcoming tumor-specific T-cell tolerance after stem cell transplantation. (United States)

    Horkheimer, Ian; Quigley, Michael; Zhu, Jiangao; Huang, Xiaopei; Chao, Nelson J; Yang, Yiping


    Tumor-specific T-cell tolerance represents one major mechanism of tumor-induced immune evasion. Myeloablative chemotherapy with stem cell transplantation may offer the best chance of achieving a state of minimal residual disease and, thus, minimize tumor-induced immune evasion. However, studies have shown that tumor-specific T-cell tolerance persists after transplantation. Here, we showed that CD4(+)CD25(+) regulatory T (T(Reg)) cells play a critical role in tumor-specific CD8(+) T-cell tolerance after transplantation. Removal of T(Reg) cells from the donor lymphocyte graft did not overcome this tolerance because of rapid conversion of donor CD4(+)CD25(-) T cells into CD4(+)CD25(+)Foxp3(+) T(Reg) cells in recipients after transplantation, and depletion of T(Reg) cells in recipients was necessary for the reversal of tumor-specific tolerance. These results suggest that strategies capable of overcoming T-cell tolerance in recipients are required to promote antitumor immunity after transplantation. Toward this goal, we showed that dendritic cell (DC) vaccines coadministered with the TLR9 ligand, CpG could effectively overcome tumor-specific tolerance, leading to significant prolongation of tumor-free survival after transplantation. We further showed that CpG-induced type I interferon was critical for the reversal of tumor-specific tolerance in vivo. Collectively, these results may suggest effective immunotherapeutic strategies for treating cancer after stem cell transplantation.

  13. Targeting head and neck cancer stem cells to overcome resistance to photon and carbon ion radiation. (United States)

    Bertrand, Gérald; Maalouf, Mira; Boivin, Antony; Battiston-Montagne, Priscillia; Beuve, Michael; Levy, Antonin; Jalade, Patrice; Fournier, Claudia; Ardail, Dominique; Magné, Nicolas; Alphonse, Gersende; Rodriguez-Lafrasse, Claire


    Although promising new radiation therapy techniques such as hadrontherapy are currently being evaluated in the treatment of head and neck malignancies, local control of head and neck squamous cell carcinoma (HNSCC) remains low. Here, we investigated the involvement of cancer stem-like cells (CSCs) in a radioresistant HNSCC cell line (SQ20B). Stem-like cells SQ20B/SidePopulation(SP)/CD44(+)/ALDH(high) were more resistant to both photon and carbon ion irradiation compared with non-CSCs. This was confirmed by a BrdU labeling experiment, which suggests that CSCs were able to proliferate and to induce tumorigenicity after irradiation. SQ20B/SP/CD44(+)/ALDH(high) were capable of an extended G2/M arrest phase in response to photon or carbon ion irradiation compared with non-CSCs. Moreover, our data strongly suggest that resistance of CSCs may result from an imbalance between exacerbated self-renewal and proliferative capacities and the decrease in apoptotic cell death triggering. In order to modulate these processes, two targeted pharmacological strategies were tested. Firstly, UCN-01, a checkpoint kinase (Chk1) inhibitor, induced the relapse of G2/M arrest and radiosensitization of SQ20B-CSCs. Secondly, all-trans retinoic acid (ATRA) resulted in an inhibition of ALDH activity, and induction of the differentiation and radiosensitization of SQ20B/SP/CD44(+)/ALDH(high) cells. The combination of ATRA and UCN-01 treatments with irradiation drastically decreased the surviving fraction at 2Gy of SQ20B-CSCs from 0.85 to 0.38 after photon irradiation, and from 0.45 to 0.21 in response to carbon ions. Taken together, our results suggest that the combination of UCN-01 and ATRA represent a promising pharmacological-targeted strategy that significantly sensitizes CSCs to photon or carbon ion radiation.

  14. Fallopia japonica, a Natural Modulator, Can Overcome Multidrug Resistance in Cancer Cells

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    Safaa Yehia Eid


    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.

  15. Sym004, a Novel EGFR Antibody Mixture, Can Overcome Acquired Resistance to Cetuximab

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    Mari Iida


    Full Text Available The epidermal growth factor receptor (EGFR is a central regulator of tumor progression in a variety of human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for head and neck and colorectal cancer treatment, but many patients treated with cetuximab don't respond or eventually acquire resistance. To determine how tumor cells acquire resistance to cetuximab, we previously developed a model of acquired resistance using the non-small cell lung cancer line NCI-H226. These cetuximab-resistant (CtxR cells exhibit increased steady-state EGFR expression secondary to alterations in EGFR trafficking and degradation and, further, retained dependence on EGFR signaling for enhanced growth potential. Here, we examined Sym004, a novel mixture of antibodies directed against distinct epitopes on the extracellular domain of EGFR, as an alternative therapy for CtxR tumor cells. Sym004 treatment of CtxR clones resulted in rapid EGFR degradation, followed by robust inhibition of cell proliferation and down-regulation of several mitogen-activated protein kinase pathways. To determine whether Sym004 could have therapeutic benefit in vivo, we established de novo CtxR NCI-H226 mouse xenografts and subsequently treated CtxR tumors with Sym004. Sym004 treatment of mice harboring CtxR tumors resulted in growth delay compared to mice continued on cetuximab. Levels of total and phospho-EGFR were robustly decreased in CtxR tumors treated with Sym004. Immunohistochemical analysis of these Sym004-treated xenograft tumors further demonstrated decreased expression of Ki67, and phospho-rpS6, as well as a modest increase in cleaved caspase-3. These results indicate that Sym004 may be an effective targeted therapy for CtxR tumors.

  16. Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance. (United States)

    Dogovski, Con; Xie, Stanley C; Burgio, Gaetan; Bridgford, Jess; Mok, Sachel; McCaw, James M; Chotivanich, Kesinee; Kenny, Shannon; Gnädig, Nina; Straimer, Judith; Bozdech, Zbynek; Fidock, David A; Simpson, Julie A; Dondorp, Arjen M; Foote, Simon; Klonis, Nectarios; Tilley, Leann


    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 with ART

  17. Role of bicarbonate/CO2 in the inhibition of Escherichia coli growth by cyanate. (United States)

    Kozliak, E I; Fuchs, J A; Guilloton, M B; Anderson, P M


    Cyanase is an inducible enzyme in Escherichia coli that catalyzes the reaction of cyanate with bicarbonate to give two CO2 molecules. The gene for cyanase is part of the cyn operon, which includes cynT and cynS, encoding carbonic anhydrase and cyanase, respectively. Carbonic anhydrase functions to prevent depletion of cellular bicarbonate during cyanate decomposition (the product CO2 can diffuse out of the cell faster than noncatalyzed hydration back to bicarbonate). Addition of cyanate to the culture medium of a delta cynT mutant strain of E. coli (having a nonfunctional carbonic anhydrase) results in depletion of cellular bicarbonate, which leads to inhibition of growth and an inability to catalyze cyanate degradation. These effects can be overcome by aeration with a higher partial CO2 pressure (M. B. Guilloton, A. F. Lamblin, E. I. Kozliak, M. Gerami-Nejad, C. Tu, D. Silverman, P. M. Anderson, and J. A. Fuchs, J. Bacteriol. 175:1443-1451, 1993). The question considered here is why depletion of bicarbonate/CO2 due to the action of cyanase on cyanate in a delta cynT strain has such an inhibitory effect. Growth of wild-type E. coli in minimal medium under conditions of limited CO2 was severely inhibited, and this inhibition could be overcome by adding certain Krebs cycle intermediates, indicating that one consequence of limiting CO2 is inhibition of carboxylation reactions. However, supplementation of the growth medium with metabolites whose syntheses are known to depend on a carboxylation reaction was not effective in overcoming inhibition related to the bicarbonate deficiency induced in the delta cynT strain by addition of cyanate. Similar results were obtained with a deltacyn strain (since cyanase is absent, this strain does not develop a bicarbonate deficiency when cyanate is added); however, as with the deltacynT strain, a higher partial CO(2) pressure in the aerating gas or expression of carbonic anhydrase activity (which contributes to a higher intercellular

  18. Sertraline reduces IL-1β and TNF-α mRNA expression and overcomes their rise induced by seizures in the rat hippocampus.

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    María Sitges

    Full Text Available We recently discovered that the antidepressant sertraline is an effective inhibitor of hippocampus presynaptic Na+ channel permeability in vitro and of tonic-clonic seizures in animals in vivo. Several studies indicate that the pro-inflammatory cytokines in the central nervous system are increased in epilepsy and depression. On the other hand inhibition of Na+ channels has been shown to decrease pro-inflammatory cytokines in microglia. Therefore, the possibility that sertraline could overcome the rise in pro-inflammatory cytokine expression induced by seizures has been investigated. For this purpose, IL-1β and TNF-α mRNA expression was determined by RT-PCR in the hippocampus of rats administered once, or for seven consecutive days with sertraline at a low dose (0.75 mg/kg. The effect of sertraline at doses within the range of 0.75 to 25 mg/kg on the increase in IL-1β and TNF-α mRNA expression accompanying generalized tonic-clonic seizures, and increase in the pro-inflammatory cytokines expression induced by lipopolysaccharide was also investigated. We found that under basal conditions, a single 0.75 mg/kg sertraline dose decreased IL-1β mRNA expression, and also TNF-α expression after repeated doses. The increase in IL-1β and TNF-α expression induced by the convulsive agents and by the inoculation of lipopolysaccharide in the hippocampus was markedly reduced by sertraline also. Present results indicate that a reduction of brain inflammatory processes may contribute to the anti-seizure sertraline action, and that sertraline can be safely and successfully used at low doses to treat depression in epileptic patients.

