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Sample records for dual specific oncolytic

  1. Preclinical pharmacology and toxicology study of Ad-hTERT-E1a-Apoptin, a novel dual cancer-specific oncolytic adenovirus

    International Nuclear Information System (INIS)

    Qi, Yanxin; Guo, Huanhuan; Hu, Ningning; He, Dongyun; Zhang, Shi; Chu, Yunjie; Huang, Yubin; Li, Xiao; Sun, LiLi; Jin, Ningyi

    2014-01-01

    Clinical studies have demonstrated that conditionally replicating adenovirus is safe. We constructed an oncolytic adenovirus, Ad-hTERT-E1a-Apoptin, using a cancer-specific promoter (human telomerase reverse transcriptase promoter, hTERTp) and a cancer cell-selective apoptosis-inducing gene (Apoptin). Ad-hTERT-E1a-Apoptin was proven effective both in vitro and in vivo in our previous study. In this study, the preclinical safety profiles of Ad-hTERT-E1a-Apoptin in animal models were investigated. At doses of 5.0 × 10 8 , 2.5 × 10 9 , and 1.25 × 10 10 viral particles (VP)/kg, Ad-hTERT-E1a-Apoptin had no adverse effects on mouse behavior, muscle cooperation, sedative effect, digestive system, and nervous systems, or on beagle cardiovascular and respiratory systems at 5.0 × 10 8 , 2.5 × 10 9 , and 1.25 × 10 10 VP/kg doses. In acute toxicity tests in mice, the maximum tolerated dose > 5 × 10 10 VP/kg. There was no inflammation or ulceration at the injection sites within two weeks. In repeat-dose toxicological studies, the no observable adverse effect levels of Ad-hTERT-E1a-Apoptin in rats (1.25 × 10 10 VP/kg) and beagles (2.5 × 10 9 VP/kg) were 62.5- and 12.5-fold of the proposed clinical dose, respectively. The anti-virus antibody was produced in animal sera. Bone marrow examination revealed no histopathological changes. Guinea pigs sensitized by three repeated intraperitoneal injections of 1.35 × 10 10 VP/mL Ad-hTERT-E1a-Apoptin each and challenged by one intravenous injection of 1.67 × 10 8 VP/kg Ad-hTERT-E1a-Apoptin did not exhibit any sign of systemic anaphylaxis. Our data from different animal models suggest that Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. - Highlights: • We use the rodents and non-rodents animal models to evaluation Ad-hTERT-E1a-Apoptin. • Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. • Demonstrate the safety and feasibility dose of injected Ad-hTERT-E1a-Apoptin

  2. Preclinical pharmacology and toxicology study of Ad-hTERT-E1a-Apoptin, a novel dual cancer-specific oncolytic adenovirus

    Energy Technology Data Exchange (ETDEWEB)

    Qi, Yanxin [State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022 (China); Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); Guo, Huanhuan [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); Changchun Brother Biotech Co., Ltd., Changchun, 130000 (China); Hu, Ningning; He, Dongyun [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122 (China); Zhang, Shi [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); School of Clinical Medicine, Jilin University, Changchun 130001 (China); Chu, Yunjie [Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun 130021 (China); Huang, Yubin [State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022 (China); Li, Xiao, E-mail: lixiao06@mails.jlu.edu.cn [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122 (China); Sun, LiLi, E-mail: linjiaxiaoya@163.com [Department of Head and Neck Surgery, Tumor Hospital of Jilin Province, Changchun 130012 (China); Jin, Ningyi, E-mail: ningyij@126.com [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122 (China)

    2014-10-15

    Clinical studies have demonstrated that conditionally replicating adenovirus is safe. We constructed an oncolytic adenovirus, Ad-hTERT-E1a-Apoptin, using a cancer-specific promoter (human telomerase reverse transcriptase promoter, hTERTp) and a cancer cell-selective apoptosis-inducing gene (Apoptin). Ad-hTERT-E1a-Apoptin was proven effective both in vitro and in vivo in our previous study. In this study, the preclinical safety profiles of Ad-hTERT-E1a-Apoptin in animal models were investigated. At doses of 5.0 × 10{sup 8}, 2.5 × 10{sup 9}, and 1.25 × 10{sup 10} viral particles (VP)/kg, Ad-hTERT-E1a-Apoptin had no adverse effects on mouse behavior, muscle cooperation, sedative effect, digestive system, and nervous systems, or on beagle cardiovascular and respiratory systems at 5.0 × 10{sup 8}, 2.5 × 10{sup 9}, and 1.25 × 10{sup 10} VP/kg doses. In acute toxicity tests in mice, the maximum tolerated dose > 5 × 10{sup 10} VP/kg. There was no inflammation or ulceration at the injection sites within two weeks. In repeat-dose toxicological studies, the no observable adverse effect levels of Ad-hTERT-E1a-Apoptin in rats (1.25 × 10{sup 10} VP/kg) and beagles (2.5 × 10{sup 9} VP/kg) were 62.5- and 12.5-fold of the proposed clinical dose, respectively. The anti-virus antibody was produced in animal sera. Bone marrow examination revealed no histopathological changes. Guinea pigs sensitized by three repeated intraperitoneal injections of 1.35 × 10{sup 10} VP/mL Ad-hTERT-E1a-Apoptin each and challenged by one intravenous injection of 1.67 × 10{sup 8} VP/kg Ad-hTERT-E1a-Apoptin did not exhibit any sign of systemic anaphylaxis. Our data from different animal models suggest that Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. - Highlights: • We use the rodents and non-rodents animal models to evaluation Ad-hTERT-E1a-Apoptin. • Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. • Demonstrate the safety and feasibility dose of injected Ad

  3. Suppression of Oncolytic Adenovirus-Mediated Hepatotoxicity by Liver-Specific Inhibition of NF-κB

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    Mitsuhiro Machitani

    2017-12-01

    Full Text Available Telomerase-specific replication-competent adenoviruses (Ads, i.e., TRADs, which possess an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, are promising agents for cancer treatment. However, even though oncolytic Ads, including TRAD, are intratumorally administered, they are disseminated from the tumor to systemic circulation, causing concern about oncolytic Ad-mediated hepatotoxicity (due mainly to leaky expression of Ad genes in liver. We reported that inhibition of nuclear factor-κB (NF-κB leads to the suppression of replication-incompetent Ad vector-mediated hepatotoxicity via reduction of the leaky expression of Ad genes in liver. Here, to develop a TRAD with an improved safety profile, we designed a TRAD that carries a liver-specific promoter-driven dominant-negative IκBα (DNIκBα expression cassette (TRAD-DNIκBα. Compared with a conventional TRAD, TRAD-DNIκBα showed hepatocyte-specific inhibition of NF-κB signaling and significantly reduced Ad gene expression and replication in the normal human hepatocyte cell line. TRAD-induced hepatotoxicity was largely suppressed in mice following intravenous administration of TRAD-DNIκBα. However, the replication profiles and oncolytic activities of TRAD-DNIκBα were comparable with those of the conventional TRAD in human non-hepatic tumor cells. These results indicate that oncolytic Ads containing the liver-specific DNIκBα expression cassette have improved safety profiles without inhibiting oncolytic activities.

  4. A hypoxia- and {alpha}-fetoprotein-dependent oncolytic adenovirus exhibits specific killing of hepatocellular carcinomas.

    Science.gov (United States)

    Kwon, Oh-Joon; Kim, Pyung-Hwan; Huyn, Steven; Wu, Lily; Kim, Minjung; Yun, Chae-Ok

    2010-12-15

    Oncolytic adenoviruses (Ad) constitute a new promising modality of cancer gene therapy that displays improved efficacy over nonreplicating Ads. We have previously shown that an E1B 19-kDa-deleted oncolytic Ad exhibits a strong cell-killing effect but lacks tumor selectivity. To achieve hepatoma-restricted cytotoxicity and enhance replication of Ad within the context of tumor microenvironment, we used a modified human α-fetoprotein (hAFP) promoter to control the replication of Ad with a hypoxia response element (HRE). We constructed Ad-HRE(6)/hAFPΔ19 and Ad-HRE(12)/hAFPΔ19 that incorporated either 6 or 12 copies of HRE upstream of promoter. The promoter activity and specificity to hepatoma were examined by luciferase assay and fluorescence-activated cell sorting analysis. In addition, the AFP expression- and hypoxia-dependent in vitro cytotoxicity of Ad-HRE(6)/hAFPΔ19 and Ad-HRE(12)/hAFPΔ19 was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and cytopathic effect assay. In vivo tumoricidal activity on subcutaneous and liver orthotopic model was monitored by noninvasive molecular imaging. Ad-HRE(12)/hAFPΔ19 exhibited enhanced tumor selectivity and cell-killing activity when compared with Ad-hAFPΔ19. The tumoricidal activity of Ad-HRE(12)/hAFPΔ19 resulted in significant inhibition of tumor growth in both subcutaneous and orthotopic models. Histologic examination of the primary tumor after treatment confirmed accumulation of viral particles near hypoxic areas. Furthermore, Ad-HRE(12)/hAFPΔ19 did not cause severe inflammatory immune response and toxicity after systemic injection. The results presented here show the advantages of incorporating HREs into a hAFP promoter-driven oncolytic virus. This system is unique in that it acts in both a tissue-specific and tumor environment-selective manner. The greatly enhanced selectivity and tumoricidal activity of Ad-HRE(12)/hAFPΔ19 make it a promising therapeutic agent in the treatment

  5. Novel Infectivity-Enhanced Oncolytic Adenovirus with a Capsid-Incorporated Dual-Imaging Moiety for Monitoring Virotherapy in Ovarian Cancer

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    Kristopher J. Kimball

    2009-09-01

    Full Text Available We sought to develop a cancer-targeted, infectivity-enhanced oncolytic adenovirus that embodies a capsid-labeling fusion for non-invasive dual-modality imaging of ovarian cancer virotherapy. A functional fusion protein composed of fluorescent and nuclear imaging tags was genetically incorporated into the capsid of an infectivity-enhanced conditionally replicative adenovirus. Incorporation of herpes simplex virus thymidine kinase (HSV-tk and monomeric red fluorescent protein 1 (mRFP1 into the viral capsid and its genomic stability were verified by molecular analyses. Replication and oncolysis were evaluated in ovarian cancer cells. Fusion functionality was confirmed by in vitro gamma camera and fluorescent microscopy imaging. Comparison of tk-mRFP virus to single-modality controls revealed similar replication efficiency and oncolytic potency. Molecular fusion did not abolish enzymatic activity of HSV-tk as the virus effectively phosphorylated thymidine both ex vivo and in vitro. In vitro fluorescence imaging demonstrated a strong correlation between the intensity of fluorescent signal and cytopathic effect in infected ovarian cancer cells, suggesting that fluorescence can be used to monitor viral replication. We have in vitro validated a new infectivity-enhanced oncolytic adenovirus with a dual-imaging modality-labeled capsid, optimized for ovarian cancer virotherapy. The new agent could provide incremental gains toward climbing the barriers for achieving conditionally replicated adenovirus efficacy in human trials.

  6. Expression of RNA interference triggers from an oncolytic herpes simplex virus results in specific silencing in tumour cells in vitro and tumours in vivo

    International Nuclear Information System (INIS)

    Anesti, Anna-Maria; Simpson, Guy R; Price, Toby; Pandha, Hardev S; Coffin, Robert S

    2010-01-01

    Delivery of small interfering RNA (siRNA) to tumours remains a major obstacle for the development of RNA interference (RNAi)-based therapeutics. Following the promising pre-clinical and clinical results with the oncolytic herpes simplex virus (HSV) OncoVEX GM-CSF , we aimed to express RNAi triggers from oncolytic HSV, which although has the potential to improve treatment by silencing tumour-related genes, was not considered possible due to the highly oncolytic properties of HSV. To evaluate RNAi-mediated silencing from an oncolytic HSV backbone, we developed novel replicating HSV vectors expressing short-hairpin RNA (shRNA) or artificial microRNA (miRNA) against the reporter genes green fluorescent protein (eGFP) and β-galactosidase (lacZ). These vectors were tested in non-tumour cell lines in vitro and tumour cells that are moderately susceptible to HSV infection both in vitro and in mice xenografts in vivo. Silencing was assessed at the protein level by fluorescent microscopy, x-gal staining, enzyme activity assay, and western blotting. Our results demonstrate that it is possible to express shRNA and artificial miRNA from an oncolytic HSV backbone, which had not been previously investigated. Furthermore, oncolytic HSV-mediated delivery of RNAi triggers resulted in effective and specific silencing of targeted genes in tumour cells in vitro and tumours in vivo, with the viruses expressing artificial miRNA being comprehensibly more effective. This preliminary data provide the first demonstration of oncolytic HSV-mediated expression of shRNA or artificial miRNA and silencing of targeted genes in tumour cells in vitro and in vivo. The vectors developed in this study are being adapted to silence tumour-related genes in an ongoing study that aims to improve the effectiveness of oncolytic HSV treatment in tumours that are moderately susceptible to HSV infection and thus, potentially improve response rates seen in human clinical trials

  7. Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus

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    Sam Illingworth

    2017-06-01

    Full Text Available Enadenotucirev is an oncolytic group B adenovirus identified by a process of bio-selection for the ability to selectively propagate in and rapidly kill carcinoma cells. It is resistant to inactivation by human blood components, potentially enabling intravenous dosing in patients with metastatic cancer. However, there are no known permissive animal models described for group B adenoviruses that could facilitate a conventional approach to preclinical safety studies. In this manuscript, we describe our tailored preclinical strategy designed to evaluate the key biological properties of enadenotucirev. As enadenotucirev does not replicate in animal cells, a panel of primary human cells was used to evaluate enadenotucirev replication selectivity in vitro, demonstrating that virus genome levels were >100-fold lower in normal cells relative to tumor cells. Acute intravenous tolerability in mice was used to assess virus particle-mediated toxicology and effects on innate immunity. These studies showed that particle toxicity could be ameliorated by dose fractionation, using an initial dose of virus to condition the host such that cytokine responses to subsequent doses were significantly attenuated. This, in turn, supported the initiation of a phase I intravenous clinical trial with a starting dose of 1 × 1010 virus particles given on days 1, 3, and 5.

  8. Nanobody Based Dual Specific CARs

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    Stijn De Munter

    2018-01-01

    Full Text Available Recent clinical trials have shown that adoptive chimeric antigen receptor (CAR T cell therapy is a very potent and possibly curative option in the treatment of B cell leukemias and lymphomas. However, targeting a single antigen may not be sufficient, and relapse due to the emergence of antigen negative leukemic cells may occur. A potential strategy to counter the outgrowth of antigen escape variants is to broaden the specificity of the CAR by incorporation of multiple antigen recognition domains in tandem. As a proof of concept, we here describe a bispecific CAR in which the single chain variable fragment (scFv is replaced by a tandem of two single-antibody domains or nanobodies (nanoCAR. High membrane nanoCAR expression levels are observed in retrovirally transduced T cells. NanoCARs specific for CD20 and HER2 induce T cell activation, cytokine production and tumor lysis upon incubation with transgenic Jurkat cells expressing either antigen or both antigens simultaneously. The use of nanobody technology allows for the production of compact CARs with dual specificity and predefined affinity.

  9. Nanobody Based Dual Specific CARs.

    Science.gov (United States)

    De Munter, Stijn; Ingels, Joline; Goetgeluk, Glenn; Bonte, Sarah; Pille, Melissa; Weening, Karin; Kerre, Tessa; Abken, Hinrich; Vandekerckhove, Bart

    2018-01-30

    Recent clinical trials have shown that adoptive chimeric antigen receptor (CAR) T cell therapy is a very potent and possibly curative option in the treatment of B cell leukemias and lymphomas. However, targeting a single antigen may not be sufficient, and relapse due to the emergence of antigen negative leukemic cells may occur. A potential strategy to counter the outgrowth of antigen escape variants is to broaden the specificity of the CAR by incorporation of multiple antigen recognition domains in tandem. As a proof of concept, we here describe a bispecific CAR in which the single chain variable fragment (scFv) is replaced by a tandem of two single-antibody domains or nanobodies (nanoCAR). High membrane nanoCAR expression levels are observed in retrovirally transduced T cells. NanoCARs specific for CD20 and HER2 induce T cell activation, cytokine production and tumor lysis upon incubation with transgenic Jurkat cells expressing either antigen or both antigens simultaneously. The use of nanobody technology allows for the production of compact CARs with dual specificity and predefined affinity.

  10. The in vivo therapeutic efficacy of the oncolytic adenovirus Delta24-RGD is mediated by tumor-specific immunity.

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    Anne Kleijn

    Full Text Available The oncolytic adenovirus Delta24-RGD represents a new promising therapeutic agent for patients with a malignant glioma and is currently under investigation in clinical phase I/II trials. Earlier preclinical studies showed that Delta24-RGD is able to effectively lyse tumor cells, yielding promising results in various immune-deficient glioma models. However, the role of the immune response in oncolytic adenovirus therapy for glioma has never been explored. To this end, we assessed Delta24-RGD treatment in an immune-competent orthotopic mouse model for glioma and evaluated immune responses against tumor and virus. Delta24-RGD treatment led to long-term survival in 50% of mice and this effect was completely lost upon administration of the immunosuppressive agent dexamethasone. Delta24-RGD enhanced intra-tumoral infiltration of F4/80+ macrophages, CD4+ and CD8+ T-cells, and increased the local production of pro-inflammatory cytokines and chemokines. In treated mice, T cell responses were directed to the virus as well as to the tumor cells, which was reflected in the presence of protective immunological memory in mice that underwent tumor rechallenge. Together, these data provide evidence that the immune system plays a vital role in the therapeutic efficacy of oncolytic adenovirus therapy of glioma, and may provide angles to future improvements on Delta24-RGD therapy.

  11. Capitalizing on Cancer Specific Replication: Oncolytic Viruses as a Versatile Platform for the Enhancement of Cancer Immunotherapy Strategies

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    Donald Bastin

    2016-08-01

    Full Text Available The past decade has seen considerable excitement in the use of biological therapies in treating neoplastic disease. In particular, cancer immunotherapy and oncolytic virotherapy have emerged as two frontrunners in this regard with the first FDA approvals for agents in both categories being obtained in the last 5 years. It is becoming increasingly apparent that these two approaches are not mutually exclusive and that much of the therapeutic benefit obtained from the use of oncolytic viruses (OVs is in fact the result of their immunotherapeutic function. Indeed, OVs have been shown to recruit and activate an antitumor immune response and much of the current work in this field centers around increasing this activity through strategies such as engineering genes for immunomodulators into OV backbones. Because of their broad immunostimulatory functions, OVs can also be rationally combined with a variety of other immunotherapeutic approaches including cancer vaccination strategies, adoptive cell transfer and checkpoint blockade. Therefore, while they are important therapeutics in their own right, the true power of OVs may lie in their ability to enhance the effectiveness of a wide range of immunotherapies.

  12. Oncolytic viral therapy: targeting cancer stem cells

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    Smith TT

    2014-02-01

    Full Text Available Tyrel T Smith,1 Justin C Roth,1 Gregory K Friedman,1 G Yancey Gillespie2 1Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA Abstract: Cancer stem cells (CSCs are defined as rare populations of tumor-initiating cancer cells that are capable of both self-renewal and differentiation. Extensive research is currently underway to develop therapeutics that target CSCs for cancer therapy, due to their critical role in tumorigenesis, as well as their resistance to chemotherapy and radiotherapy. To this end, oncolytic viruses targeting unique CSC markers, signaling pathways, or the pro-tumor CSC niche offer promising potential as CSCs-destroying agents/therapeutics. We provide a summary of existing knowledge on the biology of CSCs, including their markers and their niche thought to comprise the tumor microenvironment, and then we provide a critical analysis of the potential for targeting CSCs with oncolytic viruses, including herpes simplex virus-1, adenovirus, measles virus, reovirus, and vaccinia virus. Specifically, we review current literature regarding first-generation oncolytic viruses with their innate ability to replicate in CSCs, as well as second-generation viruses engineered to enhance the oncolytic effect and CSC-targeting through transgene expression. Keywords: oncolytic virotherapy, cancer stem cell niche

  13. Oncolytic viruses for cancer therapy II. Cell-internal factors for conditional growth in neoplastic cells.

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    Campbell, Stephanie A; Gromeier, Matthias

    2005-04-01

    Recent advances in our understanding of virus-host interactions have fueled new studies in the field of oncolytic viruses. The first part of this review explained how cell-external factors, such as cellular receptors, influence tumor tropism and specificity of oncolytic virus candidates. In the second part of this review, we focus on cellinternal factors that mediate tumor-specific virus growth. An oncolytic virus must be able to replicate within cancerous cells and kill them without collateral damage to healthy surrounding cells. This desirable property is inherent to some proposed oncolytic viral agents or has been achieved by genetic manipulation in others.

  14. Molecular imaging of oncolytic viral therapy

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    Dana Haddad

    2014-01-01

    Full Text Available Oncolytic viruses have made their mark on the cancer world as a potential therapeutic option, with the possible advantages of reduced side effects and strengthened treatment efficacy due to higher tumor selectivity. Results have been so promising, that oncolytic viral treatments have now been approved for clinical trials in several countries. However, clinical studies may benefit from the ability to noninvasively and serially identify sites of viral targeting via molecular imaging in order to provide safety, efficacy, and toxicity information. Furthermore, molecular imaging of oncolytic viral therapy may provide a more sensitive and specific diagnostic technique to detect tumor origin and, more importantly, presence of metastases. Several strategies have been investigated for molecular imaging of viral replication broadly categorized into optical and deep tissue imaging, utilizing several reporter genes encoding for fluorescence proteins, conditional enzymes, and membrane protein and transporters. Various imaging methods facilitate molecular imaging, including computer tomography, magnetic resonance imaging, positron emission tomography, single photon emission CT, gamma-scintigraphy, and photoacoustic imaging. In addition, several molecular probes are used for medical imaging, which act as targeting moieties or signaling agents. This review will explore the preclinical and clinical use of in vivo molecular imaging of replication-competent oncolytic viral therapy.