  19. Sertraline reduces IL-1β and TNF-α mRNA expression and overcomes their rise induced by seizures in the rat hippocampus. (United States)

    Sitges, María; Gómez, Carlos D; Aldana, Blanca I


    We recently discovered that the antidepressant sertraline is an effective inhibitor of hippocampus presynaptic Na+ channel permeability in vitro and of tonic-clonic seizures in animals in vivo. Several studies indicate that the pro-inflammatory cytokines in the central nervous system are increased in epilepsy and depression. On the other hand inhibition of Na+ channels has been shown to decrease pro-inflammatory cytokines in microglia. Therefore, the possibility that sertraline could overcome the rise in pro-inflammatory cytokine expression induced by seizures has been investigated. For this purpose, IL-1β and TNF-α mRNA expression was determined by RT-PCR in the hippocampus of rats administered once, or for seven consecutive days with sertraline at a low dose (0.75 mg/kg). The effect of sertraline at doses within the range of 0.75 to 25 mg/kg on the increase in IL-1β and TNF-α mRNA expression accompanying generalized tonic-clonic seizures, and increase in the pro-inflammatory cytokines expression induced by lipopolysaccharide was also investigated. We found that under basal conditions, a single 0.75 mg/kg sertraline dose decreased IL-1β mRNA expression, and also TNF-α expression after repeated doses. The increase in IL-1β and TNF-α expression induced by the convulsive agents and by the inoculation of lipopolysaccharide in the hippocampus was markedly reduced by sertraline also. Present results indicate that a reduction of brain inflammatory processes may contribute to the anti-seizure sertraline action, and that sertraline can be safely and successfully used at low doses to treat depression in epileptic patients.

  20. Acidification due to microbial dechlorination near a trichloroethene DNAPL is overcome with pH buffer or formate as electron donor: experimental demonstration in diffusion-cells. (United States)

    Philips, Jo; Maes, Nele; Springael, Dirk; Smolders, Erik


    Acidification due to microbial dechlorination of trichloroethene (TCE) can limit the bio-enhanced dissolution of TCE dense non-aqueous phase liquid (DNAPL). This study related the dissolution enhancement of a TCE DNAPL to the pH buffer capacity of the medium and the type of electron donor used. In batch systems, dechlorination was optimal at pH7.1-7.5, but was completely inhibited below pH6.2. In addition, dechlorination in batch systems led to a smaller pH decrease at an increasing pH buffer capacity or with the use of formate instead of lactate as electron donor. Subsequently, bio-enhanced TCE DNAPL dissolution was quantified in diffusion-cells with a 5.5 cm central sand layer, separating a TCE DNAPL layer from an aqueous top layer. Three different pH buffer capacities (2.9 mM-17.9 mM MOPS) and lactate or formate as electron donor were applied. In the lactate fed diffusion-cells, the DNAPL dissolution enhancement factor increased from 1.5 to 2.2 with an increase of the pH buffer capacity. In contrast, in the formate fed diffusion-cells, the DNAPL dissolution enhancement factor (2.4±0.3) was unaffected by the pH buffer capacity. Measurement of the pore water pH confirmed that the pH decreased less with an increased pH buffer capacity or with formate instead of lactate as electron donor. These results suggest that the significant impact of acidification on bio-enhanced DNAPL dissolution can be overcome by the amendment of a pH buffer or by applying a non acidifying electron donor like formate.

  1. Zoledronic acid-encapsulating self-assembling nanoparticles and doxorubicin: a combinatorial approach to overcome simultaneously chemoresistance and immunoresistance in breast tumors (United States)

    Kopecka, Joanna; Porto, Stefania; Lusa, Sara; Gazzano, Elena; Salzano, Giuseppina; Pinzòn-Daza, Martha Leonor; Giordano, Antonio; Desiderio, Vincenzo; Ghigo, Dario; De Rosa, Giuseppe; Caraglia, Michele; Riganti, Chiara


    The resistance to chemotherapy and the tumor escape from host immunosurveillance are the main causes of the failure of anthracycline-based regimens in breast cancer, where an effective chemo-immunosensitizing strategy is lacking. The clinically used aminobisphosphonate zoledronic acid (ZA) reverses chemoresistance and immunoresistance in vitro. Previously we developed a nanoparticle-based zoledronic acid-containing formulation (NZ) that allowed a higher intratumor delivery of the drug compared with free ZA in vivo. We tested its efficacy in combination with doxorubicin in breast tumors refractory to chemotherapy and immune system recognition as a new combinatorial approach to produce chemo- and immunosensitization. NZ reduced the IC50 of doxorubicin in human and murine chemoresistant breast cancer cells and restored the doxorubicin efficacy against chemo-immunoresistant tumors implanted in immunocompetent mice. By reducing the metabolic flux through the mevalonate pathway, NZ lowered the activity of Ras/ERK1/2/HIF-1α axis and the expression of P-glycoprotein, decreased the glycolysis and the mitochondrial respiratory chain, induced a cytochrome c/caspase 9/caspase 3-dependent apoptosis, thus restoring the direct cytotoxic effects of doxorubicin on tumor cell. Moreover, NZ restored the doxorubicin-induced immunogenic cell death and reversed the tumor-induced immunosuppression due to the production of kynurenine, by inhibiting the STAT3/indoleamine 2,3 dioxygenase axis. These events increased the number of dendritic cells and decreased the number of immunosuppressive T-regulatory cells infiltrating the tumors. Our work proposes the use of nanoparticle encapsulating zoledronic acid as an effective tool overcoming at the same time chemoresistance and immunoresistance in breast tumors, thanks to the effects exerted on tumor cell and tumor-infiltrating immune cells. PMID:26980746

  2. Effect of black raspberry extract in inhibiting NFkappa B dependent radioprotection in human breast cancer cells. (United States)

    Madhusoodhanan, Rakhesh; Natarajan, Mohan; Singh, Jamunarani Veeraraghavan Nisha; Jamgade, Ambarish; Awasthi, Vibhudutta; Anant, Shrikant; Herman, Terence S; Aravindan, Natarajan


    Black raspberry extracts (RSE) have been shown to inhibit cancer cell growth and stimulate apoptosis. Also, studies have demonstrated that RSE inhibits transcriptional regulators including NFkappa B. Accordingly, we investigated the effect of RSE in inhibiting radiation (IR) induced NFkappa B mediated radioprotection in breast adenocarcinoma cells. MCF-7 cells were exposed to IR (2Gy), treated with RSE (0.5, 1.0, 2.0 micro g/ml) or treated with RSE (1.0 micro g/ml) followed by IR exposure, and harvested after 1, 3, 6, 24, 48, and 72 h. NFkappa B DNA-binding activity was measured by EMSA and phosphorylated Ikappa Balpha by immunoblotting. Expression of IAP1, IAP2, XIAP and survivin were measured by QPCR and immunoblotting. Cell survival was measured using MTT assay and cell death using Caspase-3/7 activity. Effect of RSE on IR induced MnSOD, TNFalpha, IL-1alpha and MnSOD activity was also determined. RSE inhibited NFkappa B activity in a dose-dependent manner. Also, RSE inhibited IR-induced sustained activation of NFkappa B, and NFkappa B regulated IAP1, IAP2, XIAP, and survivin. In addition, RSE inhibited IR-induced TNFalpha, IL-1alpha, and MnSOD levels and MnSOD activity. RSE suppressed cell survival and enhanced cell death. These results suggest that RSE may act as a potent radiosensitizer by overcoming the effects of NFkappa B mediated radioprotection in human breast cancer cells.

  3. Rossijskij jeksklav na Baltike: jevoljucija jeksklavnosti i poisk putej ee preodolenija [Russian Exclave on the Baltic Sea: Evolution of Exclavity and Ways to Overcome It

    Directory of Open Access Journals (Sweden)

    Klemeshev Andrey


    Full Text Available The author considers peculiarities of the emergence and evolution of exclavity of the Kaliningrad region. The article analyses the influence of exclavity on the connections of the region with the Russian mainland, its economic development, exclave administration, and Kaliningrad identity and examines the ways the existing disadvantages can be overcome. Methods of overcoming these disadvantages are suggested in the article.

  4. Networking for Overcoming on Viral Hepatitis in Middle East and Central Asia: Asian Hepatitis Network

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    Seyed Moayed Alavian


    an adequate antibody response in our population is necessary. Educating infection prevention and modes of transmission, especially for groups at risk of hepatitis exposure and limiting immigration from neighboring countries are the most cost-effective ways of infection control (6. The effectiveness of routine infant hepatitis B immunization in significantly reducing or eliminating the prevalence of chronic HBV infection has been demonstrated in a variety of countries and settings. However, there are still many challenges to achieve the goal of universal childhood immunization against hepatitis B, such as poor immunization delivery infrastructure, low coverage and lack of financial sustainability. Therefore, to continue to promote access to hepatitis B vaccines worldwide, great efforts are needed to support countries to ensure sustained funding for immunization programs.Hepatitis C infection is now the most common cause of end-stage liver disease in many countries (7. It is a blood-borne infection that was a well-known cause of post-transfusion hepatitis after introduction of hepatitis B screening in blood banking and before implementation of hepatitis C-sensitive screening laboratory methods. Since the discovery of HCV and the development of diagnostic tests, almost all of the non-A non-B (NANB post-transfusion hepatitis cases were shown to be due to HCV infection (2. Recently, HCV infection has drawn great attention due to similar risk factors and coinfectivity with human immunodeficiency virus (HIV infection. World Health Organization (WHO estimations suggest that up to 3% of the world's population (170 million have been infected with HCV. HCV is an emerging disease and we should be more sensitive and more active about the important treat for the young people (8.Networking for overcoming viral hepatitis needs more cooperation between scientists in the region. It's my pleasure to inform you that "Asian Hepatitis Network" ( reaches thousands of

  5. Psychological obstacles to peace-making in the Middle East and proposals to overcome them

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    Daniel Bar-Tal


    without negotiations. After almost four years of violent confrontations, Israelis and Palestinians should try to achieve a state of peaceful coexistence, which means mutual legitimization, equalization, differentiation, and personalization, as well as the introduction of hope and mutual acceptance. In essence, coexistence refers to a state of mind shared by the members of a society. In order to achieve coexistence, it is necessary to change the psychological repertoire of the societies involved in the peace process. The achievement of this change depends first of all on the intentions, determination, activism and strength of those who support the peace process, including leaders, political parties, NGOs, and individual society members. Second, a successful process of establishing a climate of coexistence in a society depends on the mobilization of societal institutions to propagate the new messages of the peace process. Mass media and the educational system play an important role in this mission. As its final point, the paper suggests that the fundamental prerequisites for changing the psychological repertoire that inhibits the peace process are: a. negotiations between the rivals which will allow the development of mutually acceptable agreement and b. cessation, or at least a significant reduction, of all types of violence.