  15. The impact of hypoxia on oncolytic virotherapy

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    Guo ZS

    2011-11-01

    Full Text Available Z Sheng GuoUniversity of Pittsburgh Cancer Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USAAbstract: The hypoxic tumor microenvironment plays significant roles in tumor cell metabolism and survival, tumor growth, and progression. Hypoxia modulates target genes in target cells mainly through an oxygen-sensing signaling pathway mediated by hypoxia-inducible factor of transcription factors. As a result, hypoxic tumor cells are resistant to conventional therapeutics such as radiation and chemotherapy. Oncolytic virotherapy may be a promising novel therapeutic for hypoxic cancer. Some oncolytic viruses are better adapted than others to the hypoxic tumor environment. Replication of adenoviruses from both groups B and C is inhibited, yet replication of herpes simplex virus is enhanced. Hypoxia seems to exert little or no effect on the replication of other oncolytic viruses. Vaccinia virus displayed increased cytotoxicity in some hypoxic cancer cells even though viral protein synthesis and transgene expression were not affected. Vesicular stomatitis virus replicated to similar levels in both hypoxic and normoxic conditions, and is effective for killing hypoxic cancer cells. However, vesicular stomatitis virus and reovirus, but not encephalomyocarditis virus, are sensitive to elevated levels of hypoxia-inducible factor-1α in renal cancer cells with the loss of von Hippel–Lindau tumor suppressor protein, because elevated hypoxia-inducible factor activity confers dramatically enhanced resistance to cytotoxicity mediated by vesicular stomatitis virus or reovirus. A variety of hypoxia-selective and tumor-type-specific oncolytic adenoviruses, generated by incorporating hypoxia-responsive elements into synthetic promoters to control essential genes for viral replication or therapeutic genes, have been shown to be safe and efficacious. Hypoxic tumor-homing macrophages can function effectively as carrier

  16. Oncolytic Herpes Simplex Virus Vectors Fully Retargeted to Tumor- Associated Antigens.

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    Uchida, Hiroaki; Hamada, Hirofumi; Nakano, Kenji; Kwon, Heechung; Tahara, Hideaki; Cohen, Justus B; Glorioso, Joseph C

    2018-01-01

    Oncolytic virotherapy is a novel therapeutic modality for malignant diseases that exploits selective viral replication in cancer cells. Herpes simplex virus (HSV) is a promising agent for oncolytic virotherapy due to its broad cell tropism and the identification of mutations that favor its replication in tumor over normal cells. However, these attenuating mutations also tend to limit the potency of current oncolytic HSV vectors that have entered clinical studies. As an alternative, vector retargeting to novel entry receptors has the potential to achieve tumor specificity at the stage of virus entry, eliminating the need for replication-attenuating mutations. Here, we summarize the molecular mechanism of HSV entry and recent advances in the development of fully retargeted HSV vectors for oncolytic virotherapy. Retargeted HSV vectors offer an attractive platform for the creation of a new generation of oncolytic HSV with improved efficacy and specificity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Oncolytic viruses: a step into cancer immunotherapy

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    Pol JG

    2011-12-01

    Full Text Available Jonathan G Pol, Julien Rességuier, Brian D LichtyMcMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, CanadaAbstract: Oncolytic virotherapy is currently under investigation in phase I–III clinical trials for approval as a new cancer treatment. Oncolytic viruses (OVs selectively infect, replicate in, and kill tumor cells. For a long time, the therapeutic efficacy was thought to depend on the direct viral oncolysis (virocentric view. The host immune system was considered as a brake that impaired virus delivery and spread. Attention was paid primarily to approaches enhancing virus tumor selectivity and cytotoxicity and/or that limited antiviral responses. Thinking has changed over the past few years with the discovery that OV therapy was also inducing indirect oncolysis mechanisms. Among them, induction of an antitumor immunity following OV injection appeared to be a key factor for an efficient therapeutic activity (immunocentric view. Indeed, tumor-specific immune cells persist post-therapy and can search and destroy any tumor cells that escape the OVs, and thus immune memory may prevent relapse of the disease. Various strategies, which are summarized in this manuscript, have been developed to enhance the efficacy of OV therapy with a focus on its immunotherapeutic aspects. These include genetic engineering and combination with existing cancer treatments. Several are currently being evaluated in human patients and already display promising efficacy.Keywords: oncolytic virus, cancer immunotherapy, tumor antigen, cancer vaccine, combination strategies

  18. Oncolytic viruses as anticancer vaccines

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    Norman eWoller

    2014-07-01

    Full Text Available Oncolytic virotherapy has shown impressive results in preclinical studies and first promising therapeutic outcomes in clinical trials as well. Since viruses are known for a long time as excellent vaccination agents, oncolytic viruses are now designed as novel anticancer agents combining the aspect of lysis-dependent cytoreductive activity with concomitant induction of antitumoral immune responses. Antitumoral immune activation by oncolytic virus infection of tumor tissue comprises both, immediate effects of innate immunity and also adaptive responses for long lasting antitumoral activity which is regarded as the most prominent challenge in clinical oncology. To date, the complex effects of a viral tumor infection on the tumor microenvironment and the consequences for the tumor-infiltrating immune cell compartment are poorly understood. However, there is more and more evidence that a tumor infection by an oncolytic virus opens up a number of options for further immunomodulating interventions such as systemic chemotherapy, generic immunostimulating strategies, dendritic cell-based vaccines, and antigenic libraries to further support clinical efficacy of oncolytic virotherapy.

  19. Oncolytic Adenovirus: Strategies and Insights for Vector Design and Immuno-Oncolytic Applications

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    Hanni Uusi-Kerttula

    2015-11-01

    Full Text Available Adenoviruses (Ad are commonly used both experimentally and clinically, including oncolytic virotherapy applications. In the clinical area, efficacy is frequently hampered by the high rates of neutralizing immunity, estimated as high as 90% in some populations that promote vector clearance and limit bioavailability for tumor targeting following systemic delivery. Active tumor targeting is also hampered by the ubiquitous nature of the Ad5 receptor, hCAR, as well as the lack of highly tumor-selective targeting ligands and suitable targeting strategies. Furthermore, significant off-target interactions between the viral vector and cellular and proteinaceous components of the bloodstream have been documented that promote uptake into non-target cells and determine dose-limiting toxicities. Novel strategies are therefore needed to overcome the obstacles that prevent efficacious Ad deployment for wider clinical applications. The use of less seroprevalent Ad serotypes, non-human serotypes, capsid pseudotyping, chemical shielding and genetic masking by heterologous peptide incorporation are all potential strategies to achieve efficient vector escape from humoral immune recognition. Conversely, selective vector arming with immunostimulatory agents can be utilized to enhance their oncolytic potential by activation of cancer-specific immune responses against the malignant tissues. This review presents recent advantages and pitfalls occurring in the field of adenoviral oncolytic therapies.

  20. Oncolytic Herpes Simplex Viral Therapy: A Stride toward Selective Targeting of Cancer Cells.

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    Sanchala, Dhaval S; Bhatt, Lokesh K; Prabhavalkar, Kedar S

    2017-01-01

    Oncolytic viral therapy, which makes use of replication-competent lytic viruses, has emerged as a promising modality to treat malignancies. It has shown meaningful outcomes in both solid tumor and hematologic malignancies. Advancements during the last decade, mainly genetic engineering of oncolytic viruses have resulted in improved specificity and efficacy of oncolytic viruses in cancer therapeutics. Oncolytic viral therapy for treating cancer with herpes simplex virus-1 has been of particular interest owing to its range of benefits like: (a) large genome and power to infiltrate in the tumor, (b) easy access to manipulation with the flexibility to insert multiple transgenes, (c) infecting majority of the malignant cell types with quick replication in the infected cells and (d) as Anti-HSV agent to terminate HSV replication. This review provides an exhaustive list of oncolytic herpes simplex virus-1 along with their genetic alterations. It also encompasses the major developments in oncolytic herpes simplex-1 viral therapy and outlines the limitations and drawbacks of oncolytic herpes simplex viral therapy.

  1. Oncolytic Adenoviruses in Cancer Treatment

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    Ramon Alemany

    2014-02-01

    Full Text Available The therapeutic use of viruses against cancer has been revived during the last two decades. Oncolytic viruses replicate and spread inside tumors, amplifying their cytotoxicity and simultaneously reversing the tumor immune suppression. Among different viruses, recombinant adenoviruses designed to replicate selectively in tumor cells have been clinically tested by intratumoral or systemic administration. Limited efficacy has been associated to poor tumor targeting, intratumoral spread, and virocentric immune responses. A deeper understanding of these three barriers will be required to design more effective oncolytic adenoviruses that, alone or combined with chemotherapy or immunotherapy, may become tools for oncologists.

  2. Current Immunotherapeutic Strategies to Enhance Oncolytic Virotherapy

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    Daniel E. Meyers

    2017-06-01

    Full Text Available Oncolytic viruses (OV represent a promising strategy to augment the spectrum of cancer therapeutics. For efficacy, they rely on two general mechanisms: tumor-specific infection/cell-killing, followed by subsequent activation of the host’s adaptive immune response. Numerous OV genera have been utilized in clinical trials, ultimately culminating in the 2015 Food and Drug Administration approval of a genetically engineered herpes virus, Talminogene laherparepvec (T-VEC. It is generally accepted that OV as monotherapy have only modest clinical efficacy. However, due to their ability to elicit specific antitumor immune responses, they are prime candidates to be paired with other immune-modulating strategies in order to optimize therapeutic efficacy. Synergistic strategies to enhance the efficacy of OV include augmenting the host antitumor response through the insertion of therapeutic transgenes such as GM-CSF, utilization of the prime-boost strategy, and combining OV with immune-modulatory drugs such as cyclophosphamide, sunitinib, and immune checkpoint inhibitors. This review provides an overview of these immune-based strategies to improve the clinical efficacy of oncolytic virotherapy.

  3. Designing herpes viruses as oncolytics

    Directory of Open Access Journals (Sweden)

    Cole Peters

    Full Text Available Oncolytic herpes simplex virus (oHSV was one of the first genetically-engineered oncolytic viruses. Because HSV is a natural human pathogen that can cause serious disease, it is incumbent that it can be genetically-engineered or significantly attenuated for safety. Here, we present a detailed explanation of the functions of HSV-1 genes frequently mutated to endow oncolytic activity. These genes are nonessential for growth in tissue culture cells but are important for growth in postmitotic cells, interfering with intrinsic antiviral and innate immune responses or causing pathology, functions dispensable for replication in cancer cells. Understanding the function of these genes leads to informed creation of new oHSVs with better therapeutic efficacy. Virus infection and replication can also be directed to cancer cells through tumor-selective receptor binding and transcriptional- or post-transcriptional miRNA-targeting, respectively. In addition to the direct effects of oHSV on infected cancer cells and tumors, oHSV can be “armed” with transgenes that are: reporters, to track virus replication and spread; cytotoxic, to kill uninfected tumor cells; immune modulatory, to stimulate antitumor immunity; or tumor microenvironment altering, to enhance virus spread or to inhibit tumor growth. In addition to HSV-1, other alphaherpesviruses are also discussed for their oncolytic activity.

  4. Designing herpes viruses as oncolytics

    Science.gov (United States)

    Peters, Cole; Rabkin, Samuel D

    2015-01-01

    Oncolytic herpes simplex virus (oHSV) was one of the first genetically-engineered oncolytic viruses. Because HSV is a natural human pathogen that can cause serious disease, it is incumbent that it can be genetically-engineered or significantly attenuated for safety. Here, we present a detailed explanation of the functions of HSV-1 genes frequently mutated to endow oncolytic activity. These genes are nonessential for growth in tissue culture cells but are important for growth in postmitotic cells, interfering with intrinsic antiviral and innate immune responses or causing pathology, functions dispensable for replication in cancer cells. Understanding the function of these genes leads to informed creation of new oHSVs with better therapeutic efficacy. Virus infection and replication can also be directed to cancer cells through tumor-selective receptor binding and transcriptional- or post-transcriptional miRNA-targeting, respectively. In addition to the direct effects of oHSV on infected cancer cells and tumors, oHSV can be “armed” with transgenes that are: reporters, to track virus replication and spread; cytotoxic, to kill uninfected tumor cells; immune modulatory, to stimulate antitumor immunity; or tumor microenvironment altering, to enhance virus spread or to inhibit tumor growth. In addition to HSV-1, other alphaherpesviruses are also discussed for their oncolytic activity. PMID:26462293

  5. Oncolytic effects of a novel influenza A virus expressing interleukin-15 from the NS reading frame.

    Directory of Open Access Journals (Sweden)

    Marijke van Rikxoort

    Full Text Available Oncolytic influenza A viruses with deleted NS1 gene (delNS1 replicate selectively in tumour cells with defective interferon response and/or activated Ras/Raf/MEK/ERK signalling pathway. To develop a delNS1 virus with specific immunostimulatory properties, we used an optimised technology to insert the interleukin-15 (IL-15 coding sequence into the viral NS gene segment (delNS1-IL-15. DelNS1 and delNS1-IL-15 exerted similar oncolytic effects. Both viruses replicated and caused caspase-dependent apoptosis in interferon-defective melanoma cells. Virus replication was required for their oncolytic activity. Cisplatin enhanced the oncolytic activity of delNS1 viruses. The cytotoxic drug increased delNS1 replication and delNS1-induced caspase-dependent apoptosis. Interference with MEK/ERK signalling by RNAi-mediated depletion or the MEK inhibitor U0126 did not affect the oncolytic effects of the delNS1 viruses. In oncolysis sensitive melanoma cells, delNS1-IL-15 (but not delNS1 infection resulted in the production of IL-15 levels ranging from 70 to 1140 pg/mL in the cell culture supernatants. The supernatants of delNS1-IL-15-infected (but not of delNS1-infected melanoma cells induced primary human natural killer cell-mediated lysis of non-infected tumour cells. In conclusion, we constructed a novel oncolytic influenza virus that combines the oncolytic activity of delNS1 viruses with immunostimulatory properties through production of functional IL-15. Moreover, we showed that the oncolytic activity of delNS1 viruses can be enhanced in combination with cytotoxic anti-cancer drugs.

  6. Measles to the Rescue: A Review of Oncolytic Measles Virus

    Directory of Open Access Journals (Sweden)

    Sarah Aref

    2016-10-01

    Full Text Available Oncolytic virotherapeutic agents are likely to become serious contenders in cancer treatment. The vaccine strain of measles virus is an agent with an impressive range of oncolytic activity in pre-clinical trials with increasing evidence of safety and efficacy in early clinical trials. This paramyxovirus vaccine has a proven safety record and is amenable to careful genetic modification in the laboratory. Overexpression of the measles virus (MV receptor CD46 in many tumour cells may direct the virus to preferentially enter transformed cells and there is increasing awareness of the importance of nectin-4 and signaling lymphocytic activation molecule (SLAM in oncolysis. Successful attempts to retarget MV by inserting genes for tumour-specific ligands to antigens such as carcinoembryonic antigen (CEA, CD20, CD38, and by engineering the virus to express synthetic microRNA targeting sequences, and “blinding” the virus to the natural viral receptors are exciting measures to increase viral specificity and enhance the oncolytic effect. Sodium iodine symporter (NIS can also be expressed by MV, which enables in vivo tracking of MV infection. Radiovirotherapy using MV-NIS, chemo-virotherapy to convert prodrugs to their toxic metabolites, and immune-virotherapy including incorporating antibodies against immune checkpoint inhibitors can also increase the oncolytic potential. Anti-viral host immune responses are a recognized barrier to the success of MV, and approaches such as transporting MV to the tumour sites by carrier cells, are showing promise. MV Clinical trials are producing encouraging preliminary results in ovarian cancer, myeloma and cutaneous non-Hodgkin lymphoma, and the outcome of currently open trials in glioblastoma multiforme, mesothelioma and squamous cell carcinoma are eagerly anticipated.

  7. The specificity of learned parallelism in dual-memory retrieval.

    Science.gov (United States)

    Strobach, Tilo; Schubert, Torsten; Pashler, Harold; Rickard, Timothy

    2014-05-01

    Retrieval of two responses from one visually presented cue occurs sequentially at the outset of dual-retrieval practice. Exclusively for subjects who adopt a mode of grouping (i.e., synchronizing) their response execution, however, reaction times after dual-retrieval practice indicate a shift to learned retrieval parallelism (e.g., Nino & Rickard, in Journal of Experimental Psychology: Learning, Memory, and Cognition, 29, 373-388, 2003). In the present study, we investigated how this learned parallelism is achieved and why it appears to occur only for subjects who group their responses. Two main accounts were considered: a task-level versus a cue-level account. The task-level account assumes that learned retrieval parallelism occurs at the level of the task as a whole and is not limited to practiced cues. Grouping response execution may thus promote a general shift to parallel retrieval following practice. The cue-level account states that learned retrieval parallelism is specific to practiced cues. This type of parallelism may result from cue-specific response chunking that occurs uniquely as a consequence of grouped response execution. The results of two experiments favored the second account and were best interpreted in terms of a structural bottleneck model.

  8. Advances in the design and development of oncolytic measles viruses

    Directory of Open Access Journals (Sweden)

    Hutzen B

    2015-08-01

    Full Text Available Brian Hutzen,1 Corey Raffel,2 Adam W Studebaker1 1Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA; 2Department of Neurological Surgery and Pediatrics, University of California, San Francisco, San Francisco, CA, USA Abstract: A successful oncolytic virus is one that selectively propagates and destroys cancerous tissue without causing excessive damage to the normal surrounding tissue. Oncolytic measles virus (MV is one such virus that exhibits this characteristic and thus has rapidly emerged as a potentially useful anticancer modality. Derivatives of the Edmonston MV vaccine strain possess a remarkable safety record in humans. Promising results in preclinical animal models and evidence of biological activity in early phase trials contribute to the enthusiasm. Genetic modifications have enabled MV to evolve from a vaccine agent to a potential anticancer therapy. Specifically, alterations of the MV genome have led to improved tumor selectivity and delivery, therapeutic potency, and immune system modulation. In this article, we will review the advancements that have been made in the design and development of MV that have led to its use as a cancer therapy. In addition, we will discuss the evidence supporting its use, as well as the challenges associated with MV as a potential cancer therapeutic. Keywords: virotherapy, measles virus, oncolytic therapy

  9. Chemotherapy and Oncolytic Virotherapy: Advanced Tactics in the War against Cancer

    Directory of Open Access Journals (Sweden)

    Andrew eNguyen

    2014-06-01

    Full Text Available Cancer is a traitorous archenemy that threatens our survival. Its ability to evade detection and adapt to various cancer therapies means that it is a moving target that becomes increasingly difficult to attack. Through technological advancements we have developed sophisticated weapons to fight off tumor growth and invasion. However, if we are to stand a chance in this war against cancer, advanced tactics will be required to maximize the use of our available resources. Oncolytic viruses are multi-functional cancer-fighters that can be engineered to suit many different strategies; in particular, their retooling can facilitate increased capacity for direct tumor killing (oncolytic virotherapy and elicit adaptive antitumor immune responses (oncolytic immunotherapy. However, administration of these modified oncolytic viruses alone, rarely induces successful regression of established tumors. This may be attributed to host antiviral immunity that acts to eliminate viral particles, as well as the capacity for tumors to adapt to therapeutic selective pressure. It has been shown that various chemotherapeutic drugs with distinct functional properties can potentiate the antitumor efficacy of oncolytic viruses. In this review, we summarize the chemotherapeutic combinatorial strategies used to optimize virally-induced destruction of tumors. With a particular focus on pharmaceutical immunomodulators, we discuss how specific therapeutic contexts may alter the effects of these synergistic combinations and their implications for future clinical use.

  10. Oncolytic viruses in head and neck cancer: a new ray of hope in the ...

    African Journals Online (AJOL)

    This paper intends to highlight the different types of oncolytic viruses (OVs), mechanism of tumor specificity, its safety, and various obstacles in the design of treatment and combination therapy utilizing oncotherapy. Search was conducted using the internet‑based search engines and scholarly bibliographic databases with ...

  11. Comparison of Liver Detargeting Strategies for Systemic Therapy with Oncolytic Adenovirus Serotype 5

    Directory of Open Access Journals (Sweden)

    Tien V. Nguyen

    2017-08-01

    Full Text Available Oncolytic viruses would ideally be of use for systemic therapy to treat disseminated cancer. To do this safely, this may require multiple layers of cancer specificity. The pharmacology and specificity of oncolytic adenoviruses can be modified by (1 physical retargeting, (2 physical detargeting, (3 chemical shielding, or (4 by modifying the ability of viral early gene products to selectively activate in cancer versus normal cells. We explored the utility of these approaches with oncolytic adenovirus serotype 5 (Ad5 in immunocompetent Syrian hamsters bearing subcutaneous HaK tumors. After a single intravenous injection to reach the distant tumors, the physically hepatocyte-detargeted virus Ad5-hexon-BAP was more effective than conditionally replicating Ad5-dl1101/07 with mutations in its E1A protein. When these control or Ad5 treated animals were treated a second time by intratumoral injection, prior exposure to Ad5 did not affect tumor growth, suggesting that anti-Ad immunity neither prevented treatment nor amplified anti-tumor immune responses. Ad5-dl1101/07 was next chemically shielded with polyethylene glycol (PEG. While 5 kDa of PEG blunted pro-inflammatory IL-6 production induced by Ad5-dl1101/07, this shielding reduced Ad oncolytic activity.

  12. ONCOLYTIC VIRUS-MEDIATED REVERSAL OF IMPAIRED TUMOR ANTIGEN PRESENTATION

    Directory of Open Access Journals (Sweden)

    Shashi Ashok Gujar

    2014-04-01

    Full Text Available Anti-tumor immunity can eliminate existing cancer cells and also maintain a constant surveillance against possible relapse. Such an antigen-specific adaptive response begins when tumor-specific T cells become activated. T cell activation requires two signals on antigen presenting cells (APCs: antigen presentation through MHC molecules and co-stimulation. In the absence of one or both of these signals, T cells remain inactivated or can even become tolerized. Cancer cells and their associated microenvironment strategically hinder the processing and presentation of tumor antigens and consequently prevent the development of anti-tumor immunity. Many studies, however, demonstrate that interventions that overturn tumor-associated immune evasion mechanisms can establish anti-tumor immune responses of therapeutic potential. One such intervention is oncolytic virus (OV-based anti-cancer therapy. Here we discuss how OV-induced immunological events override tumor-associated antigen presentation impairment and promote appropriate T cell:APC interaction. Detailed understanding of this phenomenon is pivotal for devising the strategies that will enhance the efficacy of OV-based anti-cancer therapy by complementing its inherent oncolytic

  13. Differential biodistribution of oncolytic poxvirus administered systemically in an autochthonous model of hepatocellular carcinoma.

    Science.gov (United States)

    Baril, Patrick; Touchefeu, Yann; Cany, Jeannette; Cherel, Yan; Thorne, Steve H; Tran, Lucile; Conchon, Sophie; Vassaux, Georges

    2011-12-01

    Preclinical studies have demonstrated that, unlike oncolytic adenoviruses, oncolytic vaccinia viruses can reach implanted tumors upon systemic injection. However, the biodistribution of this oncolytic agent in in situ autochthonous tumor models remains poorly characterized. In the present study, we assessed this biodistribution in a model of mouse hepatocellular carcinoma (HCC) obtained after injection of the carcinogen diethylnitrosamine (DEN). Twelve months after DEN administration, histology, quantitative reverse transcription-polymerase chain reaction, in situ hybridization and viral titration were used to characterize tumors, as well as to assess the viral load of the livers upon either intravenous or intraperitoineal injection. The results obtained showed that the architecture of the liver was lost, with a noticeable absence of sinusoids, as well as the presence of steatosis and α-fetoprotein-positive HCC tumor nodules. Bioluminescence imaging and measures of the infective virus load demonstrated that intravenous injection of 10(8)  plaque-forming units of the recombinant vaccinia virus led to a predominant transduction of the liver, whereas intraperitoneal injection resulted in a lower level of liver transduction accompanied by an increased infection of the lungs, spleen, kidneys and bowels. Immunohistochemical analysis of liver sections of animals injected intravenously with the virus revealed a preferential localization of vaccinia-specific immunoreactivity in the tumors. The findings of the present study emphasize the importance of the route of administration of the vector and highlight the relevance of systemic injection of oncolytic vaccinia virus in the context of hepatocellular carcinoma. Copyright © 2011 John Wiley & Sons, Ltd.

  14. Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy.

    Science.gov (United States)

    Allan, Kristina J; Mahoney, Douglas J; Baird, Stephen D; Lefebvre, Charles A; Stojdl, David F

    2018-04-03

    High-throughput genome-wide RNAi (RNA interference) screening technology has been widely used for discovering host factors that impact virus replication. Here we present the application of this technology to uncovering host targets that specifically modulate the replication of Maraba virus, an oncolytic rhabdovirus, and vaccinia virus with the goal of enhancing therapy. While the protocol has been tested for use with oncolytic Maraba virus and oncolytic vaccinia virus, this approach is applicable to other oncolytic viruses and can also be utilized for identifying host targets that modulate virus replication in mammalian cells in general. This protocol describes the development and validation of an assay for high-throughput RNAi screening in mammalian cells, the key considerations and preparation steps important for conducting a primary high-throughput RNAi screen, and a step-by-step guide for conducting a primary high-throughput RNAi screen; in addition, it broadly outlines the methods for conducting secondary screen validation and tertiary validation studies. The benefit of high-throughput RNAi screening is that it allows one to catalogue, in an extensive and unbiased fashion, host factors that modulate any aspect of virus replication for which one can develop an in vitro assay such as infectivity, burst size, and cytotoxicity. It has the power to uncover biotherapeutic targets unforeseen based on current knowledge.

  15. DMPD: DUSP meet immunology: dual specificity MAPK phosphatases in control of theinflammatory response. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17114416 DUSP meet immunology: dual specificity MAPK phosphatases in control of the...ml) (.csml) Show DUSP meet immunology: dual specificity MAPK phosphatases in control of theinflammatory resp...onse. PubmedID 17114416 Title DUSP meet immunology: dual specificity MAPK phospha

  16. A VAR2CSA:CSP conjugate capable of inducing dual specificity ...

    African Journals Online (AJOL)

    Background: Vaccine antigens targeting specific P. falciparum parasite stages are under pre-clinical ... against individual antigen components in a dual stage anti-malaria vaccine. ..... (D8428, Sigma Aldrich) was prepared in Dulbecco's PBS.

  17. Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics.