  6. Activated sludge inhibition capacity index

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    V. Surerus


    Full Text Available Toxic compounds in sewage or industrial wastewater may inhibit the biological activity of activated sludge impairing the treatment process. This paper evaluates the Inhibition Capacity Index (ICI for the assessment of activated sludge in the presence of toxicants. In this study, activated sludge was obtained from industrial treatment plants and was also synthetically produced. Continuous respirometric measurements were carried out in a reactor, and the oxygen uptake rate profile obtained was used to evaluate the impact of inhibiting toxicants, such as dissolved copper, phenol, sodium alkylbenzene sulfonate and amoxicillin, on activated sludge. The results indicate that ICI is an efficient tool to quantify the intoxication capacity. The activated sludge from the pharmaceutical industry showed higher resistance than the sludge from other sources, since toxicants are widely discharged in the biological treatment system. The ICI range was from 58 to 81% when compared to the synthetic effluent with no toxic substances.

  7. Overcoming target-mediated quinolone resistance in topoisomerase IV by introducing metal-ion-independent drug-enzyme interactions. (United States)

    Aldred, Katie J; Schwanz, Heidi A; Li, Gangqin; McPherson, Sylvia A; Turnbough, Charles L; Kerns, Robert J; Osheroff, Neil


    Quinolones, which target gyrase and topoisomerase IV, are the most widely prescribed antibacterials worldwide. Unfortunately, their use is threatened by the increasing prevalence of target-mediated drug resistance. Greater than 90% of mutations that confer quinolone resistance act by disrupting enzyme-drug interactions coordinated by a critical water-metal ion bridge. Quinazolinediones are quinolone-like drugs but lack the skeletal features necessary to support the bridge interaction. These compounds are of clinical interest, however, because they retain activity against the most common quinolone resistance mutations. We utilized a chemical biology approach to determine how quinazolinediones overcome quinolone resistance in Bacillus anthracis topoisomerase IV. Quinazolinediones that retain activity against quinolone-resistant topoisomerase IV do so primarily by establishing novel interactions through the C7 substituent, rather than the drug skeleton. Because some quinolones are highly active against human topoisomerase IIα, we also determined how clinically relevant quinolones discriminate between the bacterial and human enzymes. Clinically relevant quinolones display poor activity against topoisomerase IIα because the human enzyme cannot support drug interactions mediated by the water-metal ion bridge. However, the inclusion of substituents that allow quinazolinediones to overcome topoisomerase IV-mediated quinolone resistance can cause cross-reactivity against topoisomerase IIα. Therefore, a major challenge in designing drugs that overcome quinolone resistance lies in the ability to identify substituents that mediate strong interactions with the bacterial, but not the human, enzymes. On the basis of our understanding of quinolone-enzyme interactions, we have identified three compounds that display high activity against quinolone-resistant B. anthracis topoisomerase IV but low activity against human topoisomerase IIα.

  8. Experiments to Determine Whether Recursive Partitioning (CART) or an Artificial Neural Network Overcomes Theoretical Limitations of Cox Proportional Hazards Regression (United States)

    Kattan, Michael W.; Hess, Kenneth R.; Kattan, Michael W.


    New computationally intensive tools for medical survival analyses include recursive partitioning (also called CART) and artificial neural networks. A challenge that remains is to better understand the behavior of these techniques in effort to know when they will be effective tools. Theoretically they may overcome limitations of the traditional multivariable survival technique, the Cox proportional hazards regression model. Experiments were designed to test whether the new tools would, in practice, overcome these limitations. Two datasets in which theory suggests CART and the neural network should outperform the Cox model were selected. The first was a published leukemia dataset manipulated to have a strong interaction that CART should detect. The second was a published cirrhosis dataset with pronounced nonlinear effects that a neural network should fit. Repeated sampling of 50 training and testing subsets was applied to each technique. The concordance index C was calculated as a measure of predictive accuracy by each technique on the testing dataset. In the interaction dataset, CART outperformed Cox (P less than 0.05) with a C improvement of 0.1 (95% Cl, 0.08 to 0.12). In the nonlinear dataset, the neural network outperformed the Cox model (P less than 0.05), but by a very slight amount (0.015). As predicted by theory, CART and the neural network were able to overcome limitations of the Cox model. Experiments like these are important to increase our understanding of when one of these new techniques will outperform the standard Cox model. Further research is necessary to predict which technique will do best a priori and to assess the magnitude of superiority.

  9. The Role of Social Media in Creating Intercultural Dialogue and Overcoming Prejudice – a Comparative Analysis of Pilot Survey Results

    Directory of Open Access Journals (Sweden)

    Grażyna Piechota


    Full Text Available Multiculturalism, as a political and social phenomenon, is more and more often perceived as a challenge in the realm of studying communication processes. New media make it possible to communicate and build relations in the global dimension with a simultaneous impact on the development of horizontal communication, creating groups and communities and active support for different forms of social participation. In this context a pilot study concerning the role of new media in overcoming schemata and prejudice of students in two different cities with different levels of multiculturalism in the local community was carried out.

  10. A method to overcome the diffraction limit in infrared microscopy using standing waves in an attenuated total reflection configuration (United States)

    Hendaoui, Nordine; Mani, Aladin; Liu, Ning; Tofail, Syed M.; Silien, Christophe; Peremans, André


    A method is proposed to overcome the diffraction limit of spatial resolution in infrared microscopy. To achieve this, standing waves in an attenuated total reflection configuration were generated to spatially modulate the absorbance of adsorbate vibrational transitions. A numerical simulation was undertaken. It showed that chemical imaging with a spatial resolution of approximately 100 nm is achievable in the case of self-assembled patterns (ofoctdecyltrichlorosilane [CH3-(CH2)17-SiCl3]), when probing the methyl modes located near 3.5 micrometres.

  11. How Exactly Do I “Let Go”? The Potential of Using ACT to Overcome the Relaxation Paradox

    Directory of Open Access Journals (Sweden)

    Christopher J. Wilson


    Full Text Available Relaxation induced anxiety (RIA or relaxation induced panic (RIP occurs when a person’s attempts to reduce anxiety result in increased arousal. Such paradoxical increases often occur when relaxation is viewed as the avoidance of anxiety-related experiences. In fact, passivity toward these experiences is necessary for successful relaxation. However, passivity is not always easy to understand. Acceptance and commitment therapy (ACT has attracted increasing interest in recent years and adopts a similar position with regard to experiential avoidance. Reviewing literature on the relaxation paradox, this article argues that incorporating elements of ACT into relaxation training might help overcome some problems with passivity in relaxation.

  12. Algorithm for Overcoming the Curse of Dimensionality for Certain Non-convex Hamilton-Jacobi Equations, Projections and Differential Games (United States)


    6= 0 , 0 if x = 0 where we adopt the convention 0/0 = 0. Note that shrink1(x, α) is often used in compressed sensing algorithms, e.g. in [38]. Since...convex and time dependent HJ-PDE that can overcome the curse of dimensionality. Thanks to the Hopf formula, our method is ‘exact’ in a sense that no...1983). [5] A. Chambolle, T. Pock. A First-Order Primal -Dual Algorithm for Convex Problems with Applica- tions to Imaging, J Math. Imag. and Vision , 41

  13. Overcoming the lock-out of renewable energy technologies in Spain: The cases of wind and solar electricity

    Energy Technology Data Exchange (ETDEWEB)

    Rio, Pablo del [Department of Spanish and International Economics, Econometrics and History and Economic Institutions, Facultad de Ciencias Juridicas y Sociales de Toledo, C/Cobertizo de S. Pedro Martir s/n, Universidad de Castilla-La Mancha, Toledo-45071 (Spain); Unruh, Gregory [Alumni Association Chair for Corporate Sustainability, Center for Eco-Intelligent Management, Instituto de Empresa, Serrano, 105 Madrid-28006 (Spain)


    This paper applies an evolutionary economics framework to analyse the factors leading to lock-out of renewable energy technologies (RETs). The cases of wind and solar photovoltaics (PV) in Spain are empirically analysed. The paper shows that a wide array of interrelated factors (technoeconomic characteristics of technology components, system-level infrastructure and institutional factors) can create both barriers to the wide diffusion of RETs and can also be drivers that foster an escape from a lock-in situation. Based on this analysis, the paper suggests several policy measures which may help to overcome the lock-out of promising renewable energy technologies. (author)

  14. Homo economicus belief inhibits trust. (United States)

    Xin, Ziqiang; Liu, Guofang


    As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners' benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals' homo economicus belief and inhibit their trust. It seems that people's increasing homo economicus belief may serve as one cause of the worldwide decline of trust.

  15. Methanogenic inhibition by arsenic compounds. (United States)

    Sierra-Alvarez, Reyes; Cortinas, Irail; Yenal, Umur; Field, Jim A


    The acute acetoclastic methanogenic inhibition of several inorganic and organic arsenicals was assayed. Trivalent species, i.e., methylarsonous acid and arsenite, were highly inhibitory, with 50% inhibitory concentrations of 9.1 and 15.0 microM, respectively, whereas pentavalent species were generally nontoxic. The nitrophenylarsonate derivate, roxarsone, displayed moderate toxicity.

  16. Islam Does Not Inhibit Science. (United States)

    Shanavas, T. O.