    Science.gov (United States)

    Cai, Jing; Lin, Yuan; Zhang, Haipeng; Liang, Jiankai; Tan, Yaqian; Cavenee, Webster K; Yan, Guangmei

    2017-06-27

    Oncolytic virotherapy is a treatment modality that uses native or genetically modified viruses that selectively replicate in and kill tumor cells. Viruses represent a type of pathogen-associated molecular pattern and thereby induce the up-regulation of dozens of cytokines via activating the host innate immune system. Second mitochondria-derived activator of caspases (Smac) mimetic compounds (SMCs), which antagonize the function of inhibitor of apoptosis proteins (IAPs) and induce apoptosis, sensitize tumor cells to multiple cytokines. Therefore, we sought to determine whether SMCs sensitize tumor cells to cytokines induced by the oncolytic M1 virus, thus enhancing a bystander killing effect. Here, we report that SMCs potentiate the oncolytic effect of M1 in vitro, in vivo, and ex vivo. This strengthened oncolytic efficacy resulted from the enhanced bystander killing effect caused by the M1 virus via cytokine induction. Through a microarray analysis and subsequent validation using recombinant cytokines, we identified IL-8, IL-1A, and TRAIL as the key cytokines in the bystander killing effect. Furthermore, SMCs increased the replication of M1, and the accumulation of virus protein induced irreversible endoplasmic reticulum stress- and c-Jun N-terminal kinase-mediated apoptosis. Nevertheless, the combined treatment with M1 and SMCs had little effect on normal and human primary cells. Because SMCs selectively and significantly enhance the bystander killing effect and the replication of oncolytic virus M1 specifically in cancer cells, this combined treatment may represent a promising therapeutic strategy.

  18. Oncolytic virotherapy in upper gastrointestinal tract cancers

    Directory of Open Access Journals (Sweden)

    Yokoda R

    2018-03-01

    Full Text Available Raquel Yokoda,1 Bolni M Nagalo,1 Mansi Arora,1 Jan B Egan,1 James M Bogenberger,1 Thomas T DeLeon,1 Yumei Zhou,1 Daniel H Ahn,1 Mitesh J Borad1–3 1Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, 2Department of Molecular Medicine, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 3Department of Oncology, Mayo Clinic Cancer Center, Phoenix, AZ, USA Abstract: Upper gastrointestinal tract malignancies are among the most challenging cancers with regard to response to treatment and prognosis. Cancers of the esophagus, stomach, pancreas, liver, and biliary tree have dismal 5-year survival, and very modest improvements in this rate have been made in recent times. Oncolytic viruses are being developed to address these malignancies, with a focus on high safety profiles and low off-target toxicities. Each viral platform has evolved to enhance oncolytic potency and the clinical response to either single-agent viral therapy or combined viral treatment with radiotherapy and chemotherapy. A panel of genomic alterations, chimeric proteins, and pseudotyped capsids are the breakthroughs for vector success. This article revisits developments for each viral platform to each tumor type, in an attempt to achieve maximum tumor selectivity. From the bench to clinical trials, the scope of this review is to highlight the beginnings of translational oncolytic virotherapy research in upper gastrointestinal tract malignancies and provide a bioengineering perspective of the most promising platforms. Keywords: oncolytic viruses, hepatopancreatobiliary, gastric cancer, pancreatic cancer, liver cancer, biliary cancer

  19. Oncolytic Viruses-Interaction of Virus and Tumor Cells in the Battle to Eliminate Cancer.

    Science.gov (United States)

    Howells, Anwen; Marelli, Giulia; Lemoine, Nicholas R; Wang, Yaohe

    2017-01-01

    Oncolytic viruses (OVs) are an emerging treatment option for many cancer types and have recently been the focus of extensive research aiming to develop their therapeutic potential. The ultimate aim is to design a virus which can effectively replicate within the host, specifically target and lyse tumor cells and induce robust, long lasting tumor-specific immunity. There are a number of viruses which are either naturally tumor-selective or can be modified to specifically target and eliminate tumor cells. This means they are able to infect only tumor cells and healthy tissue remains unharmed. This specificity is imperative in order to reduce the side effects of oncolytic virotherapy. These viruses can also be modified by various methods including insertion and deletion of specific genes with the aim of improving their efficacy and safety profiles. In this review, we have provided an overview of the various virus species currently being investigated for their oncolytic potential and the positive and negative effects of a multitude of modifications used to increase their infectivity, anti-tumor immunity, and treatment safety, in particular focusing on the interaction of tumor cells and OVs.

  20. Patient-derived mesenchymal stem cells as delivery vehicles for oncolytic virotherapy: novel state-of-the-art technology

    Directory of Open Access Journals (Sweden)

    Ramírez M

    2015-10-01

    Full Text Available Manuel Ramírez,1 Javier García-Castro,2 Gustavo J Melen,1 África González-Murillo,1 Lidia Franco-Luzón1 1Oncohematología, Hospital Universitario Niño Jesús, 2Unidad de Biotecnología Celular, Instituto de Salud Carlos III, Madrid, Spain Abstract: Oncolytic virotherapy is gaining interest in the clinic as a new weapon against cancer. In vivo administration of oncolytic viruses showed important limitations that decrease their effectiveness very significantly: the antiviral immune response causes the elimination of the therapeutic effect, and the poor natural ability of oncolytic viruses to infect micrometastatic lesions significantly minimizes the effective dose of virus. This review will focus on updating the technical and scientific foundations of one of the strategies developed to overcome these limitations, ie, using cells as vehicles for oncolytic viruses. Among many candidates, a special type of adult stem cell, mesenchymal stem cells (MSCs, have already been used in the clinic as cell vehicles for oncolytic viruses, partly due to the fact that these cells are actively being evaluated for other indications. MSC carrier cells are used as Trojan horses loaded with oncoviruses, are administered systemically, and release their cargos at the right places. MSCs are equipped with an array of molecules involved in cell arrest in the capillaries (integrins and selectins, migration toward specific parenchymal locations within tissues (chemokine receptors, and invasion and degradation of the extracellular matrix (proteases. In addition to anatomical targeting capacity, MSCs have a well-recognized role in modulating immune responses by affecting cells of the innate (antigen-presenting cells, natural killer cells and adaptive immune system (effector and regulatory lymphocytes. Therefore, carrier MSCs may also modulate the immune responses taking place after therapy, ie, the antiviral and the antitumor immune responses. Keywords: virotherapy

  1. A VAR2CSA:CSP conjugate capable of inducing dual specificity ...

    African Journals Online (AJOL)

    Background: Vaccine antigens targeting specific P. falciparum parasite stages are under pre-clinical and clinical development. It seems plausible that vaccine with multiple specificities will offer higher protection. With this hypothesis, we exploited the Spy- Tag/SpyCatcher conjugation system to make a, post expression, dual ...

  2. Showing the Way: Oncolytic Adenoviruses as Chaperones of Immunostimulatory Adjuncts

    Directory of Open Access Journals (Sweden)

    Jing Li Huang

    2016-09-01

    Full Text Available Oncolytic adenoviruses (OAds are increasingly recognized as vectors for immunotherapy in the treatment of various solid tumors. The myriads of advantages of using adenovirus include targeted specificity upon infection and selective replication, which lead to localized viral burst, exponential spread of OAds, and antitumor effect. OAds can also induce a strong immune reaction due to the massive release of tumor antigens upon cytolysis and the presence of viral antigens. This review will highlight recent advances in adenoviral vectors expressing immunostimulatory effectors, such as GM-CSF (granulocyte macrophage colony-stimulating factor, interferon-α, interleukin-12, and CD40L. We will also discuss the combination of OAds with other immunotherapeutic strategies and describe the current understanding of how adenoviral vectors interact with the immune system to eliminate cancer cells.

  3. Showing the Way: Oncolytic Adenoviruses as Chaperones of Immunostimulatory Adjuncts.

    Science.gov (United States)

    Huang, Jing Li; LaRocca, Christopher J; Yamamoto, Masato

    2016-09-19

    Oncolytic adenoviruses (OAds) are increasingly recognized as vectors for immunotherapy in the treatment of various solid tumors. The myriads of advantages of using adenovirus include targeted specificity upon infection and selective replication, which lead to localized viral burst, exponential spread of OAds, and antitumor effect. OAds can also induce a strong immune reaction due to the massive release of tumor antigens upon cytolysis and the presence of viral antigens. This review will highlight recent advances in adenoviral vectors expressing immunostimulatory effectors, such as GM-CSF (granulocyte macrophage colony-stimulating factor), interferon-α, interleukin-12, and CD40L. We will also discuss the combination of OAds with other immunotherapeutic strategies and describe the current understanding of how adenoviral vectors interact with the immune system to eliminate cancer cells.

  4. High-throughput screening to enhance oncolytic virus immunotherapy

    Directory of Open Access Journals (Sweden)

    Allan KJ

    2016-04-01

    Full Text Available KJ Allan,1,2 David F Stojdl,1–3 SL Swift1 1Children’s Hospital of Eastern Ontario (CHEO Research Institute, 2Department of Biology, Microbiology and Immunology, 3Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada Abstract: High-throughput screens can rapidly scan and capture large amounts of information across multiple biological parameters. Although many screens have been designed to uncover potential new therapeutic targets capable of crippling viruses that cause disease, there have been relatively few directed at improving the efficacy of viruses that are used to treat disease. Oncolytic viruses (OVs are biotherapeutic agents with an inherent specificity for treating malignant disease. Certain OV platforms – including those based on herpes simplex virus, reovirus, and vaccinia virus – have shown success against solid tumors in advanced clinical trials. Yet, many of these OVs have only undergone minimal engineering to solidify tumor specificity, with few extra modifications to manipulate additional factors. Several aspects of the interaction between an OV and a tumor-bearing host have clear value as targets to improve therapeutic outcomes. At the virus level, these include delivery to the tumor, infectivity, productivity, oncolysis, bystander killing, spread, and persistence. At the host level, these include engaging the immune system and manipulating the tumor microenvironment. Here, we review the chemical- and genome-based high-throughput screens that have been performed to manipulate such parameters during OV infection and analyze their impact on therapeutic efficacy. We further explore emerging themes that represent key areas of focus for future research. Keywords: oncolytic, virus, screen, high-throughput, cancer, chemical, genomic, immunotherapy

  5. Dual host specificity of phage SP6 is facilitated by tailspike rotation

    Energy Technology Data Exchange (ETDEWEB)

    Tu, Jiagang [Department of Pathology and Laboratory Medicine, McGovern Medical School at UTHealth, Houston, TX 77030 (United States); Park, Taehyun [Center for Infectious Disease, Department of Molecular Biosciences, Institute for Cell and Molecular Biology, University of Texas at Austin, Austin, TX 78712 (United States); Morado, Dustin R. [Department of Pathology and Laboratory Medicine, McGovern Medical School at UTHealth, Houston, TX 77030 (United States); Hughes, Kelly T. [Department of Biology, University of Utah, Salt Lake City, UT 84112 (United States); Molineux, Ian J., E-mail: molineux@austin.utexas.edu [Center for Infectious Disease, Department of Molecular Biosciences, Institute for Cell and Molecular Biology, University of Texas at Austin, Austin, TX 78712 (United States); Liu, Jun, E-mail: Jun.Liu.1@uth.tmc.edu [Department of Pathology and Laboratory Medicine, McGovern Medical School at UTHealth, Houston, TX 77030 (United States)

    2017-07-15

    Bacteriophage SP6 exhibits dual-host adsorption specificity. The SP6 tailspikes are recognized as important in host range determination but the mechanisms underlying dual host specificity are unknown. Cryo-electron tomography and sub-tomogram classification were used to analyze the SP6 virion with a particular focus on the interaction of tailspikes with host membranes. The SP6 tail is surrounded by six V-shaped structures that interconnect in forming a hand-over-hand hexameric garland. Each V-shaped structure consists of two trimeric tailspike proteins: gp46 and gp47, connected through the adaptor protein gp37. SP6 infection of Salmonella enterica serovars Typhimurium and Newport results in distinguishable changes in tailspike orientation, providing the first direct demonstration how tailspikes can confer dual host adsorption specificity. SP6 also infects S. Typhimurium strains lacking O antigen; in these infections tailspikes have no apparent specific role and the phage tail must therefore interact with a distinct host receptor to allow infection. - Highlights: •Cryo-electron tomography reveals the structural basis for dual host specificity. •Sub-tomogram classification reveals distinct orientations of the tailspikes during infection of different hosts. •Tailspike-adaptor modules rotate as they bind different O antigens. •In the absence of any O antigen, tailspikes bind weakly and without specificity to LPS. •Interaction of the phage tail with LPS is essential for infection.

  6. Oncolytic virus delivery: from nano-pharmacodynamics to enhanced oncolytic effect

    Directory of Open Access Journals (Sweden)

    Yokoda R

    2017-11-01

    Full Text Available Raquel Yokoda,1 Bolni M Nagalo,1 Brent Vernon,2 Rahmi Oklu,3 Hassan Albadawi,3 Thomas T DeLeon,1 Yumei Zhou,1 Jan B Egan,1 Dan G Duda,4 Mitesh J Borad1 1Division of Hematology Oncology, Department of Medicine, Mayo Clinic, Scottsdale, 2Department of Biomedical Engineering, Arizona State University, Tempe, 3Division of Vascular and Interventional Radiology, Department of Radiology, Mayo Clinic, Scottsdale, AZ, 4Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA Abstract: With the advancement of a growing number of oncolytic viruses (OVs to clinical development, drug delivery is becoming an important barrier to overcome for optimal therapeutic benefits. Host immunity, tumor microenvironment and abnormal vascularity contribute to inefficient vector delivery. A number of novel approaches for enhanced OV delivery are under evaluation, including use of nanoparticles, immunomodulatory agents and complex viral–particle ligands along with manipulations of the tumor microenvironment. This field of OV delivery has quickly evolved to bioengineering of complex nanoparticles that could be deposited within the tumor using minimal invasive image-guided delivery. Some of the strategies include ultrasound (US-mediated cavitation-enhanced extravasation, magnetic viral complexes delivery, image-guided infusions with focused US and targeting photodynamic virotherapy. In addition, strategies that modulate tumor microenvironment to decrease extracellular matrix deposition and increase viral propagation are being used to improve tumor penetration by OVs. Some involve modification of the viral genome to enhance their tumoral penetration potential. Here, we highlight the barriers to oncolytic viral delivery, and discuss the challenges to improving it and the perspectives of establishing new modes of active delivery to achieve enhanced oncolytic effects. Keywords: oncolytic viruses, oncolytic virotherapy, drug delivery systems, tumor

  7. uPAR-controlled oncolytic adenoviruses eliminate cancer stem cells in human pancreatic tumors.

    Science.gov (United States)

    Sobrevals, Luciano; Mato-Berciano, Ana; Urtasun, Nerea; Mazo, Adela; Fillat, Cristina

    2014-01-01

    Pancreatic tumors contain cancer stem cells highly resistant to chemotherapy. The identification of therapies that can eliminate this population of cells might provide with more effective treatments. In the current work we evaluated the potential of oncolytic adenoviruses to act against pancreatic cancer stem cells (PCSC). PCSC from two patient-derived xenograft models were isolated from orthotopic pancreatic tumors treated with saline, or with the chemotherapeutic agent gemcitabine. An enrichment in the number of PCSC expressing the cell surface marker CD133 and a marked enhancement on tumorsphere formation was observed in gemcitabine treated tumors. No significant increase in the CD44, CD24, and epithelial-specific antigen (ESA) positive cells was observed. Neoplastic sphere-forming cells were susceptible to adenoviral infection and exposure to oncolytic adenoviruses resulted in elevated cytotoxicity with both Adwt and the tumor specific AduPARE1A adenovirus. In vivo, intravenous administration of a single dose of AduPARE1A in human-derived pancreatic xenografts led to a remarkable anti-tumor effect. In contrast to gemcitabine AduPARE1A treatment did not result in PCSC enrichment. No enrichment on tumorspheres neither on the CD133(+) population was detected. Therefore our data provide evidences of the relevance of uPAR-controlled oncolytic adenoviruses for the elimination of pancreatic cancer stem cells. © 2013.

  8. Therapeutic potential of oncolytic Newcastle disease virus: a critical review.

    Science.gov (United States)

    Tayeb, Shay; Zakay-Rones, Zichria; Panet, Amos

    2015-01-01

    Newcastle disease virus (NDV) features a natural preference for replication in many tumor cells compared with normal cells. The observed antitumor effect of NDV appears to be a result of both selective killing of tumor cells and induction of immune responses. Genetic manipulations to change viral tropism and arming the virus with genes encoding for cytokines improved the oncolytic capacity of NDV. Several intracellular proteins in tumor cells, including antiapoptotic proteins (Livin) and oncogenic proteins (H-Ras), are relevant for the oncolytic activity of NDV. Defects in the interferon system, found in some tumor cells, also contribute to the oncolytic selectivity of NDV. Notwithstanding, NDV displays effective oncolytic activity in many tumor types, despite having intact interferon signaling. Taken together, several cellular systems appear to dictate the selective oncolytic activity of NDV. Some barriers, such as neutralizing antibodies elicited during NDV treatment and the extracellular matrix in tumor tissue appear to interfere with spread of NDV and reduce oncolysis. To further understand the oncolytic activity of NDV, we compared two NDV strains, ie, an attenuated virus (NDV-HUJ) and a pathogenic virus (NDV-MTH-68/H). Significant differences in amino acid sequence were noted in several viral proteins, including the fusion precursor (F0) glycoprotein, an important determinant of replication and pathogenicity. However, no difference in the oncolytic activity of the two strains was noted using human tumor tissues maintained as organ cultures or in mouse tumor models. To optimize virotherapy in clinical trials, we describe here a unique organ culture methodology, using a biopsy taken from a patient's tumor before treatment for ex vivo infection with NDV to determine the oncolytic potential on an individual basis. In conclusion, oncolytic NDV is an excellent candidate for cancer therapy, but more knowledge is needed to ensure success in clinical trials.

  9. High voltage and high specific capacity dual intercalating electrode Li-ion batteries

    Science.gov (United States)

    West, William C. (Inventor); Blanco, Mario (Inventor)

    2010-01-01

    The present invention provides high capacity and high voltage Li-ion batteries that have a carbonaceous cathode and a nonaqueous electrolyte solution comprising LiF salt and an anion receptor that binds the fluoride ion. The batteries can comprise dual intercalating electrode Li ion batteries. Methods of the present invention use a cathode and electrode pair, wherein each of the electrodes reversibly intercalate ions provided by a LiF salt to make a high voltage and high specific capacity dual intercalating electrode Li-ion battery. The present methods and systems provide high-capacity batteries particularly useful in powering devices where minimizing battery mass is important.

  10. Arabidopsis Yak1 protein (AtYak1) is a dual specificity protein kinase

    KAUST Repository

    Kim, Dongjin; Ntui, Valentine Otang; Zhang, Nianshu; Xiong, Liming

    2015-01-01

    Yak1 is a member of dual-specificity Tyr phosphorylation-regulated kinases (DYRKs) that are evolutionarily conserved. The downstream targets of Yak1 and their functions are largely unknown. Here, a homologous protein AtYAK1 was identified in Arabidopsis thaliana and the phosphoprotein profiles of the wild type and an atyak1 mutant were compared on two-dimensional gel following Pro-Q Diamond phosphoprotein gel staining. Annexin1, Annexin2 and RBD were phosphorylated at serine/ threonine residues by the AtYak1 kinase. Annexin1, Annexin2 and Annexin4 were also phosphorylated at tyrosine residues. Our study demonstrated that AtYak1 is a dual specificity protein kinase in Arabidopsis that may regulate the phosphorylation status of the annexin family proteins.

  11. Arabidopsis Yak1 protein (AtYak1) is a dual specificity protein kinase

    KAUST Repository

    Kim, Dongjin

    2015-10-09

    Yak1 is a member of dual-specificity Tyr phosphorylation-regulated kinases (DYRKs) that are evolutionarily conserved. The downstream targets of Yak1 and their functions are largely unknown. Here, a homologous protein AtYAK1 was identified in Arabidopsis thaliana and the phosphoprotein profiles of the wild type and an atyak1 mutant were compared on two-dimensional gel following Pro-Q Diamond phosphoprotein gel staining. Annexin1, Annexin2 and RBD were phosphorylated at serine/ threonine residues by the AtYak1 kinase. Annexin1, Annexin2 and Annexin4 were also phosphorylated at tyrosine residues. Our study demonstrated that AtYak1 is a dual specificity protein kinase in Arabidopsis that may regulate the phosphorylation status of the annexin family proteins.

  12. A Dual-Specific Targeting Approach Based on the Simultaneous Recognition of Duplex and Quadruplex Motifs.

    Science.gov (United States)

    Nguyen, Thi Quynh Ngoc; Lim, Kah Wai; Phan, Anh Tuân

    2017-09-20

    Small-molecule ligands targeting nucleic acids have been explored as potential therapeutic agents. Duplex groove-binding ligands have been shown to recognize DNA in a sequence-specific manner. On the other hand, quadruplex-binding ligands exhibit high selectivity between quadruplex and duplex, but show limited discrimination between different quadruplex structures. Here we propose a dual-specific approach through the simultaneous application of duplex- and quadruplex-binders. We demonstrated that a quadruplex-specific ligand and a duplex-specific ligand can simultaneously interact at two separate binding sites of a quadruplex-duplex hybrid harbouring both quadruplex and duplex structural elements. Such a dual-specific targeting strategy would combine the sequence specificity of duplex-binders and the strong binding affinity of quadruplex-binders, potentially allowing the specific targeting of unique quadruplex structures. Future research can be directed towards the development of conjugated compounds targeting specific genomic quadruplex-duplex sites, for which the linker would be highly context-dependent in terms of length and flexibility, as well as the attachment points onto both ligands.

  13. Selectivity and Efficiency of Late Transgene Expression by Transcriptionally Targeted Oncolytic Adenoviruses Are Dependent on the Transgene Insertion Strategy

    OpenAIRE

    Quirin, Christina; Rohmer, Stanimira; Fernández-Ulibarri, Inés; Behr, Michael; Hesse, Andrea; Engelhardt, Sarah; Erbs, Philippe; Enk, Alexander H.; Nettelbeck, Dirk M.

    2010-01-01

    Key challenges facing cancer therapy are the development of tumor-specific drugs and potent multimodal regimens. Oncolytic adenoviruses possess the potential to realize both aims by restricting virus replication to tumors and inserting therapeutic genes into the virus genome, respectively. A major effort in this regard is to express transgenes in a tumor-specific manner without affecting virus replication. Using both luciferase as a sensitive reporter and genetic prodrug activation, we show t...

  14. Oncolytic vaccinia therapy of squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Yu Yong A

    2009-07-01

    Full Text Available Abstract Background Novel therapies are necessary to improve outcomes for patients with squamous cell carcinomas (SCC of the head and neck. Historically, vaccinia virus was administered widely to humans as a vaccine and led to the eradication of smallpox. We examined the therapeutic effects of an attenuated, replication-competent vaccinia virus (GLV-1h68 as an oncolytic agent against a panel of six human head and neck SCC cell lines. Results All six cell lines supported viral transgene expression (β-galactosidase, green fluorescent protein, and luciferase as early as 6 hours after viral exposure. Efficient transgene expression and viral replication (>150-fold titer increase over 72 hrs were observed in four of the cell lines. At a multiplicity of infection (MOI of 1, GLV-1h68 was highly cytotoxic to the four cell lines, resulting in ≥ 90% cytotoxicity over 6 days, and the remaining two cell lines exhibited >45% cytotoxicity. Even at a very low MOI of 0.01, three cell lines still demonstrated >60% cell death over 6 days. A single injection of GLV-1h68 (5 × 106 pfu intratumorally into MSKQLL2 xenografts in mice exhibited localized intratumoral luciferase activity peaking at days 2–4, with gradual resolution over 10 days and no evidence of spread to normal organs. Treated animals exhibited near-complete tumor regression over a 24-day period without any observed toxicity, while control animals demonstrated rapid tumor progression. Conclusion These results demonstrate significant oncolytic efficacy by an attenuated vaccinia virus for infecting and lysing head and neck SCC both in vitro and in vivo, and support its continued investigation in future clinical trials.

  15. A dual-specificity isoform of the protein kinase inhibitor PKI produced by alternate gene splicing.

    Science.gov (United States)

    Kumar, Priyadarsini; Walsh, Donal A

    2002-03-15

    We have previously shown that the protein kinase inhibitor beta (PKIbeta) form of the cAMP-dependent protein kinase inhibitor exists in multiple isoforms, some of which are specific inhibitors of the cAMP-dependent protein kinase, whereas others also inhibit the cGMP-dependent enzyme [Kumar, Van Patten and Walsh (1997), J. Biol. Chem. 272, 20011-20020]. We have now demonstrated that the switch from a cAMP-dependent protein kinase (PKA)-specific inhibitor to one with dual specificity arises as a consequence of alternate gene splicing. We have confirmed using bacterially produced pure protein that a single inhibitor species has dual specificity for both PKA and cGMP-dependent protein kinase (PKG), inhibiting each with very high and closely similar inhibitory potencies. The gene splicing converted a protein with 70 amino acids into one of 109 amino acids, and did not change the inhibitory potency to PKA, but changed it from a protein that had no detectable PKG inhibitory activity to one that now inhibited PKG in the nanomolar range.

  16. A low specific on-resistance SOI MOSFET with dual gates and a recessed drain

    International Nuclear Information System (INIS)

    Luo Xiao-Rong; Hu Gang-Yi; Zhang Zheng-Yuan; Luo Yin-Chun; Fan Ye; Wang Xiao-Wei; Fan Yuan-Hang; Cai Jin-Yong; Wang Pei; Zhou Kun

    2013-01-01

    A low specific on-resistance (R on,sp ) integrable silicon-on-insulator (SOI) metal-oxide semiconductor field-effect transistor (MOSFET) is proposed and investigated by simulation. The MOSFET features a recessed drain as well as dual gates, which consist of a planar gate and a trench gate extended to the buried oxide layer (BOX) (DGRD MOSFET). First, the dual gates form dual conduction channels, and the extended trench gate also acts as a field plate to improve the electric field distribution. Second, the combination of the trench gate and the recessed drain widens the vertical conduction area and shortens the current path. Third, the P-type top layer not only enhances the drift doping concentration but also modulates the surface electric field distributions. All of these sharply reduce R on,sp and maintain a high breakdown voltage (BV). The BV of 233 V and R on,sp of 4.151 mΩ·cm 2 (V GS = 15 V) are obtained for the DGRD MOSFET with 15-μm half-cell pitch. Compared with the trench gate SOI MOSFET and the conventional MOSFET, R on,sp of the DGRD MOSFET decreases by 36% and 33% with the same BV, respectively. The trench gate extended to the BOX synchronously acts as a dielectric isolation trench, simplifying the fabrication processes. (condensed matter: electronic structure, electrical, magnetic, and optical properties)

  17. Promising oncolytic agents for metastatic breast cancer treatment

    Directory of Open Access Journals (Sweden)

    Cody JJ

    2015-06-01

    Full Text Available James J Cody,1 Douglas R Hurst2 1ImQuest BioSciences, Frederick, MD, 2Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA Abstract: New therapies for metastatic breast cancer patients are urgently needed. The long-term survival rates remain unacceptably low for patients with recurrent disease or disseminated metastases. In addition, existing therapies often cause a variety of debilitating side effects that severely impact quality of life. Oncolytic viruses constitute a developing therapeutic modality in which interest continues to build due to their ability to spare normal tissue while selectively destroying tumor cells. A number of different viruses have been used to develop oncolytic agents for breast cancer, including herpes simplex virus, adenovirus, vaccinia virus, measles virus, reovirus, and others. In general, clinical trials for several cancers have demonstrated excellent safety records and evidence of efficacy. However, the impressive tumor responses often observed in preclinical studies have yet to be realized in the clinic. In order for the promise of oncolytic virotherapy to be fully realized for breast cancer patients, effectiveness must be demonstrated in metastatic disease. This review provides a summary of oncolytic virotherapy strategies being developed to target metastatic breast cancer. Keywords: oncolytic virus, virotherapy, breast cancer, metastasis 

  18. Inhibitory effect of Survivin promoter-regulated oncolytic adenovirus carrying P53 gene against gallbladder cancer.

    Science.gov (United States)

    Liu, Chen; Sun, Bin; An, Ni; Tan, Weifeng; Cao, Lu; Luo, Xiangji; Yu, Yong; Feng, Feiling; Li, Bin; Wu, Mengchao; Su, Changqing; Jiang, Xiaoqing

    2011-12-01

    Gene therapy has become an important strategy for treatment of malignancies, but problems remains concerning the low gene transferring efficiency, poor transgene expression and limited targeting specific tumors, which have greatly hampered the clinical application of tumor gene therapy. Gallbladder cancer is characterized by rapid progress, poor prognosis, and aberrantly high expression of Survivin. In the present study, we used a human tumor-specific Survivin promoter-regulated oncolytic adenovirus vector carrying P53 gene, whose anti-cancer effect has been widely confirmed, to construct a wide spectrum, specific, safe, effective gene-viral therapy system, AdSurp-P53. Examining expression of enhanced green fluorecent protein (EGFP), E1A and the target gene P53 in the oncolytic adenovirus system validated that Survivin promoter-regulated oncolytic adenovirus had high proliferation activity and high P53 expression in Survivin-positive gallbladder cancer cells. Our in vitro cytotoxicity experiment demonstrated that AdSurp-P53 possessed a stronger cytotoxic effect against gallbladder cancer cells and hepatic cancer cells. The survival rate of EH-GB1 cells was lower than 40% after infection of AdSurp-P53 at multiplicity of infection (MOI) = 1 pfu/cell, while the rate was higher than 90% after infection of Ad-P53 at the same MOI, demonstrating that AdSurp-P53 has a potent cytotoxicity against EH-GB1 cells. The tumor growth was greatly inhibited in nude mice bearing EH-GB1 xenografts when the total dose of AdSurp-P53 was 1 × 10(9) pfu, and terminal dUTP nick end-labeling (TUNEL) revealed that the apoptotic rate of cancer cells was (33.4 ± 8.4)%. This oncolytic adenovirus system overcomes the long-standing shortcomings of gene therapy: poor transgene expression and targeting of only specific tumors, with its therapeutic effect better than the traditional Ad-P53 therapy regimen already on market; our system might be used for patients with advanced gallbladder cancer and

  19. RET Functions as a Dual-Specificity Kinase that Requires Allosteric Inputs from Juxtamembrane Elements

    Directory of Open Access Journals (Sweden)

    Iván Plaza-Menacho

    2016-12-01

    Full Text Available Receptor tyrosine kinases exhibit a variety of activation mechanisms despite highly homologous catalytic domains. Such diversity arises through coupling of extracellular ligand-binding portions with highly variable intracellular sequences flanking the tyrosine kinase domain and specific patterns of autophosphorylation sites. Here, we show that the juxtamembrane (JM segment enhances RET catalytic domain activity through Y687. This phospho-site is also required by the JM region to rescue an otherwise catalytically deficient RET activation-loop mutant lacking tyrosines. Structure-function analyses identified interactions between the JM hinge, αC helix, and an unconventional activation-loop serine phosphorylation site that engages the HRD motif and promotes phospho-tyrosine conformational accessibility and regulatory spine assembly. We demonstrate that this phospho-S909 arises from an intrinsic RET dual-specificity kinase activity and show that an equivalent serine is required for RET signaling in Drosophila. Our findings reveal dual-specificity and allosteric components for the mechanism of RET activation and signaling with direct implications for drug discovery.

  20. MicroRNA-mediated suppression of oncolytic adenovirus replication in human liver.

    Directory of Open Access Journals (Sweden)

    Erkko Ylösmäki

    Full Text Available MicroRNAs (miRNAs are important and ubiquitous regulators of gene expression that can suppress their target genes by translational inhibition as well as mRNA destruction. Cell type-specific miRNA expression patterns have been successfully exploited for targeting the expression of experimental and therapeutic gene constructs, for example to reduce pathogenic effects of cancer virotherapy in normal tissues. In order to avoid liver damage associated with systemic or intrahepatic delivery of oncolytic adenoviruses we have introduced the concept of suppressing adenovirus replication in hepatic cells by inserting target elements for the liver-specific miR122 into the viral genome. Here we show using ex vivo cultured tissue specimens that six perfectly complementary miR122 target sites in the 3' untranslated region of the viral E1A gene are sufficient in the absence of any other genetic modifications to prevent productive replication of serotype 5 adenovirus (Ad5 in normal human liver. This modification did not compromise the replicative capacity of the modified virus in cancer tissue derived from a colon carcinoma liver metastasis or its oncolytic potency in a human lung cancer xenograft mouse model. Unlike wild-type Ad5, the modified virus did not result in increased serum levels of liver enzymes in infected mice. These results provide a strong preclinical proof of concept for the use of miR122 target sites for reducing the risk of liver damage caused by oncolytic adenoviruses, and suggest that ectopic miR122 target elements should be considered as an additional safety measure included in any therapeutic virus or viral vector posing potential hazard to the liver.

  1. Oncolytic Sendai virus-based virotherapy for cancer: recent advances

    Directory of Open Access Journals (Sweden)

    Saga K

    2015-10-01

    Full Text Available Kotaro Saga, Yasufumi Kaneda Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka, Japan Abstract: Many drugs have been developed and optimized for the treatment of cancer; however, it is difficult to completely cure cancer with anticancer drugs alone. Therefore, the development of new therapeutic technologies, in addition to new anticancer drugs, is necessary for more effective oncotherapy. Oncolytic viruses are one potential new anticancer strategy. Various oncolytic viruses have been developed for safe and effective oncotherapy. Recently, Sendai virus-based oncotherapy has been reported by several groups, and attention has been drawn to its unique anticancer mechanisms, which are different from those of the conventional oncolytic viruses that kill cancer cells by cancer cell-selective replication. Here, we introduce Sendai virus-based virotherapy and its anticancer mechanisms. Keywords: HVJ-E, cancer therapy, apoptosis, necroptosis, anticancer immunity 

  2. Tumor-Associated Macrophages in Oncolytic Virotherapy: Friend or Foe?

    Directory of Open Access Journals (Sweden)

    Nicholas L. Denton

    2016-07-01

    Full Text Available Cancer therapy remains a challenge due to toxicity limitations of chemotherapy and radiation therapy. Oncolytic viruses that selectively replicate and destroy cancer cells are of increasing interest. In addition to direct cell lysis, these vectors stimulate an anti-tumor immune response. A key regulator of tumor immunity is the tumor-associated macrophage population. Macrophages can either support oncolytic virus therapy through pro-inflammatory stimulation of the anti-tumor response at the cost of hindering direct oncolysis or through immunosuppressive protection of virus replication at the cost of hindering the anti-tumor immune response. Despite similarities in macrophage interaction between adult and pediatric tumors and the abundance of research supporting macrophage modulation in adult tumors, there are few studies investigating macrophage modulation in pediatric cancers or modulation of immunotherapy. We review the current state of knowledge regarding macrophages in cancers and their influence on oncolytic virotherapy.

  3. Enhanced lysis by bispecific oncolytic measles viruses simultaneously using HER2/neu or EpCAM as target receptors

    Directory of Open Access Journals (Sweden)

    Jan RH Hanauer

    2016-01-01

    Full Text Available To target oncolytic measles viruses (MV to tumors, we exploit the binding specificity of designed ankyrin repeat proteins (DARPins. These DARPin-MVs have high tumor selectivity while maintaining excellent oncolytic potency. Stability, small size, and efficacy of DARPins allowed the generation of MVs simultaneously targeted to tumor marker HER2/neu and cancer stem cell (CSC marker EpCAM. For optimization, the linker connecting both DARPins was varied in flexibility and length. Flexibility had no impact on fusion helper activity whereas length had. MVs with bispecific MV-H are genetically stable and revealed the desired double-target specificity. In vitro, the cytolytic activity of bispecific MVs was superior or comparable to mono-targeted viruses depending on the target cells. In vivo, therapeutic efficacy of the bispecific viruses was validated in an orthotopic ovarian carcinoma model revealing an effective reduction of tumor mass. Finally, the power of bispecific targeting was demonstrated on cocultures of different tumor cells thereby mimicking tumor heterogeneity in vitro, more closely reflecting real tumors. Here, bispecific excelled monospecific viruses in efficacy. DARPin-based targeting domains thus allow the generation of efficacious oncolytic viruses with double specificity, with the potential to handle intratumoral variation of antigen expression and to simultaneously target CSCs and the bulk tumor mass.

  4. Moving oncolytic viruses into the clinic: clinical-grade production, purification, and characterization of diverse oncolytic viruses

    Directory of Open Access Journals (Sweden)

    Guy Ungerechts

    2016-01-01

    Full Text Available Oncolytic viruses (OVs are unique anticancer agents based on their pleotropic modes of action, which include, besides viral tumor cell lysis, activation of antitumor immunity. A panel of diverse viruses, often genetically engineered, has advanced to clinical investigation, including phase 3 studies. This diversity of virotherapeutics not only offers interesting opportunities for the implementation of different therapeutic regimens but also poses challenges for clinical translation. Thus, manufacturing processes and regulatory approval paths need to be established for each OV individually. This review provides an overview of clinical-grade manufacturing procedures for OVs using six virus families as examples, and key challenges are discussed individually. For example, different virus features with respect to particle size, presence/absence of an envelope, and host species imply specific requirements for measures to ensure sterility, for handling, and for determination of appropriate animal models for toxicity testing, respectively. On the other hand, optimization of serum-free culture conditions, increasing virus yields, development of scalable purification strategies, and formulations guaranteeing long-term stability are challenges common to several if not all OVs. In light of the recent marketing approval of the first OV in the Western world, strategies for further upscaling OV manufacturing and optimizing product characterization will receive increasing attention.

  5. Moving oncolytic viruses into the clinic: clinical-grade production, purification, and characterization of diverse oncolytic viruses.

    Science.gov (United States)

    Ungerechts, Guy; Bossow, Sascha; Leuchs, Barbara; Holm, Per S; Rommelaere, Jean; Coffey, Matt; Coffin, Rob; Bell, John; Nettelbeck, Dirk M

    2016-01-01

    Oncolytic viruses (OVs) are unique anticancer agents based on their pleotropic modes of action, which include, besides viral tumor cell lysis, activation of antitumor immunity. A panel of diverse viruses, often genetically engineered, has advanced to clinical investigation, including phase 3 studies. This diversity of virotherapeutics not only offers interesting opportunities for the implementation of different therapeutic regimens but also poses challenges for clinical translation. Thus, manufacturing processes and regulatory approval paths need to be established for each OV individually. This review provides an overview of clinical-grade manufacturing procedures for OVs using six virus families as examples, and key challenges are discussed individually. For example, different virus features with respect to particle size, presence/absence of an envelope, and host species imply specific requirements for measures to ensure sterility, for handling, and for determination of appropriate animal models for toxicity testing, respectively. On the other hand, optimization of serum-free culture conditions, increasing virus yields, development of scalable purification strategies, and formulations guaranteeing long-term stability are challenges common to several if not all OVs. In light of the recent marketing approval of the first OV in the Western world, strategies for further upscaling OV manufacturing and optimizing product characterization will receive increasing attention.

  6. Oncolytic Viruses: Therapeutics With an Identity Crisis

    Directory of Open Access Journals (Sweden)

    Caroline J. Breitbach

    2016-07-01

    Full Text Available Oncolytic viruses (OV are replicating viral therapeutics for the treatment of cancer and have been in laboratory development for about twenty years. Recently, the FDA approved Imlygic, a herpes virus based therapeutic for the treatment of melanoma and thus OVs have entered a new era where they are a weapon in the armament of the oncologist. OVs are unique therapeutics with multiple mechanisms of therapeutic activity. The exact path for their development and eventual uptake by pharmaceutical companies is somewhat clouded by an uncertain identity. Are they vaccines, tumour lysing therapeutics, inducers of innate immunity, gene therapy vectors, anti-vascular agents or all of the above? Should they be developed as stand-alone loco-regional therapeutics, systemically delivered tumour hunters or immune modulators best tested as combination therapeutics? We summarize data here supporting the idea, depending upon the virus, that OVs can be any or all of these things. Pursuing a “one-size fits all” approach is counter-productive to their clinical development and instead as a field we should build on the strengths of individual virus platforms.

  7. Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery.

    Science.gov (United States)

    Cheng, Ru; Meng, Fenghua; Deng, Chao; Klok, Harm-Anton; Zhong, Zhiyuan

    2013-05-01

    In the past decades, polymeric nanoparticles have emerged as a most promising and viable technology platform for targeted and controlled drug delivery. As vehicles, ideal nanoparticles are obliged to possess high drug loading levels, deliver drug to the specific pathological site and/or target cells without drug leakage on the way, while rapidly unload drug at the site of action. To this end, various "intelligent" polymeric nanoparticles that release drugs in response to an internal or external stimulus such as pH, redox, temperature, magnetic and light have been actively pursued. These stimuli-responsive nanoparticles have demonstrated, though to varying degrees, improved in vitro and/or in vivo drug release profiles. In an effort to further improve drug release performances, novel dual and multi-stimuli responsive polymeric nanoparticles that respond to a combination of two or more signals such as pH/temperature, pH/redox, pH/magnetic field, temperature/reduction, double pH, pH and diols, temperature/magnetic field, temperature/enzyme, temperature/pH/redox, temperature/pH/magnetic, pH/redox/magnetic, temperature/redox/guest molecules, and temperature/pH/guest molecules have recently been developed. Notably, these combined responses take place either simultaneously at the pathological site or in a sequential manner from nanoparticle preparation, nanoparticle transporting pathways, to cellular compartments. These dual and multi-stimuli responsive polymeric nanoparticles have shown unprecedented control over drug delivery and release leading to superior in vitro and/or in vivo anti-cancer efficacy. With programmed site-specific drug delivery feature, dual and multi-stimuli responsive nanoparticulate drug formulations have tremendous potential for targeted cancer therapy. In this review paper, we highlight the recent exciting developments in dual and multi-stimuli responsive polymeric nanoparticles for precision drug delivery applications, with a particular focus

  8. IL-12 Expressing oncolytic herpes simplex virus promotes anti-tumor activity and immunologic control of metastatic ovarian cancer in mice.

    Science.gov (United States)

    Thomas, Eric D; Meza-Perez, Selene; Bevis, Kerri S; Randall, Troy D; Gillespie, G Yancey; Langford, Catherine; Alvarez, Ronald D

    2016-10-27

    Despite advances in surgical aggressiveness and conventional chemotherapy, ovarian cancer remains the most lethal cause of gynecologic cancer mortality; consequently there is a need for new therapeutic agents and innovative treatment paradigms for the treatment of ovarian cancer. Several studies have demonstrated that ovarian cancer is an immunogenic disease and immunotherapy represents a promising and novel approach that has not been completely evaluated in ovarian cancer. Our objective was to evaluate the anti-tumor activity of an oncolytic herpes simplex virus "armed" with murine interleukin-12 and its ability to elicit tumor-specific immune responses. We evaluated the ability of interleukin-12-expressing and control oncolytic herpes simplex virus to kill murine and human ovarian cancer cell lines in vitro. We also administered interleukin-12-expressing oncolytic herpes simplex virus to the peritoneal cavity of mice that had developed spontaneous, metastatic ovarian cancer and determined overall survival and tumor burden at 95 days. We used flow cytometry to quantify the tumor antigen-specific CD8 + T cell response in the omentum and peritoneal cavity. All ovarian cancer cell lines demonstrated susceptibility to oncolytic herpes simplex virus in vitro. Compared to controls, mice treated with interleukin-12-expressing oncolytic herpes simplex virus demonstrated a more robust tumor antigen-specific CD8 + T-cell immune response in the omentum (471.6 cells vs 33.1 cells; p = 0.02) and peritoneal cavity (962.3 cells vs 179.5 cells; p = 0.05). Compared to controls, mice treated with interleukin-12-expressing oncolytic herpes simplex virus were more likely to control ovarian cancer metastases (81.2 % vs 18.2 %; p = 0.008) and had a significantly longer overall survival (p = 0.02). Finally, five of 6 mice treated with interleukin-12-expressing oHSV had no evidence of metastatic tumor when euthanized at 6 months, compared to two of 4 mice treated with

  9. Use of dual-point fluorodeoxyglucose imaging to enhance sensitivity and specificity.

    Science.gov (United States)

    Schillaci, Orazio

    2012-07-01

    Positron emission tomography (PET) and positron emission tomography/computed tomography imaging with fluorodeoxyglucose (FDG) are widely used as a powerful evaluation modality in oncological nuclear medicine not only for detecting tumors but also for staging and for therapy monitoring. Nevertheless, there are numerous causes of FDG uptake in benign processes seen on PET images. In fact, the degree of FDG uptake is related to the cellular metabolic rate and the number of glucose transporters. FDG accumulation in tumors is due, in part, to an increased number of glucose transporters in malignant cells. However, FDG is not specific for neoplasms: a similar situation exists in inflammation; activated inflammatory cells demonstrate increased expression of glucose transporters. Therefore, there is growing interest in improving the specificity of FDG-PET in patients with cancer. Preliminary studies showed that in several neoplasms, the uptake of FDG continues to increase for hours after radiopharmaceutical injection, and this difference in the time course of FDG uptake could be useful to improve the accuracy of PET to distinguish benign lesions from malignant ones. Also in experimental cultures, dual-point acquisition (early at 40-60 minutes postinjection and delayed at 90-270 minutes) demonstrated that it is able to differentiate inflammatory from neoplastic tissue. In general, inflammatory tissue is expected to reduce FDG uptake as the time goes by, whereas the uptake in the neoplastic lesions is supposed to be increasing. There is evidence in the recent literature of the clinical usefulness of dual-time-point FDG-PET imaging in a wide variety of malignancies, including those of head and neck, lung, breast, gallbladder, cervix, liver, and in brain tumors. A lesion is likely to be malignant if the standard uptake value increases over time, whereas it is likely to be benign if the standard uptake value is stable or decreases. It is worth noting that in many of these

  10. Oncolytic Vesicular Stomatitis Virus as a Viro-Immunotherapy: Defeating Cancer with a “Hammer” and “Anvil”

    Directory of Open Access Journals (Sweden)

    Michael Karl Melzer

    2017-02-01

    Full Text Available Oncolytic viruses have gained much attention in recent years, due, not only to their ability to selectively replicate in and lyse tumor cells, but to their potential to stimulate antitumor immune responses directed against the tumor. Vesicular stomatitis virus (VSV, a negative-strand RNA virus, is under intense development as an oncolytic virus due to a variety of favorable properties, including its rapid replication kinetics, inherent tumor specificity, and its potential to elicit a broad range of immunomodulatory responses to break immune tolerance in the tumor microenvironment. Based on this powerful platform, a multitude of strategies have been applied to further improve the immune-stimulating potential of VSV and synergize these responses with the direct oncolytic effect. These strategies include: 1. modification of endogenous virus genes to stimulate interferon induction; 2. virus-mediated expression of cytokines or immune-stimulatory molecules to enhance anti-tumor immune responses; 3. vaccination approaches to stimulate adaptive immune responses against a tumor antigen; 4. combination with adoptive immune cell therapy for potentially synergistic therapeutic responses. A summary of these approaches will be presented in this review.

  11. Attenuated, oncolytic, but not wild-type measles virus infection has pleiotropic effects on human neutrophil function.

    Science.gov (United States)

    Zhang, Yu; Patel, Bella; Dey, Aditi; Ghorani, Ehsan; Rai, Lena; Elham, Mohammed; Castleton, Anna Z; Fielding, Adele K

    2012-02-01

    We previously showed that neutrophils play a role in regression of human tumor xenografts in immunodeficient mice following oncolytic vaccine measles virus (MV-Vac) treatment. In this study, we sought, using normal human neutrophils, to identify potential neutrophil-mediated mechanisms for the attenuated MV-Vac induced effects seen in vivo, by comparison with those consequent on wild-type (WT-MV) infection. Both MV-Vac and WT-MV infected and replicated within neutrophils, despite lack of SLAM expression. In both cases, neutrophils survived longer ex vivo postinfection. Furthermore, MV-Vac (but not WT-MV) infection activated neutrophils and stimulated secretion of several specific antitumor cytokines (IL-8, TNF-α, MCP-1, and IFN-α) via induction of de novo RNA and protein synthesis. In addition, MV-Vac (but not WT-MV) infection caused TRAIL secretion in the absence of de novo synthesis by triggering release of prefabricated TRAIL, via a direct effect upon degranulation. The differences between the outcome of infection by MV-Vac and WT-MV were not entirely explained by differential infection and replication of the viruses within neutrophils. To our knowledge, this is the first demonstration of potential mechanisms of oncolytic activity of an attenuated MV as compared with its WT parent. Furthermore, our study suggests that neutrophils have an important role to play in the antitumor effects of oncolytic MV.