    Compares the science/religion relationship in both Christian and Islamic countries. Presents Muslim scholars' ideas about the presence of humans on earth. Presents ideas on active nature, Noah's curse, and the age of the universe. Refutes the notion that Islam inhibited science and advocates the belief that Islam promoted science. (YDS)

  17. Testing of Biologically Inhibiting Surface

    DEFF Research Database (Denmark)

    Bill Madsen, Thomas; Larsen, Erup


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

  18. Inhibition of carcinogenesis by tea. (United States)

    Yang, Chung S; Maliakal, Pius; Meng, Xiaofeng


    Tea has received a great deal of attention because tea polyphenols are strong antioxidants, and tea preparations have inhibitory activity against tumorigenesis. The bioavailability and biotransformation of tea polyphenols, however, are key factors limiting these activities in vivo. The inhibition of tumorigenesis by green or black tea preparations has been demonstrated in animal models on different organ sites such as skin, lung, oral cavity, esophagus, forestomach, stomach, small intestine, colon, pancreas, and mammary gland. Epidemiological studies, however, have not yielded clear conclusions concerning the protective effects of tea consumption against cancer formation in humans. The discrepancy between the results from humans and animal models could be due to 1) the much higher doses of tea used in animals in comparison to human consumption, 2) the differences in causative factors between the cancers in humans and animals, and 3) confounding factors limiting the power of epidemiological studies to detect an effect. It is possible that tea may be only effective against specific types of cancer caused by certain etiological factors. Many mechanisms have been proposed for the inhibition of carcinogenesis by tea, including the modulation of signal transduction pathways that leads to the inhibition of cell proliferation and transformation, induction of apoptosis of preneoplastic and neoplastic cells, as well as inhibition of tumor invasion and angiogenesis. These mechanisms need to be evaluated and verified in animal models or humans in order to gain more understanding on the effect of tea consumption on human cancer.

  19. Strigolactone inhibition of shoot branching

    NARCIS (Netherlands)

    Gomez-Roldan, M.V.; Fermas, S.; Brewer, P.B.; Puech-Pages, V.; Dun, E.A.; Pillot, J.P.; Letisse, F.; Matusova, R.; Danoun, S.; Portais, J.C.; Bouwmeester, H.J.; Becard, G.; Beveridge, C.A.; Rameau, C.; Rochange, S.F.


    A carotenoid-derived hormonal signal that inhibits shoot branching in plants has long escaped identification. Strigolactones are compounds thought to be derived from carotenoids and are known to trigger the germination of parasitic plant seeds and stimulate symbiotic fungi. Here we present evidence

  20. Infant Predictors of Behavioural Inhibition (United States)

    Moehler, Eva; Kagan, Jerome; Oelkers-Ax, Rieke; Brunner, Romuald; Poustka, Luise; Haffner, Johann; Resch, Franz


    Behavioural inhibition in the second year of life is a hypothesized predictor for shyness, social anxiety and depression in later childhood, adolescence and even adulthood. To search for the earliest indicators of this fundamental temperamental trait, this study examined whether behavioural characteristics in early infancy can predict behavioural…

  1. A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis. (United States)

    Chen, Shuang; Zhang, Yu; Zhou, Liang; Leng, Yun; Lin, Hui; Kmieciak, Maciej; Pei, Xin-Yan; Jones, Richard; Orlowski, Robert Z; Dai, Yun; Grant, Steven


    Bim contributes to resistance to various standard and novel agents. Here we demonstrate that Bim plays a functional role in bortezomib resistance in multiple myeloma (MM) cells and that targeting Bim by combining histone deacetylase inhibitors (HDACIs) with BH3 mimetics (eg, ABT-737) overcomes bortezomib resistance. BH3-only protein profiling revealed high Bim levels (Bim(hi)) in most MM cell lines and primary CD138(+) MM samples. Whereas short hairpin RNA Bim knockdown conferred bortezomib resistance in Bim(hi) cells, adaptive bortezomib-resistant cells displayed marked Bim downregulation. HDACI upregulated Bim and, when combined with ABT-737, which released Bim from Bcl-2/Bcl-xL, potently killed bortezomib-resistant cells. These events were correlated with Bim-associated autophagy attenuation, whereas Bim knockdown sharply increased autophagy in Bim(hi) cells. In Bim(low) cells, autophagy disruption by chloroquine (CQ) was required for HDACI/ABT-737 to induce Bim expression and lethality. CQ also further enhanced HDACI/ABT-737 lethality in bortezomib-resistant cells. Finally, HDACI failed to diminish autophagy or potentiate ABT-737-induced apoptosis in bim(-/-) mouse embryonic fibroblasts. Thus, Bim deficiency represents a novel mechanism of adaptive bortezomib resistance in MM cells, and Bim-targeting strategies combining HDACIs (which upregulate Bim) and BH3 mimetics (which unleash Bim from antiapoptotic proteins) overcomes such resistance, in part by disabling cytoprotective autophagy.

  2. Enhanced Oral Delivery of Protein Drugs Using Zwitterion-Functionalized Nanoparticles to Overcome both the Diffusion and Absorption Barriers. (United States)

    Shan, Wei; Zhu, Xi; Tao, Wei; Cui, Yi; Liu, Min; Wu, Lei; Li, Lian; Zheng, Yaxian; Huang, Yuan


    Oral delivery of protein drugs based on nanoparticulate delivery system requires permeation of the nanoparticles through the mucus layer and subsequent absorption via epithelial cells. However, overcoming these two barriers requires very different or even contradictory surface properties of the nanocarriers, which greatly limits the oral bioavailability of macromolecular drugs. Here we report a simple zwitterions-based nanoparticle (NP) delivery platform, which showed a great potency in simultaneously overcoming both the mucus and epithelium barriers. The dense and hydrophilic coating of zwitterions endows the NPs with excellent mucus penetrating ability. Moreover, the zwitterions-based NPs also possessed excellent affinity with epithelial cells, which significantly improved (4.5-fold) the cellular uptake of DLPC NPs, compared to PEGylated NPs. Our results also indicated that this affinity was due to the interaction between zwitterions and the cell surface transporter PEPT1. Moreover, the developed NPs loaded with insulin could induce a prominent hypoglycemic response in diabetic rats following oral administration. These results suggest that zwitterions-based NPs might provide a new perspective for oral delivery of protein therapeutics.

  3. The Influence of Creativity Level on Overcoming the Barriers of Teachers’ Professional Development

    Directory of Open Access Journals (Sweden)

    E. F. Zeer


    Full Text Available The paper summarizes the research findings concerning the influence of creativity on overcoming the barriers of teachers’ professional development. The re- search subject includes defining the interrelations between the creativity and profes- sional burn-out. The aim of the studies is to find out the influencing factors of creativ- ity eliminating the destructive trends of professional pedagogic activity. The methodology is based on the E. E. Simanyuk’s concept describing the de- structive tendencies of teachers’ professional formation and the constructive overcom- ing strategies. The teachers’ refresher course at Sverdlovsk Regional Institute of Education De- velopment was taken as the experimental ground for the research. The diagnostics of the psychological constructs relating to the discussed phenomena was carried out by using tests of high validity and reliability. The modern methods of mathematical statis- tics were applied. The research outputs are of high practical importance both for designing the content of teachers’ professional development and upgrading their readiness for educa- tional innovations. 

  4. 'We do the impossible': women overcoming barriers to cervical cancer screening in rural Honduras--a positive deviance analysis. (United States)

    Garrett, Jenna J; Barrington, Clare


    Cervical cancer is the leading cause of cancer death for women in Honduras, and sexual behaviour and low screening uptake are two major factors contributing to high rates of morbidity and mortality. A qualitative study was conducted to investigate barriers that prevent rural Honduran women from engaging in screening and ways that women overcome those barriers. This study examined examples of positive deviance, or individuals engaging in the uncommon but beneficial practise of screening. Amor por sí misma (self-love), and social support were identified as two constructs women employed to overcome barriers to screening. Participants defined self-love as the act of displaying care and concern for oneself and one's health and suggested that it compels women to participate in screening. Social support was defined as receiving tangible aid and advice from others that facilitated women's screening participation. Findings suggest that the concept of self-love could be used in future screening promotion efforts and that integrating social support would also be beneficial. Engaging men in sexual and reproductive health programming is suggested in order to ensure male partners offer social support for screening and to challenge the cultural, gender and sexual norms that place women at higher risk for cervical cancer.

  5. Overcoming a hemihedral twinning problem in tetrahydrofolate-dependent O -demethylase crystals by the microseeding method

    Energy Technology Data Exchange (ETDEWEB)

    Harada, Ayaka; Sato, Yukari; Kamimura, Naofumi; Venugopalan, Nagarajan; Masai, Eiji; Senda, Toshiya


    A tetrahydrofolate-dependentO-demethylase, LigM, fromSphingobiumsp. SYK-6 was crystallized by the hanging-drop vapour-diffusion method. However, the obtainedP3121 orP3221 crystals, which diffracted to 2.5–3.3 Å resolution, were hemihedrally twinned. To overcome the twinning problem, microseeding usingP3121/P3221 crystals as microseeds was performed with optimization of the reservoir conditions. As a result, another crystal form was obtained. The newly obtained crystal diffracted to 2.5–3.0 Å resolution and belonged to space groupP21212, with unit-cell parametersa= 102.0,b= 117.3,c= 128.1 Å. TheP21212 crystals diffracted to better than 2.0 Å resolution after optimizing the cryoconditions. Phasing using the single anomalous diffraction method was successful at 3.0 Å resolution with a Pt-derivative crystal. This experience suggested that microseeding is an effective method to overcome the twinning problem, even when twinned crystals are utilized as microseeds.

  6. The Application of Lateral Inhibition Model in Image's Contour Enhancement and Design of Its Electro-Model

    Directory of Open Access Journals (Sweden)

    Hongwei Fu


    Full Text Available For overcoming the problems such as distortion and shift of object’s edge, easily losing the object detail information of methods in image edge detection, and satisfying higher demand for object detection in the modern war, a new image edge detection method was designed. LOG edge detection as a typical image processing method was introduced and the disadvantage of this model was analyzed firstly. Based on lateral inhibition theory, an acyclic lateral inhibition network model (ALINM based on biology vision information processing mechanism was designed. The feasibility of object detection by lateral inhibition model was analyzed, in order to express the advantage such as rapid calculation easily real time operation of ALINM, the calculation magnitude of circulation difference lateral inhibition model was analyzed. Besides the correctness of ALINM was confirmed with two input cells, its transfer function was deduced. An algorithm of image edge detection based on this model was established finally, lateral inhibition effect also was confirmed by one-dimension and two-dimension circuit model based ALINM. Simulative experiment with different parameters and physics experiment prove that acyclic lateral inhibition network model can be realized easily, it can preserve the farthest detail information of object and has faster calculation speed than LOG operator. ALINM and lateral inhibition theory provide a useful method based on biology vision for object detection under difficult imaging conditions.