  12. Improvement of oncolytic adenovirus vectors through genetic capsid modifications

    NARCIS (Netherlands)

    Vrij, Jeroen de

    2012-01-01

    Recombinant viral vectors hold great promise in the field of cancer gene therapy. While a plethora of viruses is being evaluated as oncolytic agents, human adenoviruses of serotype 5 (HAdV-5) are among the most popular of viruses to be developed. Although clinical studies have demonstrated safety of

  13. Genetic Modification of Oncolytic Newcastle Disease Virus for Cancer Therapy.

    Science.gov (United States)

    Cheng, Xing; Wang, Weijia; Xu, Qi; Harper, James; Carroll, Danielle; Galinski, Mark S; Suzich, JoAnn; Jin, Hong

    2016-06-01

    Clinical development of a mesogenic strain of Newcastle disease virus (NDV) as an oncolytic agent for cancer therapy has been hampered by its select agent status due to its pathogenicity in avian species. Using reverse genetics, we have generated a lead candidate oncolytic NDV based on the mesogenic NDV-73T strain that is no longer classified as a select agent for clinical development. This recombinant NDV has a modification at the fusion protein (F) cleavage site to reduce the efficiency of F protein cleavage and an insertion of a 198-nucleotide sequence into the HN-L intergenic region, resulting in reduced viral gene expression and replication in avian cells but not in mammalian cells. In mammalian cells, except for viral polymerase (L) gene expression, viral gene expression is not negatively impacted or increased by the HN-L intergenic insertion. Furthermore, the virus can be engineered to express a foreign gene while still retaining the ability to grow to high titers in cell culture. The recombinant NDV selectively replicates in and kills tumor cells and is able to drive potent tumor growth inhibition following intratumoral or intravenous administration in a mouse tumor model. The candidate is well positioned for clinical development as an oncolytic virus. Avian paramyxovirus type 1, NDV, has been an attractive oncolytic agent for cancer virotherapy. However, this virus can cause epidemic disease in poultry, and concerns about the potential environmental and economic impact of an NDV outbreak have precluded its clinical development. Here we describe generation and characterization of a highly potent oncolytic NDV variant that is unlikely to cause Newcastle disease in its avian host, representing an essential step toward moving NDV forward as an oncolytic agent. Several attenuation mechanisms have been genetically engineered into the recombinant NDV that reduce chicken pathogenicity to a level that is acceptable worldwide without impacting viral production in

  14. Effects of Epistemological Beliefs and Topic-Specific Beliefs on Undergraduates' Cognitive and Strategic Processing of Dual-Positional Text.

    Science.gov (United States)

    Kardash, CarolAnne M.; Howell, Karen L.

    2000-01-01

    Investigates effects of epistemological beliefs and topic-specific beliefs on undergraduates' (N=40) cognitive and strategic processing of a dual-positional text. Findings reveal that epistemological beliefs about the speed of learning affected the overall number of cognitive processes exhibited, whereas topic-specific beliefs interacted with the…

  15. Individual-specific transgenerational marking of fish populations based on a barium dual-isotope procedure.

    Science.gov (United States)

    Huelga-Suarez, Gonzalo; Moldovan, Mariella; Garcia-Valiente, America; Garcia-Vazquez, Eva; Alonso, J Ignacio Garcia

    2012-01-03

    The present study focuses on the development and evaluation of an individual-specific transgenerational marking procedure using two enriched barium isotopes, (135)Ba and (137)Ba, mixed at a given and selectable molar ratio. The method is based on the deconvolution of the isotope patterns found in the sample into four molar contribution factors: natural xenon (Xe nat), natural barium (Ba nat), Ba135, and Ba137. The ratio of molar contributions between Ba137 and Ba135 is constant and independent of the contribution of natural barium in the sample. This procedure was tested in brown trout ( Salmo trutta ) kept in captivity. Trout were injected with three different Ba137/Ba135 isotopic signatures ca. 7 months and 7 days before spawning to compare the efficiency of the marking procedure at long and short term, respectively. The barium isotopic profiles were measured in the offspring by means of inductively coupled plasma mass spectrometry. Each of the three different isotopic signatures was unequivocally identified in the offspring in both whole eggs and larvae. For 9 month old offspring, the characteristic barium isotope signatures could also be detected in the otoliths even in the presence of a high and variable amount of barium of natural isotope abundance. In conclusion, it can be stated that the proposed dual-isotope marking is inheritable and can be detected after both long-term and short-term marking. Furthermore, the dual-isotope marking can be made individual-specific, so that it allows identification of offspring from a single individual or a group of individuals within a given fish group. © 2011 American Chemical Society

  16. Immune cells: more than simple carriers for systemic delivery of oncolytic viruses

    Directory of Open Access Journals (Sweden)

    Eisenstein S

    2014-11-01

    Full Text Available Samuel Eisenstein,1 Shu-Hsia Chen,2 Ping-Ying Pan21Department of Surgery, 2Department of Oncological Sciences and Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, USAAbstract: Oncolytic virotherapy on its own has numerous drawbacks, including an inability of the virus to actively target tumor cells and systemic toxicities at the high doses necessary to effectively treat tumors. Addition of immune cell-based carriers of oncolytic viruses holds promise as a technique in which oncolytic virus can be delivered directly to tumors in smaller and less toxic doses. Interestingly, the cell carriers themselves have also demonstrated antitumor effects, which can be augmented further by tailoring the appropriate oncolytic virus to the appropriate cell type. This review discusses the multiple factors that go into devising an effective, cell-based delivery system for oncolytic viruses.Keywords: oncolytic virus, cell carrier, immune cells, cancer therapy, myeloid-derived suppressor cells

  17. Genetically engineered oncolytic Newcastle disease virus mediates cytolysis of prostate cancer stem like cells.

    Science.gov (United States)

    Raghunath, Shobana; Pudupakam, Raghavendra Sumanth; Allen, Adria; Biswas, Moanaro; Sriranganathan, Nammalwar

    2017-10-20

    Oncolytic virotherapy is a promising novel approach that overcomes the limitations posed by radiation and chemotherapy. In this study, the oncolytic efficacy of a recombinant Newcastle disease virus (rNDV) BC-KLQL-GFP, against prostate cancer stem-like/tumor initiating cells was evaluated. Xenograft derived prostaspheres (XPS) induced tumor more efficiently than monolayer cell derived prostaspheres (MCPS) in nude mice. Primary and secondary XPS show enhanced self-renewal and clonogenic potential compared to MCPS. XPS also expressed embryonic stem cell markers, such as Nanog, CD44 and Nestin. Further, prostate specific antigen (PSA) activated recombinant Newcastle Disease Virus (rNDV) was selectively cytotoxic to tumor derived DU145 prostaspheres. An effective concentration (EC 50 ) of 0.11-0.14 multiplicity of infection was sufficient to cause prostasphere cell death in serum free culture. DU145 tumor xenograft derived prostaspheres were used as tumor surrogates as they were enriched for a putative tumor initiating cell population. PSA activated rNDV was efficient in inducing cell death of cells and prostaspheres derived from primary xenografts ex-vivo, thus signifying a potential in vivo efficacy. The EC 50 (∼0.1 MOI) for cytolysis of tumor initiating cells was slightly higher than that was required for the parental cell line, but within the therapeutic margin for safety and efficacy. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Permissivity of the NCI-60 cancer cell lines to oncolytic Vaccinia Virus GLV-1h68

    International Nuclear Information System (INIS)

    Ascierto, Maria Libera; Bedognetti, Davide; Uccellini, Lorenzo; Rossano, Fabio; Ascierto, Paolo A; Stroncek, David F; Restifo, Nicholas P; Wang, Ena; Szalay, Aladar A; Marincola, Francesco M; Worschech, Andrea; Yu, Zhiya; Adams, Sharon; Reinboth, Jennifer; Chen, Nanhai G; Pos, Zoltan; Roychoudhuri, Rahul; Di Pasquale, Giovanni

    2011-01-01

    Oncolytic viral therapy represents an alternative therapeutic strategy for the treatment of cancer. We previously described GLV-1h68, a modified Vaccinia Virus with exclusive tropism for tumor cells, and we observed a cell line-specific relationship between the ability of GLV-1h68 to replicate in vitro and its ability to colonize and eliminate tumor in vivo. In the current study we surveyed the in vitro permissivity to GLV-1h68 replication of the NCI-60 panel of cell lines. Selected cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain. In order to identify correlates of permissity to viral infection, we measured transcriptional profiles of the cell lines prior infection. We observed highly heterogeneous permissivity to VACV infection amongst the cell lines. The heterogeneity of permissivity was independent of tissue with the exception of B cell derivation. Cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain and a significant correlation was found suggesting a common permissive phenotype. While no clear transcriptional pattern could be identified as predictor of permissivity to infection, some associations were observed suggesting multifactorial basis permissivity to viral infection. Our findings have implications for the design of oncolytic therapies for cancer and offer insights into the nature of permissivity of tumor cells to viral infection

  19. Defining Brugia malayi and Wolbachia symbiosis by stage-specific dual RNA-seq.

    Directory of Open Access Journals (Sweden)

    Alexandra Grote

    2017-03-01

    Full Text Available Filarial nematodes currently infect up to 54 million people worldwide, with millions more at risk for infection, representing the leading cause of disability in the developing world. Brugia malayi is one of the causative agents of lymphatic filariasis and remains the only human filarial parasite that can be maintained in small laboratory animals. Many filarial nematode species, including B. malayi, carry an obligate endosymbiont, the alpha-proteobacteria Wolbachia, which can be eliminated through antibiotic treatment. Elimination of the endosymbiont interferes with development, reproduction, and survival of the worms within the mamalian host, a clear indicator that the Wolbachia are crucial for survival of the parasite. Little is understood about the mechanism underlying this symbiosis.To better understand the molecular interplay between these two organisms we profiled the transcriptomes of B. malayi and Wolbachia by dual RNA-seq across the life cycle of the parasite. This helped identify functional pathways involved in this essential symbiotic relationship provided by the co-expression of nematode and bacterial genes. We have identified significant stage-specific and gender-specific differential expression in Wolbachia during the nematode's development. For example, during female worm development we find that Wolbachia upregulate genes involved in ATP production and purine biosynthesis, as well as genes involved in the oxidative stress response.This global transcriptional analysis has highlighted specific pathways to which both Wolbachia and B. malayi contribute concurrently over the life cycle of the parasite, paving the way for the development of novel intervention strategies.

  20. A novel oncolytic adenovirus targeting Wnt signaling effectively inhibits cancer-stem like cell growth via metastasis, apoptosis and autophagy in HCC models.

    Science.gov (United States)

    Zhang, Jian; Lai, Weijie; Li, Qiang; Yu, Yang; Jin, Jin; Guo, Wan; Zhou, Xiumei; Liu, Xinyuan; Wang, Yigang

    2017-09-16

    Cancer stem cells (CSCs), which are highly differentiated and self-renewing, play an important role in the occurrence, therapeutic resistant and metastasis of hepatacellular carcinoma (HCC). Oncolytic adenoviruses have targeted killing effect on tumor cells, and are invoked as candidate drugs for cancer treatment. We designed a dual-regulated oncolytic adenovirus Ad.wnt-E1A(△24bp)-TSLC1 that targets Wnt and Rb signaling pathways respectively, and carries the tumor suppressor gene, TSLC1. Previous studies have demonstrated that oncolytic adenovirus mediated TSLC1can target liver cancer and exhibit significant cytotoxicity. However, whether Ad.wnt-E1A(△24bp)-TSLC1 can effectively eliminate liver CSCs remains to be explored. We first used the spheroid culture to enrich the liver CSCs-like cells, and detected the self-renewal capacity, differentiation, drug resistance and tumorigenicity. The results showed that Ad-wnt-E1A(△24bp)-TSLC1 could effectively lead to autophagic death. In addition, recombinant adenovirus effectively induced the apoptosis, inhibit metastasis of hepatic CSCs-like cells in vivo. Further animal experiments indicated that Ad-wnt-E1A(△24bp)-TSLC1could effectively inhibit the growth of transplanted tumor of hepatic CSCs and prolong the survival time of mice. Therefore, the novel oncolytic adenovirus Ad.wnt-E1A(△24bp)-TSLC1 has potential application as a therapeutic target for HCC stem cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Differentiating Second Language Acquisition from Specific Learning Disability: An Observational Tool Assessing Dual Language Learners' Pragmatic Competence

    Science.gov (United States)

    Farnsworth, Megan

    2018-01-01

    Overrepresentation of Dual Language Learners (DLLs) in special education remains a problem even after 40 years of inquiry. One factor is that the U.S. federal government has neither clearly explained the definition of Specific Learning Disability (SLD) nor operationally defined it to identify children for special education services. This lack of…

  2. High affinity antigen recognition of the dual specific variants of herceptin is entropy-driven in spite of structural plasticity.

    Directory of Open Access Journals (Sweden)

    Jenny Bostrom

    Full Text Available The antigen-binding site of Herceptin, an anti-human Epidermal Growth Factor Receptor 2 (HER2 antibody, was engineered to add a second specificity toward Vascular Endothelial Growth Factor (VEGF to create a high affinity two-in-one antibody bH1. Crystal structures of bH1 in complex with either antigen showed that, in comparison to Herceptin, this antibody exhibited greater conformational variability, also called "structural plasticity". Here, we analyzed the biophysical and thermodynamic properties of the dual specific variants of Herceptin to understand how a single antibody binds two unrelated protein antigens. We showed that while bH1 and the affinity-improved bH1-44, in particular, maintained many properties of Herceptin including binding affinity, kinetics and the use of residues for antigen recognition, they differed in the binding thermodynamics. The interactions of bH1 and its variants with both antigens were characterized by large favorable entropy changes whereas the Herceptin/HER2 interaction involved a large favorable enthalpy change. By dissecting the total entropy change and the energy barrier for dual interaction, we determined that the significant structural plasticity of the bH1 antibodies demanded by the dual specificity did not translate into the expected increase of entropic penalty relative to Herceptin. Clearly, dual antigen recognition of the Herceptin variants involves divergent antibody conformations of nearly equivalent energetic states. Hence, increasing the structural plasticity of an antigen-binding site without increasing the entropic cost may play a role for antibodies to evolve multi-specificity. Our report represents the first comprehensive biophysical analysis of a high affinity dual specific antibody binding two unrelated protein antigens, furthering our understanding of the thermodynamics that drive the vast antigen recognition capacity of the antibody repertoire.

  3. Hepatoma targeting peptide conjugated bio-reducible polymer complexed with oncolytic adenovirus for cancer gene therapy.

    Science.gov (United States)

    Choi, Joung-Woo; Kim, Hyun Ah; Nam, Kihoon; Na, Youjin; Yun, Chae-Ok; Kim, SungWan

    2015-12-28

    Despite adenovirus (Ad) vector's numerous advantages for cancer gene therapy, such as high ability of endosomal escape, efficient nuclear entry mechanism, and high transduction, and therapeutic efficacy, tumor specific targeting and antiviral immune response still remain as a critical challenge in clinical setting. To overcome these obstacles and achieve cancer-specific targeting, we constructed tumor targeting bioreducible polymer, an arginine grafted bio-reducible polymer (ABP)-PEG-HCBP1, by conjugating PEGylated ABP with HCBP1 peptides which has high affinity and selectivity towards hepatoma. The ABP-PEG-HCBP1-conjugated replication incompetent GFP-expressing ad, (Ad/GFP)-ABP-PEG-HCBP1, showed a hepatoma cancer specific uptake and transduction compared to either naked Ad/GFP or Ad/GFP-ABP. Competition assays demonstrated that Ad/GFP-ABP-PEG-HCBP1-mediated transduction was specifically inhibited by HCBP1 peptide rather than coxsackie and adenovirus receptor specific antibody. In addition, ABP-PEG-HCBP1 can protect biological activity of Ad against serum, and considerably reduced both innate and adaptive immune response against Ad. shMet-expressing oncolytic Ad (oAd; RdB/shMet) complexed with ABP-PEG-HCBP1 delivered oAd efficiently into hepatoma cancer cells. The oAd/ABP-PEG-HCBP1 demonstrated enhanced cancer cell killing efficacy in comparison to oAd/ABP complex. Furthermore, Huh7 and HT1080 cancer cells treated with oAd/shMet-ABP-PEG-HCBP1 complex had significantly decreased Met and VEGF expression in hepatoma cancer, but not in non-hepatoma cancer. In sum, these results suggest that HCBP1-conjugated bioreducible polymer could be used to deliver oncolytic Ad safely and efficiently to treat hepatoma. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Specific transfer effects following variable priority dual-task training in older adults.

    Science.gov (United States)

    Lussier, Maxime; Bugaiska, Aurélia; Bherer, Louis

    2017-01-01

    Past divided attention training studies in older adults have suggested that variable priority training (VPT) tends to show larger improvement than fixed priority training (FPT). However, it remains unclear whether VPT leads to larger transfer effects. In this study, eighty-three older adults aged between 55 and 65 received five 1-hour sessions of VPT, FPT or of an active placebo. VPT and FPT subjects trained on a complex dual-task condition with variable stimulus timings in order to promote more flexible and self-guided strategies with regard to attentional priority devoted to the concurrent tasks. Real-time individualized feedback was provided to encourage improvement. The active placebo group attended computer classes. Near and far modality transfer tasks were used to assess the generalization of transfer effects. Results showed that VPT induced significantly larger transfer effects than FPT on a near modality transfer task. Evidence for larger transfer effects in VPT than FPT on a far modality transfer task was also observed. Furthermore, the superiority of VPT on FPT in transfer effects was specific to the ability to coordinate two concurrent tasks. Results of this study help better understand the benefits of VPT attentional training on transfer effects, which is an essential outcome for cognitive training effectiveness and relevancy.

  5. Structural and biochemical analysis of atypically low dephosphorylating activity of human dual-specificity phosphatase 28.

    Directory of Open Access Journals (Sweden)

    Bonsu Ku

    Full Text Available Dual-specificity phosphatases (DUSPs constitute a subfamily of protein tyrosine phosphatases, and are intimately involved in the regulation of diverse parameters of cellular signaling and essential biological processes. DUSP28 is one of the DUSP subfamily members that is known to be implicated in the progression of hepatocellular and pancreatic cancers, and its biological functions and enzymatic characteristics are mostly unknown. Herein, we present the crystal structure of human DUSP28 determined to 2.1 Å resolution. DUSP28 adopts a typical DUSP fold, which is composed of a central β-sheet covered by α-helices on both sides and contains a well-ordered activation loop, as do other enzymatically active DUSP proteins. The catalytic pocket of DUSP28, however, appears hardly accessible to a substrate because of the presence of nonconserved bulky residues in the protein tyrosine phosphatase signature motif. Accordingly, DUSP28 showed an atypically low phosphatase activity in the biochemical assay, which was remarkably improved by mutations of two nonconserved residues in the activation loop. Overall, this work reports the structural and biochemical basis for understanding a putative oncological therapeutic target, DUSP28, and also provides a unique mechanism for the regulation of enzymatic activity in the DUSP subfamily proteins.

  6. Immunostimulatory Gene Therapy Using Oncolytic Viruses as Vehicles

    Directory of Open Access Journals (Sweden)

    Angelica Loskog

    2015-11-01

    Full Text Available Immunostimulatory gene therapy has been developed during the past twenty years. The aim of immunostimulatory gene therapy is to tilt the suppressive tumor microenvironment to promote anti-tumor immunity. Hence, like a Trojan horse, the gene vehicle can carry warriors and weapons into enemy territory to combat the tumor from within. The most promising immune stimulators are those activating and sustaining Th1 responses, but even if potent effects were seen in preclinical models, many clinical trials failed to show objective responses in cancer patients. However, with new tools to control ongoing immunosuppression in cancer patients, immunostimulatory gene therapy is now emerging as an interesting option. In parallel, oncolytic viruses have been shown to be safe in patients. To prolong immune stimulation and to increase efficacy, these two fields are now merging and oncolytic viruses are armed with immunostimulatory transgenes. These novel agents are racing towards approval as established cancer immunotherapeutics.

  7. [Genes of insecticidal crystal proteins with dual specificity in Bacillus thuringiensis strains, isolated in the Crimea territory].

    Science.gov (United States)

    Rymar, S Iu; Isakova, I A; Kuznietsova, L M; Kordium, V A

    2006-01-01

    The insecticidal crystal proteins of 15 B. thuringiensis strains, isolated in the Crimea territory that are toxical for some Lepidoptera and Colorado potato beetle larvae were identified by PAGE electrophoresis. Ten strains produced the crystal proteins with high molecular weight (> 120 kD). PCR with use of broad specificity primers and DNA of these B. thuringiensis strains as template demonstrated the specific PCR products (1000 bp). Amplified DNA fragments were cloned and sequenced. The nucleotide sequence analysis revealed that the genomes of ten strains of B. thuringiensis carried Cry1B genes, which are responsible for production of the insecticidal crystal proteins with dual specificity. The influence of the solubilization conditions on the structure and toxicity of Cry1B protein for Colorado potato beetle larvae was shown. The dual toxicity of studied B. thuringiensis strains is explained by the Cry1B genes presence in their genomes. These strains may be used to develop the broad specificity bioinsecticides.

  8. Dual-specificity phosphatase 3 deficiency or inhibition limits platelet activation and arterial thrombosis.

    Science.gov (United States)

    Musumeci, Lucia; Kuijpers, Marijke J; Gilio, Karen; Hego, Alexandre; Théâtre, Emilie; Maurissen, Lisbeth; Vandereyken, Maud; Diogo, Catia V; Lecut, Christelle; Guilmain, William; Bobkova, Ekaterina V; Eble, Johannes A; Dahl, Russell; Drion, Pierre; Rascon, Justin; Mostofi, Yalda; Yuan, Hongbin; Sergienko, Eduard; Chung, Thomas D Y; Thiry, Marc; Senis, Yotis; Moutschen, Michel; Mustelin, Tomas; Lancellotti, Patrizio; Heemskerk, Johan W M; Tautz, Lutz; Oury, Cécile; Rahmouni, Souad

    2015-02-17

    A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. A better understanding of the molecular mechanisms leading to platelet activation is important for the development of improved therapies. Recently, protein tyrosine phosphatases have emerged as critical regulators of platelet function. This is the first report implicating the dual-specificity phosphatase 3 (DUSP3) in platelet signaling and thrombosis. This phosphatase is highly expressed in human and mouse platelets. Platelets from DUSP3-deficient mice displayed a selective impairment of aggregation and granule secretion mediated by the collagen receptor glycoprotein VI and the C-type lectin-like receptor 2. DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism compared with wild-type mice and showed severely impaired thrombus formation on ferric chloride-induced carotid artery injury. Intriguingly, bleeding times were not altered in DUSP3-deficient mice. At the molecular level, DUSP3 deficiency impaired Syk tyrosine phosphorylation, subsequently reducing phosphorylation of phospholipase Cγ2 and calcium fluxes. To investigate DUSP3 function in human platelets, a novel small-molecule inhibitor of DUSP3 was developed. This compound specifically inhibited collagen- and C-type lectin-like receptor 2-induced human platelet aggregation, thereby phenocopying the effect of DUSP3 deficiency in murine cells. DUSP3 plays a selective and essential role in collagen- and C-type lectin-like receptor 2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a protein tyrosine phosphatase, implicated in platelet signaling, has been targeted with a small-molecule drug. © 2014 American Heart Association, Inc.

  9. Oncolytic Replication of E1b-Deleted Adenoviruses

    Directory of Open Access Journals (Sweden)

    Pei-Hsin Cheng

    2015-11-01

    Full Text Available Various viruses have been studied and developed for oncolytic virotherapies. In virotherapy, a relatively small amount of viruses used in an intratumoral injection preferentially replicate in and lyse cancer cells, leading to the release of amplified viral particles that spread the infection to the surrounding tumor cells and reduce the tumor mass. Adenoviruses (Ads are most commonly used for oncolytic virotherapy due to their infection efficacy, high titer production, safety, easy genetic modification, and well-studied replication characteristics. Ads with deletion of E1b55K preferentially replicate in and destroy cancer cells and have been used in multiple clinical trials. H101, one of the E1b55K-deleted Ads, has been used for the treatment of late-stage cancers as the first approved virotherapy agent. However, the mechanism of selective replication of E1b-deleted Ads in cancer cells is still not well characterized. This review will focus on three potential molecular mechanisms of oncolytic replication of E1b55K-deleted Ads. These mechanisms are based upon the functions of the viral E1B55K protein that are associated with p53 inhibition, late viralmRNAexport, and cell cycle disruption.