  7. Corrosion Chemistry in Inhibited HDA. (United States)


    Titanium and chromium have sufficiently low Flade potentials to pass- ivate in non-oxidising acids, but Iron will only exhibit self-passivity if the...inhibition e.g. involving organic and pickling inhibitors* the rest potential can actually 4.5,4.6become more negative " This is due to cathodic 321 stainless steel, titanium stabilised, was the particular steel studied, being very similar in composition to the 347also stainless steel

  8. Current status of anti-human epidermal growth factor receptor 2 therapies: predicting and overcoming herceptin resistance. (United States)

    Chung, Alice; Cui, Xiaojiang; Audeh, William; Giuliano, Armando


    Human epidermal growth factor receptor 2-overexpressing (HER2+) breast cancer occurs in 20% to 25% of cases and is associated with poor prognosis. Trastuzumab (Herceptin; Genentech, South San Francisco, CA) is a monoclonal antibody targeting the HER2 extracellular domain that has been shown to significantly reduce relapse rates. However, some patients with HER2+ tumors do not respond to Herceptin, and 60% to 85% of patients with HER2+ metastatic breast cancer acquire resistance within a short time period. In this review, we discuss proposed mechanisms of action of trastuzumab and trastuzumab resistance and various drugs that have been developed to overcome drug resistance. We introduce the basal molecular subtype as a predictor of increased risk in HER2+ breast cancer and a possible alternative cause of drug resistance.

  9. Overcoming the barrier of narrative adherence in conflicts through awareness of the psychological bias of naïve realism. (United States)

    Nasie, Meytal; Bar-Tal, Daniel; Pliskin, Ruthie; Nahhas, Eman; Halperin, Eran


    One significant socio-psychological barrier for peaceful resolution of conflicts is each party's adherence to its own collective narrative. We hypothesized that raising awareness to the psychological bias of naïve realism and its identification in oneself would provide a path to overcoming this barrier, thus increasing openness to the adversary's narrative. We conducted three experimental studies in the context of the Israeli-Palestinian conflict. Studies 1 and 2, conducted among Jewish Israelis and Palestinian Israelis, respectively, revealed that participants with hawkish political ideology reported greater openness to the adversary's narrative when they were made aware of naïve realism bias. Study 3 revealed that hawkish participants at the baseline adhered to the ingroup narrative and resisted the adversary's narrative more than dovish participants. They were also more able to identify the bias in themselves upon learning about it. This identification may explain why the manipulation led to bias correction only among hawkish participants.

  10. Barriers to blood pressure control in African Americans. Overcoming obstacles is challenging, but target goals can be attained. (United States)

    Douglas, Janice G; Ferdinand, Keith C; Bakris, George L; Sowers, James R


    Outdated and biased attitudes and care standards impede optimal care of hypertension in African Americans. The negative expectations that blood pressure targets cannot be reached must be overcome by systematic and appropriate education and treatment. However, physicians should expect that (1) African American patients with elevated blood pressure benefit from early and intensive management, (2) blood pressure can be maintained at goal with appropriate therapeutic lifestyle changes and medications, and (3) complications related to high blood pressure can be avoided. To bring blood pressure down to the target goal, combination pharmacologic therapy is often required. When extensive efforts to achieve blood pressure control prove unattainable in the primary care setting, consultation with a hypertension specialist should be considered.

  11. Conditioned inhibition and reinforcement rate. (United States)

    Harris, Justin A; Kwok, Dorothy W S; Andrew, Benjamin J


    We investigated conditioned inhibition in a magazine approach paradigm. Rats were trained on a feature negative discrimination between an auditory conditioned stimulus (CS) reinforced at one rate versus a compound of that CS and a visual stimulus (L) reinforced at a lower rate. This training established L as a conditioned inhibitor. We then tested the inhibitory strength of L by presenting it in compound with other auditory CSs. L reduced responding when tested with a CS that had been reinforced at a high rate, but had less or even no inhibitory effect when tested with a CS that had been reinforced at a low rate. The inhibitory strength of L was greater if it signaled a decrease in reinforcement from an already low rate than if it signaled an equivalent decrease in reinforcement from a high rate. We conclude that the strength of inhibition is not a linear function of the change in reinforcement that it signals. We discuss the implications of this finding for models of learning (e.g., Rescorla & Wagner, 1972) that identify inhibition with a difference (subtraction) rule.

  12. Th2 cytokines inhibit lymphangiogenesis.

    Directory of Open Access Journals (Sweden)

    Ira L Savetsky

    Full Text Available Lymphangiogenesis is the process by which new lymphatic vessels grow in response to pathologic stimuli such as wound healing, inflammation, and tumor metastasis. It is well-recognized that growth factors and cytokines regulate lymphangiogenesis by promoting or inhibiting lymphatic endothelial cell (LEC proliferation, migration and differentiation. Our group has shown that the expression of T-helper 2 (Th2 cytokines is markedly increased in lymphedema, and that these cytokines inhibit lymphatic function by increasing fibrosis and promoting changes in the extracellular matrix. However, while the evidence supporting a role for T cells and Th2 cytokines as negative regulators of lymphatic function is clear, the direct effects of Th2 cytokines on isolated LECs remains poorly understood. Using in vitro and in vivo studies, we show that physiologic doses of interleukin-4 (IL-4 and interleukin-13 (IL-13 have profound anti-lymphangiogenic effects and potently impair LEC survival, proliferation, migration, and tubule formation. Inhibition of these cytokines with targeted monoclonal antibodies in the cornea suture model specifically increases inflammatory lymphangiogenesis without concomitant changes in angiogenesis. These findings suggest that manipulation of anti-lymphangiogenic pathways may represent a novel and potent means of improving lymphangiogenesis.

  13. Species-specific activity of SIV Nef and HIV-1 Vpu in overcoming restriction by tetherin/BST2.

    Directory of Open Access Journals (Sweden)

    Bin Jia


    Full Text Available Tetherin, also known as BST2, CD317 or HM1.24, was recently identified as an interferon-inducible host-cell factor that interferes with the detachment of virus particles from infected cells. HIV-1 overcomes this restriction by expressing an accessory protein, Vpu, which counteracts tetherin. Since lentiviruses of the SIV(smm/mac/HIV-2 lineage do not have a vpu gene, this activity has likely been assumed by other viral gene products. We found that deletion of the SIV(mac239 nef gene significantly impaired virus release in cells expressing rhesus macaque tetherin. Virus release could be restored by expressing Nef in trans. However, Nef was unable to facilitate virus release in the presence of human tetherin. Conversely, Vpu enhanced virus release in the presence of human tetherin, but not in the presence of rhesus tetherin. In accordance with the species-specificity of Nef in mediating virus release, SIV Nef downregulated cell-surface expression of rhesus tetherin, but did not downregulate human tetherin. The specificity of SIV Nef for rhesus tetherin mapped to four amino acids in the cytoplasmic domain of the molecule that are missing from human tetherin, whereas the specificity of Vpu for human tetherin mapped to amino acid differences in the transmembrane domain. Nef alleles of SIV(smm, HIV-2 and HIV-1 were also able to rescue virus release in the presence of both rhesus macaque and sooty mangabey tetherin, but were generally ineffective against human tetherin. Thus, the ability of Nef to antagonize tetherin from these Old World primates appears to be conserved among the primate lentiviruses. These results identify Nef as the viral gene product of SIV that opposes restriction by tetherin in rhesus macaques and sooty mangabeys, and reveal species-specificity in the activities of both Nef and Vpu in overcoming tetherin in their respective hosts.

  14. Enzastaurin inhibits tumours sensitive and resistant to anti-EGFR drugs (United States)

    Gelardi, T; Caputo, R; Damiano, V; Daniele, G; Pepe, S; Ciardiello, F; Lahn, M; Bianco, R; Tortora, G


    We investigated the antitumour effect and ability to overcome the resistance to anti-EGFR drugs of enzastaurin, an inhibitor of VEGFR-dependent PKCβ signalling. Enzastaurin was evaluated alone and in combination with the EGFR inhibitor gefitinib, on growth and signalling protein expression in human cancer cells sensitive and resistant to anti-EGFR drugs, both in vitro and in nude mice. We demonstrated the marked inhibitory activity of enzastaurin against GEO colon and PC3 prostate cancer cells and their gefitinib-resistant counterparts GEO-GR and PC3-GR, accompanied by inhibition of pAkt and its effector pp70S6K, pGSK3β and VEGF expression and secretion. Moreover, enzastaurin showed a cooperative effect with gefitinib in parental and in gefitinib-resistant cells. Remarkably, these results were confirmed in vivo, where enzastaurin showed antitumour activity and cooperativity with gefitinib in mice grafted with GEO and GEO-GR tumours, incrementing their median survival and inhibiting the aforesaid protein expression and secretion in tumour specimens. In conclusion, enzastaurin by interfering with signalling proteins implicated in EGFR drug resistance markedly cooperates with gefitinib in sensitive and gefitinib-resistant tumours, thus overcoming and reverting such resistance and providing a rational basis for its development in patients resistant to anti-EGFR drugs. PMID:18665191

  15. Overcoming Language Barriers (United States)

    De Buda, Yvonne


    Many family physicians in Canada experience language and cultural barriers between themselves and their patients. Several aspects of the ensuing problems are described and some practical suggestions for solutions are made. The importance of health education for new Canadians in the family physician's office as well as through the media and community projects is stressed. Imagesp68-ap68-bp70-a PMID:21308059

  16. Overcoming Resistance to Change (United States)

    Heath, Chip; Heath, Dan


    In 2004, Donald Berwick, a doctor and the CEO of the Institute for Healthcare Improvement, had some ideas about how to save lives--massive numbers of lives. The institute he led had analyzed patient care applying the analytical tools used to assess the quality of cars coming off a production line. Berwick and colleagues discovered the "defect"…

  17. Overcoming feelings of envy. (United States)


    How should professionals help clients deal with feelings of envy about their fellow service users? Psychotherapist David O'Driscoll, writing in Learning Disability Practice, uses the case of a young man in a day service who had met all the markers of normal grief after his mother's death. Yet nine months following her loss, he was prone to angry outbursts if other service users mentioned their mothers. His first aim was to help his client acknowledge his envy. Then the client was able to discuss his feelings of injustice and anger at losing his mother.

  18. Overcoming job stress (United States)

    ... or not advancing in your career. How Job Stress Affects Your Health Like any kind of stress, job stress that continues for a long time can affect your health. Job stress may increase your risk for health problems such ...

  19. Overcoming priors anxiety

    CERN Document Server

    D'Agostini, Giulio


    The choice of priors may become an insoluble problem if priors and Bayes' rule are not seen and accepted in the framework of subjectivism. Therefore, the meaning and the role of subjectivity in science is considered and defended from the pragmatic point of view of an ``experienced scientist''. The case for the use of subjective priors is then supported and some recommendations for routine and frontier measurement applications are given. The issue of reference priors is also considered from the practical point of view and in the general context of ``Bayesian dogmatism''.

  20. Overcoming breastfeeding problems (United States)

    ... slow evaporation. Using soaps or solutions that remove natural skin oils can cause dry skin. Olive oil, expressed ... lump that can be felt close to the skin Sometimes, a tiny white dot can be ... your health care provider if you develop these symptoms. Treatment often ...

  1. Inhibiting your native language: the role of retrieval-induced forgetting during second-language acquisition. (United States)

    Levy, Benjamin J; McVeigh, Nathan D; Marful, Alejandra; Anderson, Michael C


    After immersion in a foreign language, speakers often have difficulty retrieving native-language words--a phenomenon known as first-language attrition. We propose that first-language attrition arises in part from the suppression of native-language phonology during second-language use, and thus is a case of phonological retrieval-induced forgetting. In two experiments, we investigated this hypothesis by having native English speakers name visual objects in a language they were learning (Spanish). Repeatedly naming the objects in Spanish reduced the accessibility of the corresponding English words, as measured by an independent-probe test of inhibition. The results establish that the phonology of the words was inhibited, as access to the concepts underlying the presented objects was facilitated, not impaired. More asymmetry between English and Spanish fluency was associated with more inhibition for native-language words. This result supports the idea that inhibition plays a functional role in overcoming interference during the early stages of second-language acquisition.

  2. Involvement of lipids in dimethoate-induced inhibition of testosterone biosynthesis in rat interstitial cells. (United States)

    Astiz, Mariana; Hurtado de Catalfo, Graciela E; de Alaniz, María J T; Marra, Carlos Alberto


    The mechanism involved in the inhibition of testosterone (Te) biosynthesis after a sub-chronic exposure to low doses of dimethoate (D) was studied in rat interstitial cells (IC). Expression of COX-2 in IC isolated from D-treated rats increased by 44% over C data, while transcription of StAR decreased by approx. 50% and the expression of this protein was diminished by approximately 40%. PGE(2) and PGF(2alpha) were increased by 61 and 78%, respectively. Te concentration decreased by 49% in IC homogenates. Concomitantly, plasma concentration of LH and FSH both increased. Araquidonate (ARA) and C(22) fatty acyl chains in phospholipids from IC mitochondrial fraction decreased by approx. 30% after D treatment. Protein carbonyls, lipoperoxides and nitrite content increased while alpha-tocopherol and the antioxidant capacity of the soluble cellular fraction decreased significantly. Stimulation with h-CG 10 nM overnight failed to overcome the inhibition caused by D on both Te biosynthesis and 3beta- and 17beta-hydroxysteroid dehydrogenases. Decreased Te biosynthesis may be attributed to (1) inhibition of StAR protein activity due to the stimulation of COX-2 and the overproduction of PGF(2alpha), (2) decreased stimulatory effect of ARA on StAR with a subsequent reduction in the availability of CHO for the androgenic pathway, and/or (3) indirect inhibition of steroidogenic enzymes by a lower transcriptional rate caused by elevated PGF(2alpha). Rofecoxib administration prevents the deleterious effect(s) exerted by D.

  3. Electrochemical study of corrosion inhibition of stainless steel in phosphoric medium

    Energy Technology Data Exchange (ETDEWEB)

    Hnini, K.; Chtaini, A. [Laboratoire d' Electrochimie et de Bio Corrosion, Faculte des Sciences et Techniques, Beni-Mellal (Morocco); Khouili, M.; Elbouadili, A. [Laboratoire de Chimie Organique et Analytique, Faculte des Sciences et Techniques, Beni-Mellal (Morocco)


    The corrosion of metals represents a terrible waste of both natural resources and money, the failure of some stainless steel resulting from pitting corrosion is some times considered a technological problem, consequently, much effort has been expended in attempting to understand and overcome the corrosion therefore, many stainless steel/ environment combinations have been studied. The use of heterocyclic compounds as inhibitors is one of the most practical methods for protection against corrosion in acidic media. In continuation of our work on development of macrocyclic compounds as corrosion inhibitors we report in our study the corrosion inhibiting behaviour of organic compound Methoxy-2-Allyl-4 Phenol (MAP) containing coordinating and conjugation groups, at three forms (natural, polymerized and chemically treated) on the corrosion of stainless steel in phosphoric acid. This study focused on the comparison for corrosion inhibition proprieties of these different applications using potentiodynamic polarization, electrochemical impedance spectroscopy and SEM. The specimen was evaluated to determine change in his corrosion potential and resistance polarization; These MAP products have exhibited corrosion inhibition by maintaining a high resistance polarization (low corrosion rate) in each application. These results reveal that this compound is efficient inhibitor in all forms; the most inhibition efficiency is obtained with polymerized form. To further evaluate the test data, the steel surfaces were analyzed using scanning electron microscopy, SEM observations of surface treated concrete confirmed presence of inhibitor on the steel surfaces. (authors)

  4. Ground-Source Heat Pumps. Overview of Market Status, Barriers to Adoption, and Options for Overcoming Barriers

    Energy Technology Data Exchange (ETDEWEB)

    Goetzler, William [Navigant Consulting, Inc., Chicago, IL (United States); Zogg, Robert [Navigant Consulting, Inc., Chicago, IL (United States); Lisle, Heather [Navigant Consulting, Inc., Chicago, IL (United States); Burgos, Javier [Navigant Consulting, Inc., Chicago, IL (United States)


    February 2009 final report submitted to DOE by Navigant Consulting, Inc. This report summarizes the status of ground-source heat pump (GSHP) technology and market penetration globally, estimates the energy saving potential of GSHPs in the U.S., identifies key market barriers that are inhibiting wider market adoption of GSHPs, and recommends initiatives that can be implemented or facilitated by the DOE to accelerate market adoption.

  5. 3-Halo Chloroquine Derivatives Overcome Plasmodium falciparum Chloroquine Resistance Transporter-Mediated Drug Resistance in P. falciparum. (United States)

    Edaye, Sonia; Tazoo, Dagobert; Bohle, D Scott; Georges, Elias


    Polymorphism in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) was shown to cause chloroquine resistance. In this report, we examined the antimalarial potential of novel 3-halo chloroquine derivatives (3-chloro, 3-bromo, and 3-iodo) against chloroquine-susceptible and -resistant P. falciparum. All three derivatives inhibited the proliferation of P. falciparum; with 3-iodo chloroquine being most effective. Moreover, 3-iodo chloroquine was highly effective at potentiating and reversing chloroquine toxicity of drug-susceptible and -resistant P. falciparum.

  6. Treating triple negative breast cancer cells with erlotinib plus a select antioxidant overcomes drug resistance by targeting cancer cell heterogeneity (United States)

    Bao, Bin; Mitrea, Cristina; Wijesinghe, Priyanga; Marchetti, Luca; Girsch, Emily; Farr, Rebecca L.; Boerner, Julie L; Mohammad, Ramzi; Dyson, Greg; Terlecky, Stanley R.; Bollig-Fischer, Aliccia


    Among breast cancer patients, those diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst prog-nosis. TNBC does not express estrogen receptor-alpha, progesterone receptor, or the HER2 oncogene; therefore, TNBC lacks targets for molecularly-guided therapies. The concept that EGFR oncogene inhibitor drugs could be used as targeted treatment against TNBC has been put forth based on estimates that 30–60% of TNBC express high levels of EGFR. However, results from clinical trials testing EGFR inhibitors, alone or in combination with cytotoxic chemotherapy, did not improve patient outcomes. Results herein offer an explanation as to why EGFR inhibitors failed TNBC patients and support how combining a select antioxidant and an EGFR-specific small molecule kinase inhibitor (SMKI) could be an effective, novel therapeutic strategy. Treatment with CAT-SKL—a re-engineered protein form of the antioxidant enzyme catalase—inhibited cancer stem-like cells (CSCs), and treatment with the EGFR-specific SMKI erlotinib inhibited non-CSCs. Thus, combining the antioxidant CAT-SKL with erlotinib targeted both CSCs and bulk cancer cells in cultures of EGFR-expressing TNBC-derived cells. We also report evidence that the mechanism for CAT-SKL inhibition of CSCs may depend on antioxidant-induced downregulation of a short alternative mRNA splicing variant of the methyl-CpG binding domain 2 gene, isoform MBD2c. PMID:28281569

  7. Treating triple negative breast cancer cells with erlotinib plus a select antioxidant overcomes drug resistance by targeting cancer cell heterogeneity. (United States)

    Bao, Bin; Mitrea, Cristina; Wijesinghe, Priyanga; Marchetti, Luca; Girsch, Emily; Farr, Rebecca L; Boerner, Julie L; Mohammad, Ramzi; Dyson, Greg; Terlecky, Stanley R; Bollig-Fischer, Aliccia


    Among breast cancer patients, those diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst prog-nosis. TNBC does not express estrogen receptor-alpha, progesterone receptor, or the HER2 oncogene; therefore, TNBC lacks targets for molecularly-guided therapies. The concept that EGFR oncogene inhibitor drugs could be used as targeted treatment against TNBC has been put forth based on estimates that 30-60% of TNBC express high levels of EGFR. However, results from clinical trials testing EGFR inhibitors, alone or in combination with cytotoxic chemotherapy, did not improve patient outcomes. Results herein offer an explanation as to why EGFR inhibitors failed TNBC patients and support how combining a select antioxidant and an EGFR-specific small molecule kinase inhibitor (SMKI) could be an effective, novel therapeutic strategy. Treatment with CAT-SKL-a re-engineered protein form of the antioxidant enzyme catalase-inhibited cancer stem-like cells (CSCs), and treatment with the EGFR-specific SMKI erlotinib inhibited non-CSCs. Thus, combining the antioxidant CAT-SKL with erlotinib targeted both CSCs and bulk cancer cells in cultures of EGFR-expressing TNBC-derived cells. We also report evidence that the mechanism for CAT-SKL inhibition of CSCs may depend on antioxidant-induced downregulation of a short alternative mRNA splicing variant of the methyl-CpG binding domain 2 gene, isoform MBD2c.