  10. Smart dual-functional warhead for folate receptor-specific activatable imaging and photodynamic therapy.

    Science.gov (United States)

    Kim, Jisu; Tung, Ching-Hsuan; Choi, Yongdoo

    2014-09-21

    A smart dual-targeted theranostic agent becomes highly fluorescent and phototoxic only when its linker is cleaved by tumor-associated lysosomal enzyme cathepsin B after internalization into folate receptor-positive cancer cells.

  11. Oncolytic virotherapy in veterinary medicine: current status and future prospects for canine patients

    Directory of Open Access Journals (Sweden)

    Patil Sandeep S

    2012-01-01

    Full Text Available Abstract Oncolytic viruses refer to those that are able to eliminate malignancies by direct targeting and lysis of cancer cells, leaving non-cancerous tissues unharmed. Several oncolytic viruses including adenovirus strains, canine distemper virus and vaccinia virus strains have been used for canine cancer therapy in preclinical studies. However, in contrast to human studies, clinical trials with oncolytic viruses for canine cancer patients have not been reported. An 'ideal' virus has yet to be identified. This review is focused on the prospective use of oncolytic viruses in the treatment of canine tumors - a knowledge that will undoubtedly contribute to the development of oncolytic viral agents for canine cancer therapy in the future.

  12. New frontiers in oncolytic viruses: optimizing and selecting for virus strains with improved efficacy

    Directory of Open Access Journals (Sweden)

    Lundstrom K

    2018-02-01

    Full Text Available Kenneth Lundstrom PanTherapeutics, Lutry, Switzerland Abstract: Oncolytic viruses have demonstrated selective replication and killing of tumor cells. Different types of oncolytic viruses – adenoviruses, alphaviruses, herpes simplex viruses, Newcastle disease viruses, rhabdoviruses, Coxsackie viruses, and vaccinia viruses – have been applied as either naturally occurring or engineered vectors. Numerous studies in animal-tumor models have demonstrated substantial tumor regression and prolonged survival rates. Moreover, clinical trials have confirmed good safety profiles and therapeutic efficacy for oncolytic viruses. Most encouragingly, the first cancer gene-therapy drug – Gendicine, based on oncolytic adenovirus type 5 – was approved in China. Likewise, a second-generation oncolytic herpes simplex virus-based drug for the treatment of melanoma has been registered in the US and Europe as talimogene laherparepvec. Keywords: immunotherapy, viral vectors, clinical trials, drug approval

  13. Oncolytic herpes viruses, chemotherapeutics, and other cancer drugs

    Directory of Open Access Journals (Sweden)

    Braidwood L

    2013-12-01

    Full Text Available Lynne Braidwood,1 Sheila V Graham,2 Alex Graham,1 Joe Conner11Virttu Biologics Ltd, Department of Neurology, Southern General Hospital, Glasgow, UK; 2MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Jarrett Building, University of Glasgow, Glasgow, UKAbstract: Oncolytic viruses are emerging as a potential new way of treating cancers. They are selectively replication-competent viruses that propagate only in actively dividing tumor cells but not in normal cells and, as a result, destroy the tumor cells by consequence of lytic infection. At least six different oncolytic herpes simplex viruses (oHSVs have undergone clinical trials worldwide to date, and they have demonstrated an excellent safety profile and intimations of efficacy. The first pivotal Phase III trial with an oHSV, talimogene laherparepvec (T-Vec [OncoVexGM-CSF], is almost complete, with extremely positive early results reported. Intuitively, therapeutically beneficial interactions between oHSV and chemotherapeutic and targeted therapeutic drugs would be limited as the virus requires actively dividing cells for maximum replication efficiency and most anticancer agents are cytotoxic or cytostatic. However, combinations of such agents display a range of responses, with antagonistic, additive, or, perhaps most surprisingly, synergistic enhancement of antitumor activity. When synergistic interactions in cancer cell killing are observed, chemotherapy dose reductions that achieve the same overall efficacy may be possible, resulting in a valuable reduction of adverse side effects. Therefore, the combination of an oHSV with “standard-of-care” drugs makes a logical and reasonable approach to improved therapy, and the addition of a targeted oncolytic therapy with “standard-of-care” drugs merits further investigation, both preclinically and in the clinic. Numerous publications report

  14. Purification and characterization of a polyisoprenyl phosphate phosphatase from pig brain. Possible dual specificity.

    Science.gov (United States)

    Frank, D W; Waechter, C J

    1998-05-08

    Microsomal fractions from pig and calf brain catalyze the enzymatic dephosphorylation of endogenous and exogenous dolichyl monophosphate (Dol-P) (Sumbilla, C. A., and Waechter, C. J. (1985) Methods Enzymol. 111, 471-482). The Dol-P phosphatase (EC 3.1.3.51) has been solubilized by extracting pig brain microsomes with the nonionic detergent Nonidet P-40 and purified approximately 1,107-fold by a combination of anion exchange chromatography, polyethylene glycol fractionation, dye-ligand chromatography, and wheat germ agglutinin affinity chromatography. Treatment of the enzyme with neuraminidase prevented binding to wheat germ agglutinin-Sepharose, indicating the presence of one or more N-acetylneuraminyl residues per molecule of enzyme. When the highly purified polyisoprenyl phosphate phosphatase was analyzed by SDS-polyacrylamide gel electrophoresis, a major 33-kDa polypeptide was observed. Enzymatic dephosphorylation of Dol-P by the purified phosphatase was 1) optimal at pH 7; 2) potently inhibited by F-, orthovanadate, and Zn2+ > Co2+ > Mn2+ but unaffected by Mg2+; 3) exhibited an approximate Km for C95-Dol-P of 45 microM; and 4) was sensitive to N-ethylmaleimide, phenylglyoxal, and diethylpyrocarbonate. The pig brain phosphatase did not dephosphorylate glucose 6-phosphate, mannose 6-phosphate, 5'-AMP, or p-nitrophenylphosphate, but it dephosphorylated dioleoyl-phosphatidic acid at initial rates similar to those determined for Dol-P. Based on the virtually identical sensitivity of Dol-P and phosphatidic acid dephosphorylation by the highly purified enzyme to N-ethylmaleimide, F-, phenylglyoxal, and diethylpyrocarbonate, both substrates appear to be hydrolyzed by a single enzyme with an apparent dual specificity. This is the first report of the purification of a neutral Dol-P phosphatase from mammalian tissues. Although the enzyme is Mg2+-independent and capable of dephosphorylating Dol-P and PA, several enzymological properties distinguish this lipid

  15. Obstructive sleep apnea and intermittent hypoxia increase expression of dual specificity phosphatase 1.

    Science.gov (United States)

    Hoffmann, Michal S; Singh, Prachi; Wolk, Robert; Narkiewicz, Krzysztof; Somers, Virend K

    2013-12-01

    Dual specificity phosphatase 1 (DUSP1) inhibits mitogen activated protein kinase activity, and is activated by several stimuli such as sustained hypoxia, oxidative stress, and hormones. However, the effect of intermittent hypoxia is not known. The aim of this study was to evaluate the role of intermittent hypoxia on DUSP1 expression, and to validate its role in a human model of intermittent hypoxia, as seen in obstructive sleep apnea (OSA). OSA is characterized by recurrent episodes of hypoxemia/reoxygenation and is a known risk factor for cardiovascular morbidity. In-vitro studies using human coronary artery endothelial cells (HCAEC) and ex-vivo studies using white blood cells isolated from healthy and OSA subjects. Intermittent hypoxia induced DUSP1 expression in human coronary artery endothelial cells (HCAEC), and in granulocytes isolated from healthy human subjects. Functionally, DUSP1 increased the expression and activity of manganese superoxide dismutase (MnSOD) in HCAEC. Further, significant increases in DUSP1 mRNA from total blood, and in DUSP1 protein in mononuclear cells and granulocytes isolated from OSA subjects, were observed in the early morning hours after one night of intermittent hypoxemia due to untreated OSA. This early-morning OSA-induced augmentation of DUSP1 gene expression was attenuated by continuous positive airway pressure (CPAP) treatment of OSA. Intermittent hypoxia increases MnSOD activity via increased DUSP1 expression in HCAEC. Similarly, overnight intermittent hypoxemia in patients with OSA induces expression of DUSP1, which may mediate increases of MnSOD expression and activity. This may contribute significantly to neutralizing the effects of reactive oxygen species, a consequence of the intermittent hypoxemia/reperfusion elicited by OSA. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  16. Oncolytic adenovirus Ad657 for systemic virotherapy against prostate cancer

    Directory of Open Access Journals (Sweden)

    Nguyen TV

    2018-05-01

    Full Text Available Tien V Nguyen,1,* Catherine M Crosby,2,* Gregory J Heller,3 Zachary I Mendel,3 Mary E Barry,1 Michael A Barry1,4,5 1Department of Internal Medicine, Division of Infectious Diseases, 2Virology and Gene Therapy Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, 3Postbaccalaureate Research Education Program, Mayo Clinic Graduate School of Biomedical Sciences, 4Department of Immunology, 5Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA *These authors contributed equally to this work Background: Human species C adenovirus serotype 5 (Ad5 is the archetype oncolytic adenovirus and has been used in the vast majority of preclinical and clinical tests. While Ad5 can be robust, species C Ad6 has lower seroprevalence, side effects, and appears to be more potent as a systemic therapy against a number of tumors than Ad5. Historically, there have only been four species C human adenoviruses: serotypes 1, 2, 5, and 6. More recently a new species C adenovirus, Ad57, was identified. Ad57 is most similar to Ad6 with virtually all variation in their capsid proteins occurring in the hypervariable regions (HVRs of their hexon proteins. Most adenovirus neutralizing antibodies target the HVRs on adenoviruses. This led us to replace the hexon HVRs in Ad6 with those from Ad57 to create a new virus called Ad657 and explore this novel species C platform’s utility as an oncolytic virus. Methods: The HVR region from Ad57 was synthesized and used to replace the Ad6 HVR region by homologous recombination in bacteria generating a new viral platform that we call Ad657. Replication-competent Ad5, Ad6, and Ad657 were compared in vitro and in vivo for liver damage and oncolytic efficacy against prostate cancers after single intravenous treatment in mice. Results: Ad5, Ad6, and Ad657 had similar in vitro oncolytic activity against human prostate cancer cells. Ad5 provoked the highest level of liver toxicity after intravenous injection and Ad657

  17. Parainfluenza Virus Infection Sensitizes Cancer Cells to DNA-Damaging Agents: Implications for Oncolytic Virus Therapy.

    Science.gov (United States)

    Fox, Candace R; Parks, Griffith D

    2018-04-01

    A parainfluenza virus 5 (PIV5) with mutations in the P/V gene (P/V-CPI - ) is restricted for spread in normal cells but not in cancer cells in vitro and is effective at reducing tumor burdens in mouse model systems. Here we show that P/V-CPI - infection of HEp-2 human laryngeal cancer cells results in the majority of the cells dying, but unexpectedly, over time, there is an emergence of a population of cells that survive as P/V-CPI - persistently infected (PI) cells. P/V-CPI - PI cells had elevated levels of basal caspase activation, and viability was highly dependent on the activity of cellular inhibitor-of-apoptosis proteins (IAPs) such as Survivin and XIAP. In challenge experiments with external inducers of apoptosis, PI cells were more sensitive to cisplatin-induced DNA damage and cell death. This increased cisplatin sensitivity correlated with defects in DNA damage signaling pathways such as phosphorylation of Chk1 and translocation of damage-specific DNA binding protein 1 (DDB1) to the nucleus. Cisplatin-induced killing of PI cells was sensitive to the inhibition of wild-type (WT) p53-inducible protein 1 (WIP1), a phosphatase which acts to terminate DNA damage signaling pathways. A similar sensitivity to cisplatin was seen with cells during acute infection with P/V-CPI - as well as during acute infections with WT PIV5 and the related virus human parainfluenza virus type 2 (hPIV2). Our results have general implications for the design of safer paramyxovirus-based vectors that cannot establish PI as well as the potential for combining chemotherapy with oncolytic RNA virus vectors. IMPORTANCE There is intense interest in developing oncolytic viral vectors with increased potency against cancer cells, particularly those cancer cells that have gained resistance to chemotherapies. We have found that infection with cytoplasmically replicating parainfluenza virus can result in increases in the killing of cancer cells by agents that induce DNA damage, and this is linked

  18. A dynamical systems model for combinatorial cancer therapy enhances oncolytic adenovirus efficacy by MEK-inhibition.

    Science.gov (United States)

    Bagheri, Neda; Shiina, Marisa; Lauffenburger, Douglas A; Korn, W Michael

    2011-02-01

    Oncolytic adenoviruses, such as ONYX-015, have been tested in clinical trials for currently untreatable tumors, but have yet to demonstrate adequate therapeutic efficacy. The extent to which viruses infect targeted cells determines the efficacy of this approach but many tumors down-regulate the Coxsackievirus and Adenovirus Receptor (CAR), rendering them less susceptible to infection. Disrupting MAPK pathway signaling by pharmacological inhibition of MEK up-regulates CAR expression, offering possible enhanced adenovirus infection. MEK inhibition, however, interferes with adenovirus replication due to resulting G1-phase cell cycle arrest. Therefore, enhanced efficacy will depend on treatment protocols that productively balance these competing effects. Predictive understanding of how to attain and enhance therapeutic efficacy of combinatorial treatment is difficult since the effects of MEK inhibitors, in conjunction with adenovirus/cell interactions, are complex nonlinear dynamic processes. We investigated combinatorial treatment strategies using a mathematical model that predicts the impact of MEK inhibition on tumor cell proliferation, ONYX-015 infection, and oncolysis. Specifically, we fit a nonlinear differential equation system to dedicated experimental data and analyzed the resulting simulations for favorable treatment strategies. Simulations predicted enhanced combinatorial therapy when both treatments were applied simultaneously; we successfully validated these predictions in an ensuing explicit test study. Further analysis revealed that a CAR-independent mechanism may be responsible for amplified virus production and cell death. We conclude that integrated computational and experimental analysis of combinatorial therapy provides a useful means to identify treatment/infection protocols that yield clinically significant oncolysis. Enhanced oncolytic therapy has the potential to dramatically improve non-surgical cancer treatment, especially in locally advanced

  19. The current status of oncolytic viral therapy for head and neck cancer

    Directory of Open Access Journals (Sweden)

    Matthew O. Old

    2016-06-01

    Full Text Available Objective: Cancer affects the head and neck region frequently and leads to significant morbidity and mortality. Oncolytic viral therapy has the potential to make a big impact in cancers that affect the head and neck. We intend to review the current state of oncolytic viruses in the treatment of cancers that affect the head and neck region. Method: Data sources are from National clinical trials database, literature, and current research. Results: There are many past and active trials for oncolytic viruses that show promise for treating cancers of the head and neck. The first oncolytic virus was approved by the FDA October 2015 (T-VEC, Amgen for the treatment of melanoma. Active translational research continues for this and many other oncolytic viruses. Conclusion: The evolving field of oncolytic viruses is impacting the treatment of head and neck cancer and further trials and agents are moving forward in the coming years. Keywords: Head and neck squamous cell carcinoma, Oncolytic viruses, Clinical trials, Novel therapeutics

  20. Expanding the Substrate Specificity of Thermoanaerobacter pseudoethanolicus Secondary Alcohol Dehydrogenase by a Dual Site Mutation

    KAUST Repository

    Musa, Musa M.; Bsharat, Odey; Karume, Ibrahim; Vieille, Claire; Takahashi, Masateru; Hamdan, Samir

    2017-01-01

    Here, we report the asymmetric reduction of selected phenyl-ring-containing ketones by various single and dual site mutants of Thermoanaerobacter pseudoethanolicus secondary alcohol dehydrogenase (TeSADH). Further expanding the size of the substrate binding pocket in the mutant W110A/I86A not only allowed substrates of the single mutants W110A and I86A to be accommodated within the expanded active site, but also expanded the enzyme's substrate range to ketones bearing two sterically demanding groups (bulky-bulky ketones), which are not substrates for TeSADH single mutants. We also report the regio- and enantioselective reduction of diketones using W110A/I86A TeSADH and single TeSADH mutants. The double mutant exhibited dual stereopreference generating the Prelog products most of the time and the anti-Prelog products in a few cases.

  1. Expanding the Substrate Specificity of Thermoanaerobacter pseudoethanolicus Secondary Alcohol Dehydrogenase by a Dual Site Mutation

    KAUST Repository

    Musa, Musa M.

    2017-12-14

    Here, we report the asymmetric reduction of selected phenyl-ring-containing ketones by various single and dual site mutants of Thermoanaerobacter pseudoethanolicus secondary alcohol dehydrogenase (TeSADH). Further expanding the size of the substrate binding pocket in the mutant W110A/I86A not only allowed substrates of the single mutants W110A and I86A to be accommodated within the expanded active site, but also expanded the enzyme\\'s substrate range to ketones bearing two sterically demanding groups (bulky-bulky ketones), which are not substrates for TeSADH single mutants. We also report the regio- and enantioselective reduction of diketones using W110A/I86A TeSADH and single TeSADH mutants. The double mutant exhibited dual stereopreference generating the Prelog products most of the time and the anti-Prelog products in a few cases.

  2. Dual-functioning peptides discovered by phage display increase the magnitude and specificity of BMSC attachment to mineralized biomaterials.

    Science.gov (United States)

    Ramaraju, Harsha; Miller, Sharon J; Kohn, David H

    2017-07-01

    Design of biomaterials for cell-based therapies requires presentation of specific physical and chemical cues to cells, analogous to cues provided by native extracellular matrices (ECM). We previously identified a peptide sequence with high affinity towards apatite (VTKHLNQISQSY, VTK) using phage display. The aims of this study were to identify a human MSC-specific peptide sequence through phage display, combine it with the apatite-specific sequence, and verify the specificity of the combined dual-functioning peptide to both apatite and human bone marrow stromal cells. In this study, a combinatorial phage display identified the cell binding sequence (DPIYALSWSGMA, DPI) which was combined with the mineral binding sequence to generate the dual peptide DPI-VTK. DPI-VTK demonstrated significantly greater binding affinity (1/K D ) to apatite surfaces compared to VTK, phosphorylated VTK (VTK phos ), DPI-VTK phos , RGD-VTK, and peptide-free apatite surfaces (p biomaterial surfaces and subsequently increase cell proliferation and differentiation. These new peptides expand biomaterial design methodology for cell-based regeneration of bone defects. This strategy of combining cell and material binding phage display derived peptides is broadly applicable to a variety of systems requiring targeted adhesion of specific cell populations, and may be generalized to the engineering of any adhesion surface. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Insertion of the human sodium iodide symporter to facilitate deep tissue imaging does not alter oncolytic or replication capability of a novel vaccinia virus

    Directory of Open Access Journals (Sweden)

    Mittra Arjun

    2011-03-01

    Full Text Available Abstract Introduction Oncolytic viruses show promise for treating cancer. However, to assess therapeutic efficacy and potential toxicity, a noninvasive imaging modality is needed. This study aimed to determine if insertion of the human sodium iodide symporter (hNIS cDNA as a marker for non-invasive imaging of virotherapy alters the replication and oncolytic capability of a novel vaccinia virus, GLV-1h153. Methods GLV-1h153 was modified from parental vaccinia virus GLV-1h68 to carry hNIS via homologous recombination. GLV-1h153 was tested against human pancreatic cancer cell line PANC-1 for replication via viral plaque assays and flow cytometry. Expression and transportation of hNIS in infected cells was evaluated using Westernblot and immunofluorescence. Intracellular uptake of radioiodide was assessed using radiouptake assays. Viral cytotoxicity and tumor regression of treated PANC-1tumor xenografts in nude mice was also determined. Finally, tumor radiouptake in xenografts was assessed via positron emission tomography (PET utilizing carrier-free 124I radiotracer. Results GLV-1h153 infected, replicated within, and killed PANC-1 cells as efficiently as GLV-1h68. GLV-1h153 provided dose-dependent levels of hNIS expression in infected cells. Immunofluorescence detected transport of the protein to the cell membrane prior to cell lysis, enhancing hNIS-specific radiouptake (P In vivo, GLV-1h153 was as safe and effective as GLV-1h68 in regressing pancreatic cancer xenografts (P 124I-PET. Conclusion Insertion of the hNIS gene does not hinder replication or oncolytic capability of GLV-1h153, rendering this novel virus a promising new candidate for the noninvasive imaging and tracking of oncolytic viral therapy.

  4. Enrichment of intersubtype HIV-1 recombinants in a dual infection system using HIV-1 strain-specific siRNAs

    Science.gov (United States)

    2011-01-01

    Background Intersubtype HIV-1 recombinants in the form of unique or stable circulating recombinants forms (CRFs) are responsible for over 20% of infections in the worldwide epidemic. Mechanisms controlling the generation, selection, and transmission of these intersubtype HIV-1 recombinants still require further investigation. All intersubtype HIV-1 recombinants are generated and evolve from initial dual infections, but are difficult to identify in the human population. In vitro studies provide the most practical system to study mechanisms, but the recombination rates are usually very low in dual infections with primary HIV-1 isolates. This study describes the use of HIV-1 isolate-specific siRNAs to enrich intersubtype HIV-1 recombinants and inhibit the parental HIV-1 isolates from a dual infection. Results Following a dual infection with subtype A and D primary HIV-1 isolates and two rounds of siRNA treatment, nearly 100% of replicative virus was resistant to a siRNA specific for an upstream target sequence in the subtype A envelope (env) gene as well as a siRNA specific for a downstream target sequence in the subtype D env gene. Only 20% (10/50) of the replicating virus had nucleotide substitutions in the siRNA-target sequence whereas the remaining 78% (39/50) harbored a recombination breakpoint that removed both siRNA target sequences, and rendered the intersubtype D/A recombinant virus resistant to the dual siRNA treatment. Since siRNAs target the newly transcribed HIV-1 mRNA, the siRNAs only enrich intersubtype env recombinants and do not influence the recombination process during reverse transcription. Using this system, a strong bias is selected for recombination breakpoints in the C2 region, whereas other HIV-1 env regions, most notably the hypervariable regions, were nearly devoid of intersubtype recombination breakpoints. Sequence conservation plays an important role in selecting for recombination breakpoints, but the lack of breakpoints in many conserved

  5. Pediatric glioma stem cells: biologic strategies for oncolytic HSV virotherapy

    Directory of Open Access Journals (Sweden)

    Gregory K Friedman

    2013-02-01

    Full Text Available While glioblastoma multiforme (GBM is the most common adult malignant brain tumor, GBMs in childhood represent less than 10% of pediatric malignant brain tumors and are phenotypically and molecularly distinct from adult GBMs. Similar to adult patients, outcomes for children with high-grade gliomas (HGGs remain poor. Furthermore, the significant morbidity and mortality yielded by pediatric GBM is compounded by neurotoxicity for the developing brain caused by current therapies. Poor outcomes have been attributed to a subpopulation of chemotherapy and radiotherapy resistant cells, termed ‘glioma stem cells’ (GSCs, ‘glioma progenitor cells’, or ‘glioma-initiating cells', which have the ability to initiate and maintain the tumor and to repopulate the recurring tumor after conventional therapy. Future innovative therapies for pediatric HGGs must be able to eradicate these therapy-resistant GSCs. Oncolytic herpes simplex viruses, genetically engineered to be safe for normal cells and to express diverse foreign anti-tumor therapeutic genes, have been demonstrated in preclinical studies to infect and kill GSCs and tumor cells equally while sparing normal brain cells. In this review, we discuss the unique aspects of pediatric GSCs, including markers to identify them, the microenvironment they reside in, signaling pathways that regulate them, mechanisms of cellular resistance, and approaches to target GSCs, with a focus on the promising therapeutic, genetically engineered oncolytic herpes simplex virus (HSV.

  6. Oncolytic Maraba Virus MG1 as a Treatment for Sarcoma.

    Science.gov (United States)

    Le Boeuf, Fabrice; Selman, Mohammed; Son, Hwan Hee; Bergeron, Anabel; Chen, Andrew; Tsang, Jovian; Butterwick, Derek; Arulanandam, Rozanne; Forbes, Nicole E; Tzelepis, Fanny; Bell, John C; Werier, Joel; Abdelbary, Hesham; Diallo, Jean-Simon

    2017-09-15

    The poor prognosis of patients with advanced bone and soft-tissue sarcoma has not changed in the past several decades, highlighting the necessity for new therapeutic approaches. Immunotherapies, including oncolytic viral (OV) therapy, have shown great promise in a number of clinical trials for a variety of tumor types. However, the effective application of OV in treating sarcoma still remains to be demonstrated. Although few pre-clinical studies using distinct OVs have been performed and demonstrated therapeutic benefit in sarcoma models, a side-by-side comparison of clinically relevant OV platforms has not been performed. Four clinically relevant OV platforms (Reovirus, Vaccinia virus, Herpes-simplex virus and Rhabdovirus) were screened for their ability to infect and kill human and canine sarcoma cell lines in vitro, and human sarcoma specimens ex vivo. In vivo treatment efficacy was tested in a murine model. The rhabdovirus MG1 demonstrated the highest potency in vitro. Ex vivo, MG1 productively infected more than 80% of human sarcoma tissues tested, and treatment in vivo led to a significant increase in long-lasting cures in sarcoma-bearing mice. Importantly, MG1 treatment induced the generation of memory immune response that provided protection against a subsequent tumor challenge. This study opens the door for the use of MG1-based oncolytic immunotherapy strategies as treatment for sarcoma or as a component of a combined therapy. © 2017 UICC.

  7. Use of an oncolytic virus secreting GM-CSF as combined oncolytic and immunotherapy for treatment of colorectal and hepatic adenocarcinomas.

    Science.gov (United States)

    Malhotra, Sandeep; Kim, Teresa; Zager, Jonathan; Bennett, Joseph; Ebright, Michael; D'Angelica, Michael; Fong, Yuman

    2007-04-01

    Oncolytic cancer therapy using herpes simplex viruses (HSV) that have direct tumoricidal effects and cancer immunotherapy using the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) have each been effective in preclinical testing. NV1034 is a multimutated oncolytic HSV carrying the gene for murine GM-CSF that attempts to combine these 2 anticancer strategies. The purpose of this study was to compare NV1034 to NV1023, the parent HSV mutants lacking GM-CSF, to determine if such combined oncolytic and immunotherapy using a single vector has advantages over oncolytic therapy alone. Expression GM-CSF in vitro did not alter the infectivity, cytotoxicity, or replication of NV1034 compared to the noncytokine-secreting control. Tumors infected with NV1034 produced GM-CSF in picogram quantities. In vivo efficacy of the viruses against murine colorectal carcinoma CT26 and murine hepatoma Hepa l-6 was then tested in subcutaneous tumors in syngeneic Balb/c and C57 L/J mice, respectively. In these immune-competent models, NV1034 and NV1023 each demonstrated potent antitumor activity. Treatment with NV1034 had significantly better antitumor effect compared to treatment with NV1023. Furthermore, there was no difference in the antitumor efficacy of these viruses in mice depleted of CD4+ and CD8+ T lymphocytes. Viral vectors combining oncolytic and immunotherapy are promising agents in treatment of colorectal carcinoma and hepatoma.

  8. A Fusogenic Oncolytic Herpes Simplex Virus for Therapy of Advanced Ovarian Cancer

    National Research Council Canada - National Science Library

    Zhang, Xiaoliu

    2004-01-01

    The tasks that were originally planned for the first year of this 3 year project are to demonstrate that the fusogenic oncolytic herpes simplex viruses are potent anti-tumor agents for advanced ovarian cancer...

  9. A Potent Oncolytic Herpes Simplex Virus for Therapy of Advanced Prostate Cancer

    National Research Council Canada - National Science Library

    Zhang, Xiaoliu

    2005-01-01

    ... only. Therefore fusogenic oncolytic HSV should be no more toxic than its parental construct. Nonetheless, we proposed in the year 2 of this funded project to conduct extensive studies in animal models...

  10. A Potent Oncolytic Herpes Simplex Virus for the Therapy of Advanced Prostate

    National Research Council Canada - National Science Library

    Zhang, Xiaoliu

    2006-01-01

    .... WE PROPOSED IN THE AIM 3 OF THIS FUNDED PROJECT TO ADDRESS THIS ISSUE WITH TWO STRATEGIES: 1) TO DELIVER ONCOLYTIC HSVS THROUGH LIPOSOME-FORMULATED VIRAL DNA INSTEAD OF THE TRADITIONAL VIRAL PARTICLES AND 2...

  11. Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Manbok, E-mail: manbok66@dankook.ac.kr [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States); Rahman, Masmudur M. [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States); Cogle, Christopher R. [Department of Hematology/Oncology, University of Florida, Gainesville, FL 32610 (United States); McFadden, Grant [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States)

    2015-07-10

    Epstein–Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. - Highlights: • Myxoma virus effectively infects and purges EBV lymphoma cells in vivo. • Oncolytic myxoma virus effectively eradicates oncogenic EBV tumorigenesis. • Ex vivo pre-treatment of myxoma virus can be effective as a preventive treatment modality for post-transplant lymphoproliferative diseases.

  12. Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease

    International Nuclear Information System (INIS)

    Kim, Manbok; Rahman, Masmudur M.; Cogle, Christopher R.; McFadden, Grant

    2015-01-01

    Epstein–Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. - Highlights: • Myxoma virus effectively infects and purges EBV lymphoma cells in vivo. • Oncolytic myxoma virus effectively eradicates oncogenic EBV tumorigenesis. • Ex vivo pre-treatment of myxoma virus can be effective as a preventive treatment modality for post-transplant lymphoproliferative diseases

  13. Effects of heat transfer, friction and variable specific heats of working fluid on performance of an irreversible dual cycle

    International Nuclear Information System (INIS)

    Chen Lingen; Ge Yanlin; Sun Fengrui; Wu Chih

    2006-01-01

    The thermodynamic performance of an air standard dual cycle with heat transfer loss, friction like term loss and variable specific heats of working fluid is analyzed. The relations between the power output and the compression ratio, between the thermal efficiency and the compression ratio, as well as the optimal relation between power output and the efficiency of the cycle, are derived by detailed numerical examples. Moreover, the effects of variable specific heats of the working fluid and the friction like term loss on the irreversible cycle performance are analyzed. The results show that the effects of variable specific heats of working fluid and friction like term loss on the cycle performance are obvious, and they should be considered in practical cycle analysis. The results obtained in this paper may provide guidance for the design of practical internal combustion engines

  14. Task-specificity of unilateral anodal and dual-M1 tDCS effects on motor learning.

    Science.gov (United States)

    Karok, Sophia; Fletcher, David; Witney, Alice G

    2017-01-08

    Task-specific effects of transcranial direct current stimulation (tDCS) on motor learning were investigated in 30 healthy participants. In a sham-controlled, mixed design, participants trained on 3 different motor tasks (Purdue Pegboard Test, Visuomotor Grip Force Tracking Task and Visuomotor Wrist Rotation Speed Control Task) over 3 consecutive days while receiving either unilateral anodal over the right primary motor cortex (M1), dual-M1 or sham stimulation. Retention sessions were administered 7 and 28 days after the end of training. In the Purdue Pegboard Test, both anodal and dual-M1 stimulation reduced average completion time approximately equally, an improvement driven by online learning effects and maintained for about 1 week. The Visuomotor Grip Force Tracking Task and the Visuomotor Wrist Rotation Speed Control Task were associated with an advantage of dual-M1 tDCS in consolidation processes both between training sessions and when testing at long-term retention; both were maintained for at least 1 month. This study demonstrates that M1-tDCS enhances and sustains motor learning with different electrode montages. Stimulation-induced effects emerged at different learning phases across the tasks, which strongly suggests that the influence of tDCS on motor learning is dynamic with respect to the functional recruitment of the distributed motor system at the time of stimulation. Divergent findings regarding M1-tDCS effects on motor learning may partially be ascribed to task-specific consequences and the effects of offline consolidation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. An oncolytic adenovirus regulated by a radiation-inducible promoter selectively mediates hSulf-1 gene expression and mutually reinforces antitumor activity of I131-metuximab in hepatocellular carcinoma.

    Science.gov (United States)

    Zhang, Yan; Fang, Lin; Zhang, Quan'an; Zheng, Qin; Tong, Jinlong; Fu, Xiaohui; Jiang, Xiaoqing; Su, Changqing; Zheng, Junnian

    2013-06-01

    Gene therapy and antibody approaches are crucial auxiliary strategies for hepatocellular carcinoma (HCC) treatment. Previously, we established a survivin promoter-regulated oncolytic adenovirus that has inhibitory effect on HCC growth. The human sulfatase-1 (hSulf-1) gene can suppress the growth factor signaling pathways, then inhibit the proliferation of cancer cells and enhance cellular sensitivity to radiotherapy and chemotherapy. I(131)-metuximab (I(131)-mab) is a monoclonal anti-HCC antibody that conjugated to I(131) and specifically recognizes the HAb18G/CD147 antigen on HCC cells. To integrate the oncolytic adenovirus-based gene therapy and the I(131)-mab-based radioimmunotherapy, this study combined the CArG element of early growth response-l (Egr-l) gene with the survivin promoter to construct a radiation-inducible enhanced promoter, which was used to recombine a radiation-inducible oncolytic adenovirus as hSulf-1 gene vector. When I(131)-mab was incorporated into the treatment regimen, not only could the antibody produce radioimmunotherapeutic effect, but the I(131) radiation was able to further boost adenoviral proliferation. We demonstrated that the CArG-enhanced survivin promoter markedly improved the proliferative activity of the oncolytic adenovirus in HCC cells, thereby augmenting hSulf-1 expression and inducing cancer cell apoptosis. This novel strategy that involved multiple, synergistic mechanisms, including oncolytic therapy, gene therapy and radioimmunotherapy, was demonstrated to exert an excellent anti-cancer outcome, which will be a promising approach in HCC treatment. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  16. A family of fluoride-specific ion channels with dual-topology architecture.

    Science.gov (United States)

    Stockbridge, Randy B; Robertson, Janice L; Kolmakova-Partensky, Ludmila; Miller, Christopher

    2013-08-27

    Fluoride ion, ubiquitous in soil, water, and marine environments, is a chronic threat to microorganisms. Many prokaryotes, archea, unicellular eukaryotes, and plants use a recently discovered family of F(-) exporter proteins to lower cytoplasmic F(-) levels to counteract the anion's toxicity. We show here that these 'Fluc' proteins, purified and reconstituted in liposomes and planar phospholipid bilayers, form constitutively open anion channels with extreme selectivity for F(-) over Cl(-). The active channel is a dimer of identical or homologous subunits arranged in antiparallel transmembrane orientation. This dual-topology assembly has not previously been seen in ion channels but is known in multidrug transporters of the SMR family, and is suggestive of an evolutionary antecedent of the inverted repeats found within the subunits of many membrane transport proteins. DOI:http://dx.doi.org/10.7554/eLife.01084.001.

  17. Synthesis and application of dual functionalized task specific ionic liquid for bamboo dissolution

    Directory of Open Access Journals (Sweden)

    Hameed Sultan Nor Shahroon

    2017-01-01

    Full Text Available A new class of dual functionalized imidazolium based ionic liquid (IL namely 3-(2-cyano-ethyl-1-(2-ethoxy-ethyl-3-imidazolium bromide [CNEIM][Br], was synthesized and characterized to study their potential in bamboo dissolution. The chemical structure for the IL was characterized using NMR (1H and 13C. Thermal properties, surface morphology and functional group of the native bamboo and IL treated bamboo were analyzed by Thermal Gravimetric Anaylysis (TGA, Scanning Electron Microscopy (SEM and Fourier Transform Infrared Spectroscopy (FTIR respectively. The new IL was able to dissolve up to 5wt% of bamboo biomass within 48 hours and 100°C.

  18. Oncolytic Virotherapy Targeting Lung Cancer Drug Resistance

    Science.gov (United States)

    2013-08-01

    Von Hoff DD, Kim DH: ONYX..01S. an E1B gene- attenuated adenovirus , cau888 tumor-specific cytolysis and antitumoral efficacy that can be augmented...ORGANIZATION: Vaccine & Gene Therapy Institute of Florida Port St. Lucie, FL 34987...NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER Vaccine & Gene Therapy Institute of

  19. The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivo.

    Science.gov (United States)

    Bueno, O F; De Windt, L J; Lim, H W; Tymitz, K M; Witt, S A; Kimball, T R; Molkentin, J D

    2001-01-19

    Mitogen-activated protein kinase (MAPK) signaling pathways are important regulators of cell growth, proliferation, and stress responsiveness. A family of dual-specificity MAP kinase phosphatases (MKPs) act as critical counteracting factors that directly regulate the magnitude and duration of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) activation. Here we show that constitutive expression of MKP-1 in cultured primary cardiomyocytes using adenovirus-mediated gene transfer blocked the activation of p38, JNK1/2, and ERK1/2 and prevented agonist-induced hypertrophy. Transgenic mice expressing physiological levels of MKP-1 in the heart showed (1) no activation of p38, JNK1/2, or ERK1/2; (2) diminished developmental myocardial growth; and (3) attenuated hypertrophy in response to aortic banding and catecholamine infusion. These results provide further evidence implicating MAPK signaling factors as obligate regulators of cardiac growth and hypertrophy and demonstrate the importance of dual-specificity phosphatases as counterbalancing regulatory factors in the heart.

  20. Measles virus: Background and oncolytic virotherapy

    OpenAIRE

    Sankhajit Bhattacharjee; Pramod Kumar Yadava

    2018-01-01

    Measles is a highly transmissible disease caused by measles virus and remains a major cause of child mortality in developing countries. Measles virus nucleoprotein (N) encapsidates the RNA genome of the virus for providing protection from host cell endonucleases and for specific recognition of viral RNA as template for transcription and replication. This protein is over-expressed at the time of viral replication. The C-terminal of N protein is intrinsically disordered, which enables this prot...

  1. Evaluation of dual target-specific real-time PCR for the detection of Kingella kingae in a Danish paediatric population

    DEFF Research Database (Denmark)

    de Knegt, Victoria Elizabeth; Kristiansen, Gitte Qvist; Schønning, Kristian

    2017-01-01

    BACKGROUND: We aimed to evaluate the relevance of dual target real-time polymerase chain (PCR) assays targeting the rtxA and cpn60 genes of the paediatric pathogen Kingella kingae. We also studied for the first time the clinical and epidemiological features of K. kingae infections in a Danish pop......-value: peak in autumn. CONCLUSION: Dual target-specific real-time PCR markedly improved the detection of K. kingae in clinical specimens when compared to culture methods....

  2. A VAR2CSA:CSP conjugate capable of inducing dual specificity antibody responses

    DEFF Research Database (Denmark)

    Matondo, Sungwa; Thrane, Susan; Janitzek, Christoph Mikkel

    2017-01-01

    Catcher peptide. The covalent interaction between SpyTag/SpyCatcher enables the formation of DBL1x-DBL2x-ID2a:CSP conjugate vaccine. Immunogenicity and quality of antibody responses induced by the conjugate vaccine, as well as a control CSP-SpyCatcher vaccine, was tested in BALB/c mice.  Results: Serum samples...... obtained from mice immunized with the conjugate vaccine were able to recognize both untagged DBL1x-DBL2x-ID2a as well as CSP antigen. Moreover, the geometric mean anti-CSP antibody titer was 1.9-fold higher in serum (at day 35 and 55 post-first immunization) from mice immunized with the conjugate vaccine......, as compared to mice receiving the control vaccine.  Conclusion: The data obtained in this study serves as proof-of-concept for the simultaneous induction of antibodies directed against individual antigen components in a dual stage anti-malaria vaccine....

  3. Attacking Postoperative Metastases using Perioperative Oncolytic Viruses and Viral Vaccines

    Science.gov (United States)

    Tai, Lee-Hwa; Auer, Rebecca

    2014-01-01

    Surgical resection of solid primary malignancies is a mainstay of therapy for cancer patients. Despite being the most effective treatment for these tumors, cancer surgery has been associated with impaired metastatic clearance due to immunosuppression. In preclinical surgery models and human cancer patients, we and others have demonstrated a profound suppression of both natural killer (NK) and T cell function in the postoperative period and this plays a major role in the enhanced development of metastases following surgery. Oncolytic viruses (OV) were originally designed to selectively infect and replicate in tumors, with the primary objective of directly lysing cancer cells. It is becoming increasingly clear, however, that OV infection results in a profound inflammatory reaction within the tumor, initiating innate and adaptive immune responses against it that is critical for its therapeutic benefit. This anti-tumor immunity appears to be mediated predominantly by NK and cytotoxic T cells. In preclinical models, we found that preoperative OV prevents postoperative NK cell dysfunction and attenuates tumor dissemination. Due to theoretical safety concerns of administering live virus prior to surgery in cancer patients, we characterized safe, attenuated versions of OV, and viral vaccines that could stimulate NK cells and reduce metastases when administered in the perioperative period. In cancer patients, we observed that in vivo infusion with oncolytic vaccinia virus and ex vivo stimulation with viral vaccines promote NK cell activation. These preclinical studies provide a novel and clinically relevant setting for OV therapy. Our challenge is to identify safe and promising OV therapies that will activate NK and T cells in the perioperative period preventing the establishment of micrometastatic disease in cancer patients. PMID:25161958

  4. In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis.

    Directory of Open Access Journals (Sweden)

    Antony M Latham

    Full Text Available Protein kinases play a central role in tumor progression, regulating fundamental processes such as angiogenesis, proliferation and metastasis. Such enzymes are an increasingly important class of drug target with small molecule kinase inhibitors being a major focus in drug development. However, balancing drug specificity and efficacy is problematic with off-target effects and toxicity issues.We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2 and cyclin-dependent kinase 1 (CDK1. This compound acts by simultaneously inhibiting pro-angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A-mediated signaling response and CDK1-mediated mitotic entry elicits anti-angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis.We deduce that JK-31 reduces the growth of both human endothelial cells and human breast cancer cells in vitro. This novel synthetic molecule has broad implications for development of similar multi-kinase inhibitors with anti-angiogenic and anti-cancer properties. In silico design is an attractive and innovative method to aid such drug discovery.

  5. In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis.

    Science.gov (United States)

    Latham, Antony M; Kankanala, Jayakanth; Fearnley, Gareth W; Gage, Matthew C; Kearney, Mark T; Homer-Vanniasinkam, Shervanthi; Wheatcroft, Stephen B; Fishwick, Colin W G; Ponnambalam, Sreenivasan

    2014-01-01

    Protein kinases play a central role in tumor progression, regulating fundamental processes such as angiogenesis, proliferation and metastasis. Such enzymes are an increasingly important class of drug target with small molecule kinase inhibitors being a major focus in drug development. However, balancing drug specificity and efficacy is problematic with off-target effects and toxicity issues. We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 1 (CDK1). This compound acts by simultaneously inhibiting pro-angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A)-mediated signaling response and CDK1-mediated mitotic entry elicits anti-angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis. We deduce that JK-31 reduces the growth of both human endothelial cells and human breast cancer cells in vitro. This novel synthetic molecule has broad implications for development of similar multi-kinase inhibitors with anti-angiogenic and anti-cancer properties. In silico design is an attractive and innovative method to aid such drug discovery.

  6. Stem Cell-Based Cell Carrier for Targeted Oncolytic Virotherapy: Translational Opportunity and Open Questions

    Directory of Open Access Journals (Sweden)

    Janice Kim

    2015-11-01

    Full Text Available Oncolytic virotherapy for cancer is an innovative therapeutic option where the ability of a virus to promote cell lysis is harnessed and reprogrammed to selectively destroy cancer cells. Such treatment modalities exhibited antitumor activity in preclinical and clinical settings and appear to be well tolerated when tested in clinical trials. However, the clinical success of oncolytic virotherapy has been significantly hampered due to the inability to target systematic metastasis. This is partly due to the inability of the therapeutic virus to survive in the patient circulation, in order to target tumors at distant sites. An early study from various laboratories demonstrated that cells infected with oncolytic virus can protect the therapeutic payload form the host immune system as well as function as factories for virus production and enhance the therapeutic efficacy of oncolytic virus. While a variety of cell lineages possessed potential as cell carriers, copious investigation has established stem cells as a very attractive cell carrier system in oncolytic virotherapy. The ideal cell carrier desire to be susceptible to viral infection as well as support viral infection, maintain immunosuppressive properties to shield the loaded viruses from the host immune system, and most importantly possess an intrinsic tumor homing ability to deliver loaded viruses directly to the site of the metastasis—all qualities stem cells exhibit. In this review, we summarize the recent work in the development of stem cell-based carrier for oncolytic virotherapy, discuss the advantages and disadvantages of a variety of cell carriers, especially focusing on why stem cells have emerged as the leading candidate, and finally propose a future direction for stem cell-based targeted oncolytic virotherapy that involves its establishment as a viable treatment option for cancer patients in the clinical setting.

  7. Dual-specificity anti-sigma factor reinforces control of cell-type specific gene expression in Bacillus subtilis.

    Directory of Open Access Journals (Sweden)

    Mónica Serrano

    2015-04-01

    Full Text Available Gene expression during spore development in Bacillus subtilis is controlled by cell type-specific RNA polymerase sigma factors. σFand σE control early stages of development in the forespore and the mother cell, respectively. When, at an intermediate stage in development, the mother cell engulfs the forespore, σF is replaced by σG and σE is replaced by σK. The anti-sigma factor CsfB is produced under the control of σF and binds to and inhibits the auto-regulatory σG, but not σF. A position in region 2.1, occupied by an asparagine in σG and by a glutamate in οF, is sufficient for CsfB discrimination of the two sigmas, and allows it to delay the early to late switch in forespore gene expression. We now show that following engulfment completion, csfB is switched on in the mother cell under the control of σK and that CsfB binds to and inhibits σE but not σK, possibly to facilitate the switch from early to late gene expression. We show that a position in region 2.3 occupied by a conserved asparagine in σE and by a conserved glutamate in σK suffices for discrimination by CsfB. We also show that CsfB prevents activation of σG in the mother cell and the premature σG-dependent activation of σK. Thus, CsfB establishes negative feedback loops that curtail the activity of σE and prevent the ectopic activation of σG in the mother cell. The capacity of CsfB to directly block σE activity may also explain how CsfB plays a role as one of the several mechanisms that prevent σE activation in the forespore. Thus the capacity of CsfB to differentiate between the highly similar σF/σG and σE/σK pairs allows it to rinforce the cell-type specificity of these sigma factors and the transition from early to late development in B. subtilis, and possibly in all sporeformers that encode a CsfB orthologue.

  8. Dual-Specificity Anti-HER-2/neu Antisense DNA Agents for Breast Cancer Therapy

    National Research Council Canada - National Science Library

    Stein, Stanley

    2001-01-01

    .... To achieve high avidity and specificity, we designed chimeric antisense molecules consisting of a short active DNA fused to a short "anchor" 2'-0-methyl RNA complementary to non-contiguous single...

  9. Production Functions for Water Delivery Systems: Analysis and Estimation Using Dual Cost Function and Implicit Price Specifications

    Science.gov (United States)

    Teeples, Ronald; Glyer, David

    1987-05-01

    Both policy and technical analysis of water delivery systems have been based on cost functions that are inconsistent with or are incomplete representations of the neoclassical production functions of economics. We present a full-featured production function model of water delivery which can be estimated from a multiproduct, dual cost function. The model features implicit prices for own-water inputs and is implemented as a jointly estimated system of input share equations and a translog cost function. Likelihood ratio tests are performed showing that a minimally constrained, full-featured production function is a necessary specification of the water delivery operations in our sample. This, plus the model's highly efficient and economically correct parameter estimates, confirms the usefulness of a production function approach to modeling the economic activities of water delivery systems.

  10. Self-dual cluster renormalization group approach for the square lattice Ising model specific heat and magnetization

    International Nuclear Information System (INIS)

    Martin, H.O.; Tsallis, C.