  8. Nitrite reductase activity of sulphate-reducing bacteria prevents their inhibition by nitrate-reducing, sulphide-oxidizing bacteria. (United States)

    Greene, E A; Hubert, C; Nemati, M; Jenneman, G E; Voordouw, G


    Sulphate-reducing bacteria (SRB) can be inhibited by nitrate-reducing, sulphide-oxidizing bacteria (NR-SOB), despite the fact that these two groups are interdependent in many anaerobic environments. Practical applications of this inhibition include the reduction of sulphide concentrations in oil fields by nitrate injection. The NR-SOB Thiomicrospira sp. strain CVO was found to oxidize up to 15 mM sulphide, considerably more than three other NR-SOB strains that were tested. Sulphide oxidation increased the environmental redox potential (Eh) from -400 to +100 mV and gave 0.6 nitrite per nitrate reduced. Within the genus Desulfovibrio, strains Lac3 and Lac6 were inhibited by strain CVO and nitrate for the duration of the experiment, whereas inhibition of strains Lac15 and D. vulgaris Hildenborough was transient. The latter had very high nitrite reductase (Nrf) activity. Southern blotting with D. vulgaris nrf genes as a probe indicated the absence of homologous nrf genes from strains Lac3 and Lac6 and their presence in strain Lac15. With respect to SRB from other genera, inhibition of the known nitrite reducer Desulfobulbus propionicus by strain CVO and nitrate was transient, whereas inhibition of Desulfobacterium autotrophicum and Desulfobacter postgatei was long-lasting. The results indicate that inhibition of SRB by NR-SOB is caused by nitrite production. Nrf-containing SRB can overcome this inhibition by further reducing nitrite to ammonia, preventing a stalling of the favourable metabolic interactions between these two bacterial groups. Nrf, which is widely distributed in SRB, can thus be regarded as a resistance factor that prevents the inhibition of dissimilatory sulphate reduction by nitrite.

  9. VitruCare: Using digital health to overcome the bounded willpower of patients with long term conditions

    Directory of Open Access Journals (Sweden)

    Carolyn Louise Wilson


    Full Text Available Background: Long term conditions affect 40% of the UK population whilst utilising 70% of the health and social care funding. Digital health has emerged as a solution, to aid patients in self-managing their health and alter unhealthy behaviours. However, for digital health to be effective, the field must have an understanding of what hinders or motivates patient behaviour change. Behavioural economics, as a combination of psychology and economics, can provide this knowledge with relevant concepts, biases and heuristics. One such concept is bounded willpower, which explains why people struggle to make decisions based on their long term interests but are more susceptible to short-term benefits or costs. Aims: The aim of this research is to explore the concept of bounded willpower in relation to digital health within the UK. The focus is primarily on the product VitruCare and its effectiveness at overcoming the bounded willpower of patients with long term conditions. Method: VitruCare used feedback, commitment contracts and channel factors to help overcome bounded willpower in an intervention on 144 patients in the Bradford region who were suffering from hypertension. Quantitative variables of patients’ weight, blood pressure, GP attendances, A&E attendances, acute admissions and outpatient visits were recorded before and after usage. A paired samples t-test was used to indicate significant differences in these two conditions. Results: Results indicated significant improvements in weight (t = 7.377, p = 0.000, systolic (t = 6.743, p = 0.000 and diastolic (t = 11.936, p = 0.000 blood pressure, alongside a significant reduction in GP practice visits (t = 12.643, p = 0.000 and outpatient visits (t = 5.951, p = 0.000. There were no significant differences in A&E attendances (t = 1.440, p = 0.152 and acute admissions (t = 1.029, p = 0.305. Conclusions: VitruCare's understanding of behavioural economics and the potential psychological pitfalls in the

  10. Overcoming Barriers to the Market Access of Biosimilars in the European Union: The Case of Biosimilar Monoclonal Antibodies (United States)

    Moorkens, Evelien; Jonker-Exler, Clara; Huys, Isabelle; Declerck, Paul; Simoens, Steven; Vulto, Arnold G.


    Background: In 2014, six of the top ten blockbuster medicines were monoclonal antibodies. This multibillion-dollar market with expiring patents is the main driver for the development of biosimilar mAbs. With the ever-increasing cost of healthcare and the economic pressure to reduce or sustain healthcare expenses, biosimilars could be instrumental in reducing costs for medication and increasing patient access to treatment. Objectives: The aim of this study is to identify and describe the barriers to market access of biosimilar mAbs in the European Union and to analyze how these barriers could be overcome. Methods: A narrative literature review was carried out using the databases PubMed, Embase, and EconLit. Studies were published in English or Dutch. Additionally, the reference list of the articles was checked for relevant studies. Articles and conference papers known to the authors were included as well. Articles were also identified by searching on the website of the Generics and Biosimilars Initiative (GaBI) journal. Results: Six barriers were identified based on available literature: The manufacturing process, the regulatory process, intellectual property rights, lack of incentive, the impossibility of substitution, and the innovator's reach. These six barriers are presented as a possible framework to study the market access of biosimilar mAbs. Based on the literature search, recommendations can be made to overcome these barriers: (i) invest initially in advanced production processes with the help of single-use technology, experience or outsourcing (ii) gain experience with the regulatory process and establish alignment between stakeholders (iii) limit patent litigation, eliminate evergreening benefits, build out further the unitary patent and unified patent litigation system within the EU (iv) create demand-side policies, disseminate objective information (v) change attitude toward biosimilar switching/substitution, starting with physician, and patient

  11. Self-regulation, ego depletion, and inhibition. (United States)

    Baumeister, Roy F


    Inhibition is a major form of self-regulation. As such, it depends on self-awareness and comparing oneself to standards and is also susceptible to fluctuations in willpower resources. Ego depletion is the state of reduced willpower caused by prior exertion of self-control. Ego depletion undermines inhibition both because restraints are weaker and because urges are felt more intensely than usual. Conscious inhibition of desires is a pervasive feature of everyday life and may be a requirement of life in civilized, cultural society, and in that sense it goes to the evolved core of human nature. Intentional inhibition not only restrains antisocial impulses but can also facilitate optimal performance, such as during test taking. Self-regulation and ego depletion- may also affect less intentional forms of inhibition, even chronic tendencies to inhibit. Broadly stated, inhibition is necessary for human social life and nearly all societies encourage and enforce it.

  12. LINGO-1, a transmembrane signaling protein, inhibits oligodendrocyte differentiation and myelination through intercellular self-interactions. (United States)

    Jepson, Scott; Vought, Bryan; Gross, Christian H; Gan, Lu; Austen, Douglas; Frantz, J Daniel; Zwahlen, Jacque; Lowe, Derek; Markland, William; Krauss, Raul


    Overcoming remyelination failure is a major goal of new therapies for demyelinating diseases like multiple sclerosis. LINGO-1, a key negative regulator of myelination, is a transmembrane signaling protein expressed in both neurons and oligodendrocytes. In neurons, LINGO-1 is an integral component of the Nogo receptor complex, which inhibits axonal growth via RhoA. Because the only ligand-binding subunit of this complex, the Nogo receptor, is absent in oligodendrocytes, the extracellular signals that inhibit myelination through a LINGO-1-mediated mechanism are unknown. Here we show that LINGO-1 inhibits oligodendrocyte terminal differentiation through intercellular interactions and is capable of a self-association in trans. Consistent with previous reports, overexpression of full-length LINGO-1 inhibited differentiation of oligodendrocyte precursor cells (OPCs). Unexpectedly, treatment with a soluble recombinant LINGO-1 ectodomain also had an inhibitory effect on OPCs and decreased myelinated axonal segments in cocultures with neurons from dorsal root ganglia. We demonstrated LINGO-1-mediated inhibition of OPCs through intercellular signaling by using a surface-bound LINGO-1 construct expressed ectopically in astrocytes. Further investigation showed that the soluble LINGO-1 ectodomain can interact with itself in trans by binding to CHO cells expressing full-length LINGO-1. Finally, we observed that soluble LINGO-1 could activate RhoA in OPCs. We propose that LINGO-1 acts as both a ligand and a receptor and that the mechanism by which it negatively regulates OPC differentiation and myelination is mediated by a homophilic intercellular interaction. Disruption of this protein-protein interaction could lead to a decrease of LINGO-1 inhibition and an increase in myelination.

  13. Graphene: corrosion-inhibiting coating. (United States)

    Prasai, Dhiraj; Tuberquia, Juan Carlos; Harl, Robert R; Jennings, G Kane; Rogers, Bridget R; Bolotin, Kirill I


    We report the use of atomically thin layers of graphene as a protective coating that inhibits corrosion of underlying metals. Here, we employ electrochemical methods to study the corrosion inhibition of copper and nickel by either growing graphene on these metals, or by mechanically transferring multilayer graphene onto them. Cyclic voltammetry measurements reveal that the graphene coating effectively suppresses metal oxidation and oxygen reduction. Electrochemical impedance spectroscopy measurements suggest that while graphene itself is not damaged, the metal under it is corroded at cracks in the graphene film. Finally, we use Tafel analysis to quantify the corrosion rates of samples with and without graphene coatings. These results indicate that copper films coated with graphene grown via chemical vapor deposition are corroded 7 times slower in an aerated Na(2)SO(4) solution as compared to the corrosion rate of bare copper. Tafel analysis reveals that nickel with a multilayer graphene film grown on it corrodes 20 times slower while nickel surfaces coated with four layers of mechanically transferred graphene corrode 4 times slower than bare nickel. These findings establish graphene as the thinnest known corrosion-protecting coating.

  14. Intrusion Detection System to Overcome a Novel Form of Replay Attack (Data Replay in Wireless Sensor Networks

    Directory of Open Access Journals (Sweden)

    Yasmine Medjadba


    Full Text Available Wireless Sensor Networks (WSNs are widely and successfully employed in various application domains. They are easily deployed to collect valuable information and monitor potential environmental phenomena. However, the special nature of WSNs as well as their severe constraints and resource limitations make them vulnerable to various types of threats. Replay attack, is one example. According to this attack, the adversary intercepts and replays several times the same (old message leading either to missed alerts or to false alerts. Many solutions have been proposed to mitigate message replay attack. However, all these solutions are of cryptographic natures and consider only external attacks exercising a trivial scenario of replay attack. In fact, the attacker could be a lot smarter, and in this case, it replays only the data field in the message while keeping the remaining fields updated. This novel form of replay attack is much more dangerous and difficult to be detected. We call this attack variant by data replay attack. As sensor nodes may be easily captured and compromised, the worst scenario occurs if data replay attack is performed by an internal intruder. In this paper we propose an efficient intrusion detection framework to overcome data replay attack in WSNs. The proposed intrusion detection system is named DR-IDS (Data Replay Intrusion Detection System. The performance evaluations performed under NS2 simulator show that the proposed solution is sufficiently robust.

  15. Uniting Christian Students� Association�s pilgrimage to overcome colonial racism: A southern African postcolonial missiological dialogue

    Directory of Open Access Journals (Sweden)

    R.W. (Reggie Nel


    Full Text Available World Christianity has been enriched by Christian student movements such as the Uniting Christian Students� Association (UCSA from South Africa. This article, based on my recent doctoral research, starts with the affirmation of the ambiguous relations of these movements with colonial racism. However, faced with new challenges in a postcolonial context, there are key impulses to be gained by an inter-subjective, but also interdisciplinary dialogue with these movements as they negotiate their calling. By focussing on one movement within the southern African context, UCSA, in particular its formation and development since the demise of apartheid in South Africa, the article aims to present an attempt to understand the missionary praxis of UCSA through a postcolonial missiological matrix. The article draws on the theological disciplines of missiology, systematic theology, church history, contextual theology, as well as the methodologies in non-theologic disciplines like sociology, in particular social movement studies, and history. The findings show, amongst others, a growing complexity in relation to its agency, how it frames its world and also how it used its authoritative sources to discern its calling. The article closes with some key insights and pointers relevant for faith communities in their mission to overcome colonial racism.Intradisciplinary and/or interdisciplinary implications: The teaching and research in missiology and systematic theology in how the challenge of colonial racism is addressed, methodologically.

  16. Mechanisms of Trastuzumab resistance in ErbB2-driven breast cancer and newer opportunities to overcome therapy resistance

    Directory of Open Access Journals (Sweden)

    Tameka A Bailey


    Full Text Available The Human Epidermal Growth Factor Receptor 2 (Her2, ErbB2 or Neu is overexpressed in about 20 - 25% of breast cancers and is causally linked to oncogenesis, providing opportunities for targeted therapy. Trastuzumab (Herceptin™, Genentech Inc, San Francisco, CA, a humanized monoclonal antibody against ErbB2, is a successful example of this concept and has vastly improved the response to treatment and overall survival in a majority of ErbB2+ breast cancer patients. However, lack of response in some patients as well as relapse during the course of therapy in others, continue to challenge researchers and clinicians alike towards a better understanding of the fundamental mechanisms of Trastuzumab action and resistance to treatment. The exact in vivo mechanism of action of Trastuzumab remains enigmatic, given its direct effects on the ErbB2 signaling pathway as well as indirect contributions from the immune system, by virtue of the ability of Trastuzumab to elicit Antibody-Dependent Cellular Cytotoxicity. Consequently, multiple mechanisms of resistance have been proposed. We present here a comprehensive review of our current understanding of the mechanisms, both of Trastuzumab action and clinical resistance to Trastuzumab-based therapies. We also review newer strategies (based on ErbB2 receptor biology that are being explored to overcome resistance to Trastuzumab therapy.

  17. A crystallographic study of human NONO (p54(nrb)): overcoming pathological problems with purification, data collection and noncrystallographic symmetry. (United States)

    Knott, Gavin J; Panjikar, Santosh; Thorn, Andrea; Fox, Archa H; Conte, Maria R; Lee, Mihwa; Bond, Charles S


    Non-POU domain-containing octamer-binding protein (NONO, a.k.a. p54(nrb)) is a central player in nuclear gene regulation with rapidly emerging medical significance. NONO is a member of the highly conserved Drosophila behaviour/human splicing (DBHS) protein family, a dynamic family of obligatory dimeric nuclear regulatory mediators. However, work with the NONO homodimer has been limited by rapid irreversible sample aggregation. Here, it is reported that L-proline stabilizes purified NONO homodimers, enabling good-quality solution small-angle X-ray structure determination and crystallization. NONO crystallized in the apparent space group P21 with a unique axis (b) of 408.9 Å and with evidence of twinning, as indicated by the cumulative intensity distribution L statistic, suggesting the possibility of space group P1. Structure solution by molecular replacement shows a superhelical arrangement of six NONO homodimers (or 12 in P1) oriented parallel to the long axis, resulting in extensive noncrystallographic symmetry. Further analysis revealed that the crystal was not twinned, but the collected data suffered from highly overlapping reflections that obscured the L-test. Optimized data collection on a new crystal using higher energy X-rays, a smaller beam width and an increased sample-to-detector distance produced non-overlapping reflections to 2.6 Å resolution. The steps taken to analyse and overcome this series of practical difficulties and to produce a biologically informative structure are discussed.

  18. Rural veteran access to healthcare services: investigating the role of information and communication technologies in overcoming spatial barriers. (United States)

    Schooley, Benjamin L; Horan, Thomas A; Lee, Pamela W; West, Priscilla A


    This multimethod pilot study examined patient and practitioner perspectives on the influence of spatial barriers to healthcare access and the role of health information technology in overcoming these barriers. The study included a survey administered to patients attending a Department of Veterans Affairs (VA) health visit, and a focus group with VA care providers. Descriptive results and focus group findings are presented. Spatial distance is a significant factor for many rural veterans when seeking healthcare. For this sample of rural veterans, a range of telephone, computer, and Internet technologies may become more important for accessing care as Internet access becomes more ubiquitous and as younger veterans begin using the VA health system. The focus group highlighted the negative impact of distance, economic considerations, geographic barriers, and specific medical conditions on access to care. Lack of adequate technology infrastructure was seen as an obstacle to utilization. This study discusses the need to consider distance, travel modes, age, and information technology infrastructure and adoption when designing health information technology to care for rural patients.

  19. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. (United States)

    Romanski, Annette; Uherek, Christoph; Bug, Gesine; Seifried, Erhard; Klingemann, Hans; Wels, Winfried S; Ottmann, Oliver G; Tonn, Torsten


    Many B-cell acute and chronic leukaemias tend to be resistant to killing by natural killer (NK) cells. The introduction of chimeric antigen receptors (CAR) into T cells or NK cells could potentially overcome this resistance. Here, we extend our previous observations on the resistance of malignant lymphoblasts to NK-92 cells, a continuously growing NK cell line, showing that anti-CD19-CAR (αCD19-CAR) engineered NK-92 cells can regain significant cytotoxicity against CD19 positive leukaemic cell lines and primary leukaemia cells that are resistant to cytolytic activity of parental NK-92 cells. The 'first generation' CAR was generated from a scFv (CD19) antibody fragment, coupled to a flexible hinge region, the CD3ζ chain and a Myc-tag and cloned into a retrovirus backbone. No difference in cytotoxic activity of NK-92 and transduced αCD19-CAR NK-92 cells towards CD19 negative targets was found. However, αCD19-CAR NK-92 cells specifically and efficiently lysed CD19 expressing B-precursor leukaemia cell lines as well as lymphoblasts from leukaemia patients. Since NK-92 cells can be easily expanded to clinical grade numbers under current Good Manufactoring Practice (cGMP) conditions and its safety has been documented in several phase I clinical studies, treatment with CAR modified NK-92 should be considered a treatment option for patients with lymphoid malignancies.

  20. Overcoming Statistical Complexity: Selective Coordination of Three Different Metal Ions to a Ligand with Three Different Coordination Sites. (United States)

    Akine, Shigehisa; Matsumoto, Takashi; Nabeshima, Tatsuya


    In general, it is difficult to selectively introduce different metal ions at specific positions of a cluster-like structure. This is mainly due to statistical problems as well as the reversibility of the formation of coordination bonds. To overcome this statistical problem, we used a carefully designed ligand, H6 L, which can accommodate three different kinds of metal ions in three types of coordination sites. The complex [LNiZn2La](3+), which contains three different metals, was quantitatively obtained by a stepwise procedure, but different products were obtained when the metal ions were added in a different order. However, equilibration studies indicated that this complex was almost solely formed among 54 (=3×3×3H2) possible products upon heating; the formation efficiency (ca. 100%) was significantly higher than the statistical probability (2.47%). Such carefully designed ligands should be useful for the synthesis multimetallic systems, which are of interest because of the interplay between the different metals.