    1981-01-01

    A simple renormalization group approach based on self-dual clusters is proposed for two-dimensional nearest-neighbour 1/2 - spin Ising model on the square lattice; it reproduces the exact critical point. The internal energy and the specific heat for vanishing external magnetic field, spontaneous magnetization and the thermal (Y sub(T)) and magnetic (Y sub(H)) critical exponents are calculated. The results obtained from the first four smallest cluster sizes strongly suggest the convergence towards the exact values when the cluster sizes increases. Even for the smallest cluster, where the calculation is very simple, the results are quite accurate, particularly in the neighbourhood of the critical point. (Author) [pt

  11. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling

    DEFF Research Database (Denmark)

    Ungureanu, Daniela; Wu, Jinhua; Pekkala, Tuija

    2011-01-01

    Human JAK2 tyrosine kinase mediates signaling through numerous cytokine receptors. The JAK2 JH2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of JAK2 remains unknown. Mutations in JH2 lead to increased...... JAK2 activity, contributing to myeloproliferative neoplasms (MPNs). Here we show that JH2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in JAK2: Ser523 and Tyr570. Inactivation of JH2 catalytic activity increased JAK2 basal activity and downstream signaling....... Notably, different MPN mutations abrogated JH2 activity in cells, and in MPN (V617F) patient cells phosphorylation of Tyr570 was reduced, suggesting that loss of JH2 activity contributes to the pathogenesis of MPNs. These results identify the catalytic activity of JH2 as a previously unrecognized...

  12. Low Expression of DYRK2 (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 2 Correlates with Poor Prognosis in Colorectal Cancer.

    Directory of Open Access Journals (Sweden)

    Haiyan Yan

    Full Text Available Dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2 is a member of dual-specificity kinase family, which could phosphorylate both Ser/Thr and Tyr substrates. The role of DYRK2 in human cancer remains controversial. For example, overexpression of DYRK2 predicts a better survival in human non-small cell lung cancer. In contrast, amplification of DYRK2 gene occurs in esophageal/lung adenocarcinoma, implying the role of DYRK2 as a potential oncogene. However, its clinical role in colorectal cancer (CRC has not been explored. In this study, we analyzed the expression of DYRK2 from Oncomine database and found that DYRK2 level is lower in primary or metastatic CRC compared to adjacent normal colon tissue or non-metastatic CRC, respectively, in 6 colorectal carcinoma data sets. The correlation between DYRK2 expression and clinical outcome in 181 CRC patients was also investigated by real-time PCR and IHC. DYRK2 expression was significantly down-regulated in colorectal cancer tissues compared with adjacent non-tumorous tissues. Functional studies confirmed that DYRK2 inhibited cell invasion and migration in both HCT116 and SW480 cells and functioned as a tumor suppressor in CRC cells. Furthermore, the lower DYRK2 levels were correlated with tumor sites (P = 0.023, advanced clinical stages (P = 0.006 and shorter survival in the advanced clinical stages. Univariate and multivariate analyses indicated that DYRK2 expression was an independent prognostic factor (P < 0.001. Taking all, we concluded that DYRK2 a novel prognostic biomarker of human colorectal cancer.

  13. Dual substrate feedback control of specific growth-rate in vaccine production

    NARCIS (Netherlands)

    Neeleman, R.; Beuvery, E.C.; Vries, D.; Straten, van G.; Boxtel, van A.J.B.

    2004-01-01

    Abstract: Unexpectedly, primary concern of bio-pharmaceutical industry is not optimisation of product yield or cost reduction, but consistency in production and product quality. This paper describes the methodology and experimental results of specific growth-rate control for vaccine production. The

  14. Oncolytic Immunotherapy: Dying the Right Way is a Key to Eliciting Potent Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    Zong Sheng eGuo

    2014-04-01

    Full Text Available Oncolytic viruses (OVs are novel immunotherapeutic agents whose anticancer effects come from both oncolysis and elicited antitumor immunity. OVs induce mostly immunogenic cancer cell death (ICD, including immunogenic apoptosis, necrosis/necroptosis, pyroptosis and autophagic cell death, leading to exposure of calreticulin and heat-shock proteins to the cell surface, and/or released ATP, high mobility group box-1 [HMGB1], uric acid, and other DAMPs as well as PAMPs as danger signals, along with tumor-associated antigens, to activate dendritic cells (DCs and elicit adaptive antitumor immunity. Dying the right way may greatly potentiate adaptive antitumor immunity. The mode of cancer cell death may be modulated by individual OVs and cancer cells as they often encode and express genes that inhibit/promote apoptosis, necroptosis or autophagic cell death. We can genetically engineer OVs with death-pathway-modulating genes and thus skew the infected cancer cells towards certain death pathways for the enhanced immunogenicity. Strategies combining with some standard therapeutic regimens may also change the immunological consequence of cancer cell death. In this review, we discuss recent advances in our understanding of danger signals, modes of cancer cell death induced by OVs, the induced danger signals and functions in eliciting subsequent antitumor immunity. We also discuss potential combination strategies to target cells into specific modes of ICD and enhance cancer immunogenicity, including blockade of immune checkpoints, in order to break immune tolerance, improve antitumor immunity and thus the overall therapeutic efficacy.

  15. The hTERT promoter enhances the antitumor activity of an oncolytic adenovirus under a hypoxic microenvironment.

    Directory of Open Access Journals (Sweden)

    Yuuri Hashimoto

    Full Text Available Hypoxia is a microenvironmental factor that contributes to the invasion, progression and metastasis of tumor cells. Hypoxic tumor cells often show more resistance to conventional chemoradiotherapy than normoxic tumor cells, suggesting the requirement of novel antitumor therapies to efficiently eliminate the hypoxic tumor cells. We previously generated a tumor-specific replication-competent oncolytic adenovirus (OBP-301: Telomelysin, in which the human telomerase reverse transcriptase (hTERT promoter drives viral E1 expression. Since the promoter activity of the hTERT gene has been shown to be upregulated by hypoxia, we hypothesized that, under hypoxic conditions, the antitumor effect of OBP-301 with the hTERT promoter would be more efficient than that of the wild-type adenovirus 5 (Ad5. In this study, we investigated the antitumor effects of OBP-301 and Ad5 against human cancer cells under a normoxic (20% oxygen or a hypoxic (1% oxygen condition. Hypoxic condition induced nuclear accumulation of the hypoxia-inducible factor-1α and upregulation of hTERT promoter activity in human cancer cells. The cytopathic activity of OBP-301 was significantly higher than that of Ad5 under hypoxic condition. Consistent with their cytopathic activity, the replication of OBP-301 was significantly higher than that of Ad5 under the hypoxic condition. OBP-301-mediated E1A was expressed within hypoxic areas of human xenograft tumors in mice. These results suggest that the cytopathic activity of OBP-301 against hypoxic tumor cells is mediated through hypoxia-mediated activation of the hTERT promoter. Regulation of oncolytic adenoviruses by the hTERT promoter is a promising antitumor strategy, not only for induction of tumor-specific oncolysis, but also for efficient elimination of hypoxic tumor cells.

  16. Selectivity and Efficiency of Late Transgene Expression by Transcriptionally Targeted Oncolytic Adenoviruses Are Dependent on the Transgene Insertion Strategy

    Science.gov (United States)

    Quirin, Christina; Rohmer, Stanimira; Fernández-Ulibarri, Inés; Behr, Michael; Hesse, Andrea; Engelhardt, Sarah; Erbs, Philippe; Enk, Alexander H.

    2011-01-01

    Abstract Key challenges facing cancer therapy are the development of tumor-specific drugs and potent multimodal regimens. Oncolytic adenoviruses possess the potential to realize both aims by restricting virus replication to tumors and inserting therapeutic genes into the virus genome, respectively. A major effort in this regard is to express transgenes in a tumor-specific manner without affecting virus replication. Using both luciferase as a sensitive reporter and genetic prodrug activation, we show that promoter control of E1A facilitates highly selective expression of transgenes inserted into the late transcription unit. This, however, required multistep optimization of late transgene expression. Transgene insertion via internal ribosome entry site (IRES), splice acceptor (SA), or viral 2A sequences resulted in replication-dependent expression. Unexpectedly, analyses in appropriate substrates and with matching control viruses revealed that IRES and SA, but not 2A, facilitated indirect transgene targeting via tyrosinase promoter control of E1A. Transgene expression via SA was more selective (up to 1,500-fold) but less effective than via IRES. Notably, we also revealed transgene-dependent interference with splicing. Hence, the prodrug convertase FCU1 (a cytosine deaminase–uracil phosphoribosyltransferase fusion protein) was expressed only after optimizing the sequence surrounding the SA site and mutating a cryptic splice site within the transgene. The resulting tyrosinase promoter-regulated and FCU1-encoding adenovirus combined effective oncolysis with targeted prodrug activation therapy of melanoma. Thus, prodrug activation showed potent bystander killing and increased cytotoxicity of the virus up to 10-fold. We conclude that armed oncolytic viruses can be improved substantially by comparing and optimizing strategies for targeted transgene expression, thereby implementing selective and multimodal cancer therapies. PMID:20939692

  17. Oncolytic virotherapy using herpes simplex virus: how far have we come?

    Directory of Open Access Journals (Sweden)

    Sokolowski NAS

    2015-11-01

    Full Text Available Nicolas AS Sokolowski,1 Helen Rizos,2 Russell J Diefenbach1 1Centre for Virus Research, Westmead Millennium Institute for Medical Research, The University of Sydney, 2Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, NSW, Australia Abstract: Oncolytic virotherapy exploits the properties of human viruses to naturally cause cytolysis of cancer cells. The human pathogen herpes simplex virus (HSV has proven particularly amenable for use in oncolytic virotherapy. The relative safety of HSV coupled with extensive knowledge on how HSV interacts with the host has provided a platform for manipulating HSV to enhance the targeting and killing of human cancer cells. This has culminated in the approval of talimogene laherparepvec for the treatment of melanoma. This review focuses on the development of HSV as an oncolytic virus and where the field is likely to head in the future. Keywords: herpes simplex virus, cancer, immunity, combination therapy, oncolysis

  18. Dual specificity of activin type II receptor ActRIIb in dorso-ventral patterning during zebrafish embryogenesis.

    Science.gov (United States)

    Nagaso, H; Suzuki, A; Tada, M; Ueno, N

    1999-04-01

    Members of the transforming growth factor-beta (TGF-beta) superfamily are thought to regulate specification of a variety of tissue types in early embryogenesis. These effects are mediated through a cell surface receptor complex, consisting of two classes of ser/thr kinase receptor, type I and type II. In the present study, cDNA encoding zebrafish activin type II receptors, ActRIIa and ActRIIb was cloned and characterized. Overexpression of ActRIIb in zebrafish embryos caused dorsalization of embryos, as observed in activin-overexpressing embryos. However, in blastula stage embryos, ActRIIb induced formation of both dorsal and ventro-lateral mesoderm. It has been suggested that these inducing signals from ActRIIb are mediated through each specific type I receptor, TARAM-A and BMPRIA, depending on activin and bone morphogenetic protein (BMP), respectively. In addition, it was shown that a kinase-deleted form of ActRIIb (dnActRIIb) suppressed both activin- and BMP-like signaling pathways. These results suggest that ActRIIb at least has dual roles in both activin and BMP signaling pathways during zebrafish embryogenesis.

  19. Aptamer-Based Dual-Functional Probe for Rapid and Specific Counting and Imaging of MCF-7 Cells.

    Science.gov (United States)

    Yang, Bin; Chen, Beibei; He, Man; Yin, Xiao; Xu, Chi; Hu, Bin

    2018-02-06

    Development of multimodal detection technologies for accurate diagnosis of cancer at early stages is in great demand. In this work, we report a novel approach using an aptamer-based dual-functional probe for rapid, sensitive, and specific counting and visualization of MCF-7 cells by inductively coupled plasma-mass spectrometry (ICP-MS) and fluorescence imaging. The probe consists of a recognition unit of aptamer to catch cancer cells specifically, a fluorescent dye (FAM) moiety for fluorescence resonance energy transfer (FRET)-based "off-on" fluorescence imaging as well as gold nanoparticles (Au NPs) tag for both ICP-MS quantification and fluorescence quenching. Due to the signal amplification effect and low spectral interference of Au NPs in ICP-MS, an excellent linearity and sensitivity were achieved. Accordingly, a limit of detection of 81 MCF-7 cells and a relative standard deviation of 5.6% (800 cells, n = 7) were obtained. The dynamic linear range was 2 × 10 2 to 1.2 × 10 4 cells, and the recoveries in human whole blood were in the range of 98-110%. Overall, the established method provides quantitative and visualized information on MCF-7 cells with a simple and rapid process and paves the way for a promising strategy for biomedical research and clinical diagnostics.

  20. Aptamer-fluorescent silica nanoparticles bioconjugates based dual-color flow cytometry for specific detection of Staphylococcus aureus.

    Science.gov (United States)

    He, Xiaoxiao; Li, Yuhong; He, Dinggen; Wang, Kemin; Shangguan, Jingfang; Shi, Hui

    2014-07-01

    This paper describes a sensitive and specific determination strategy for Staphylococcus aureus (S. aureus) detection using aptamer recognition and fluorescent silica nanoparticles (FSiNPs) label based dual-color flow cytometry assay (Aptamer/FSiNPs-DCFCM). In the protocol, an aptamer, having high affinity to S. aureus, was first covalently immobilized onto chloropropyl functionalized FSiNPs through a click chemistry approach to generate aptamer-nanoparticles bioconjugates (Aptamer/FSiNPs). Next, S. aureus was incubated with Aptamer/FSiNPs, and then stained with SYBR Green I (a special staining material for the duplex DNA). Upon target binding and nucleic acid staining with SYBR Green I, the S. aureus was determined using two-color flow cytometry. The method took advantage of the specificity of aptamer, signal amplification of FSiNPs label and decreased false positives of two-color flow cytometry assay. It was demonstrated that these Aptamer/FSiNPs could efficiently recognize and fluorescently label target S. aureus. Through multiparameter determination with flow cytometry, this assay allowed for detection of as low as 1.5 x 10(2) and 7.6 x 10(2) cells mL(-1) S. aureus in buffer and spiked milk, respectively, with higher sensitivity than the Aptamer/FITC based flow cytometry.

  1. Combining Oncolytic Virotherapy with p53 Tumor Suppressor Gene Therapy

    Directory of Open Access Journals (Sweden)

    Christian Bressy

    2017-06-01

    Full Text Available Oncolytic virus (OV therapy utilizes replication-competent viruses to kill cancer cells, leaving non-malignant cells unharmed. With the first U.S. Food and Drug Administration-approved OV, dozens of clinical trials ongoing, and an abundance of translational research in the field, OV therapy is poised to be one of the leading treatments for cancer. A number of recombinant OVs expressing a transgene for p53 (TP53 or another p53 family member (TP63 or TP73 were engineered with the goal of generating more potent OVs that function synergistically with host immunity and/or other therapies to reduce or eliminate tumor burden. Such transgenes have proven effective at improving OV therapies, and basic research has shown mechanisms of p53-mediated enhancement of OV therapy, provided optimized p53 transgenes, explored drug-OV combinational treatments, and challenged canonical roles for p53 in virus-host interactions and tumor suppression. This review summarizes studies combining p53 gene therapy with replication-competent OV therapy, reviews preclinical and clinical studies with replication-deficient gene therapy vectors expressing p53 transgene, examines how wild-type p53 and p53 modifications affect OV replication and anti-tumor effects of OV therapy, and explores future directions for rational design of OV therapy combined with p53 gene therapy.

  2. Oncolytic Immunotherapy: Conceptual Evolution, Current Strategies, and Future Perspectives

    Directory of Open Access Journals (Sweden)

    Zong Sheng Guo

    2017-05-01

    Full Text Available The concept of oncolytic virus (OV-mediated cancer therapy has been shifted from an operational virotherapy paradigm to an immunotherapy. OVs often induce immunogenic cell death (ICD of cancer cells, and they may interact directly with immune cells as well to prime antitumor immunity. We and others have developed a number of strategies to further stimulate antitumor immunity and to productively modulate the tumor microenvironment (TME for potent and sustained antitumor immune cell activity. First, OVs have been engineered or combined with other ICD inducers to promote more effective T cell cross-priming, and in many cases, the breaking of functional immune tolerance. Second, OVs may be armed to express Th1-stimulatory cytokines/chemokines or costimulators to recruit and sustain the potent antitumor immunity into the TME to focus their therapeutic activity within the sites of disease. Third, combinations of OV with immunomodulatory drugs or antibodies that recondition the TME have proven to be highly promising in early studies. Fourth, combinations of OVs with other immunotherapeutic regimens (such as prime-boost cancer vaccines, CAR T cells; armed with bispecific T-cell engagers have also yielded promising preliminary findings. Finally, OVs have been combined with immune checkpoint blockade, with robust antitumor efficacy being observed in pilot evaluations. Despite some expected hurdles for the rapid translation of OV-based state-of-the-art protocols, we believe that a cohort of these novel approaches will join the repertoire of standard cancer treatment options in the near future.

  3. Characterization of a human cell line stably over-expressing the candidate oncogene, dual specificity phosphatase 12.

    Directory of Open Access Journals (Sweden)

    Erica L Cain

    2011-04-01

    Full Text Available Analysis of chromosomal rearrangements within primary tumors has been influential in the identification of novel oncogenes. Identification of the "driver" gene(s within cancer-derived amplicons is, however, hampered by the fact that most amplicons contain many gene products. Amplification of 1q21-1q23 is strongly associated with liposarcomas and microarray-based comparative genomic hybridization narrowed down the likely candidate oncogenes to two: the activating transcription factor 6 (atf6 and the dual specificity phosphatase 12 (dusp12. While atf6 is an established transcriptional regulator of the unfolded protein response, the potential role of dusp12 in cancer remains uncharacterized.To evaluate the oncogenic potential of dusp12, we established stable cell lines that ectopically over-express dusp12 in isolation and determined whether this cell line acquired properties frequently associated with transformed cells. Here, we demonstrate that cells over-expressing dusp12 display increased cell motility and resistance to apoptosis. Additionally, over-expression of dusp12 promoted increased expression of the c-met proto-oncogene and the collagen and laminin receptor intergrin alpha 1 (itga1 which is implicated in metastasis.Collectively, these results suggest that dusp12 is oncologically relevant and exposes a potential association between dusp12 and established oncogenes that could be therapeutically targeted.

  4. A Sol-gel Integrated Dual-readout Microarray Platform for Quantification and Identification of Prostate-specific Antigen.

    Science.gov (United States)

    Lee, SangWook; Lee, Jong Hyun; Kwon, Hyuck Gi; Laurell, Thomas; Jeong, Ok Chan; Kim, Soyoun

    2018-01-01

    Here, we report a sol-gel integrated affinity microarray for on-chip matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) that enables capture and identification of prostate?specific antigen (PSA) in samples. An anti-PSA antibody (H117) was mixed with a sol?gel, and the mixture was spotted onto a porous silicon (pSi) surface without additional surface modifications. The antibody easily penetrates the sol-gel macropore fluidic network structure, making possible high affinities. To assess the capture affinity of the platform, we performed a direct assay using fluorescein isothiocyanate-labeled PSA. Pure PSA was subjected to on-chip MALDI-TOF-MS analysis, yielding three clear mass peptide peaks (m/z = 1272, 1407, and 1872). The sol-gel microarray platform enables dual readout of PSA both fluorometric and MALDI-TOF MS analysis in biological samples. Here we report a useful method for a means for discovery of biomarkers in complex body fluids.

  5. Oncolytic adenovirus targeting cyclin E overexpression repressed tumor growth in syngeneic immunocompetent mice

    International Nuclear Information System (INIS)

    Cheng, Pei-Hsin; Rao, Xiao-Mei; Wechman, Stephen L.; Li, Xiao-Feng; McMasters, Kelly M.; Zhou, Heshan Sam

    2015-01-01

    Clinical trials have indicated that preclinical results obtained with human tumor xenografts in mouse models may overstate the potential of adenovirus (Ad)-mediated oncolytic therapies. We have previously demonstrated that the replication of human Ads depends on cyclin E dysregulation or overexpression in cancer cells. ED-1 cell derived from mouse lung adenocarcinomas triggered by transgenic overexpression of human cyclin E may be applied to investigate the antitumor efficacy of oncolytic Ads. Ad-cycE was used to target cyclin E overexpression in ED-1 cells and repress tumor growth in a syngeneic mouse model for investigation of oncolytic virotherapies. Murine ED-1 cells were permissive for human Ad replication and Ad-cycE repressed ED-1 tumor growth in immunocompetent FVB mice. ED-1 cells destroyed by oncolytic Ads in tumors were encircled in capsule-like structures, while cells outside the capsules were not infected and survived the treatment. Ad-cycE can target cyclin E overexpression in cancer cells and repress tumor growth in syngeneic mouse models. The capsule structures formed after Ad intratumoral injection may prevent viral particles from spreading to the entire tumor. The online version of this article (doi:10.1186/s12885-015-1731-x) contains supplementary material, which is available to authorized users

  6. Pediatric cancer gone viral. Part I: strategies for utilizing oncolytic herpes simplex virus-1 in children

    Science.gov (United States)

    Cripe, Timothy P; Chen, Chun-Yu; Denton, Nicholas L; Haworth, Kellie B; Hutzen, Brian; Leddon, Jennifer L; Streby, Keri A; Wang, Pin-Yi; Markert, James M; Waters, Alicia M; Gillespie, George Yancey; Beierle, Elizabeth A; Friedman, Gregory K

    2015-01-01

    Progress for improving outcomes in pediatric patients with solid tumors remains slow. In addition, currently available therapies are fraught with numerous side effects, often causing significant life-long morbidity for long-term survivors. The use of viruses to kill tumor cells based on their increased vulnerability to infection is gaining traction, with several viruses moving through early and advanced phase clinical testing. The prospect of increased efficacy and decreased toxicity with these agents is thus attractive for pediatric cancer. In part I of this two-part review, we focus on strategies for utilizing oncolytic engineered herpes simplex virus (HSV) to target pediatric malignancies. We discuss mechanisms of action, routes of delivery, and the role of preexisting immunity on antitumor efficacy. Challenges to maximizing oncolytic HSV in children are examined, and we highlight how these may be overcome through various arming strategies. We review the preclinical and clinical evidence demonstrating safety of a variety of oncolytic HSVs. In Part II, we focus on the antitumor efficacy of oncolytic HSV in pediatric tumor types, pediatric clinical advances made to date, and future prospects for utilizing HSV in pediatric patients with solid tumors. PMID:26436135

  7. Neuroblastoma cell lines contain pluripotent tumor initiating cells that are susceptible to a targeted oncolytic virus.

    Directory of Open Access Journals (Sweden)

    Yonatan Y Mahller

    Full Text Available Although disease remission can frequently be achieved for patients with neuroblastoma, relapse is common. The cancer stem cell theory suggests that rare tumorigenic cells, resistant to conventional therapy, are responsible for relapse. If true for neuroblastoma, improved cure rates may only be achieved via identification and therapeutic targeting of the neuroblastoma tumor initiating cell. Based on cues from normal stem cells, evidence for tumor populating progenitor cells has been found in a variety of cancers.Four of eight human neuroblastoma cell lines formed tumorspheres in neural stem cell media, and all contained some cells that expressed neurogenic stem cell markers including CD133, ABCG2, and nestin. Three lines tested could be induced into multi-lineage differentiation. LA-N-5 spheres were further studied and showed a verapamil-sensitive side population, relative resistance to doxorubicin, and CD133+ cells showed increased sphere formation and tumorigenicity. Oncolytic viruses, engineered to be clinically safe by genetic mutation, are emerging as next generation anticancer therapeutics. Because oncolytic viruses circumvent typical drug-resistance mechanisms, they may represent an effective therapy for chemotherapy-resistant tumor initiating cells. A Nestin-targeted oncolytic herpes simplex virus efficiently replicated within and killed neuroblastoma tumor initiating cells preventing their ability to form tumors in athymic nude mice.These results suggest that human neuroblastoma contains tumor initiating cells that may be effectively targeted by an oncolytic virus.

  8. Presage of oncolytic virotherapy for oral cancer with herpes simplex virus

    Directory of Open Access Journals (Sweden)

    Yoshiaki Yura

    2017-05-01

    Full Text Available A virus is a pathogenic organism that causes a number of infectious diseases in humans. The oral cavity is the site at which viruses enter and are excreted from the human body. Herpes simplex virus type 1 (HSV-1 produces the primary infectious disease, gingivostomatitis, and recurrent disease, labial herpes. HSV-1 is one of the most extensively investigated viruses used for cancer therapy. In principle, HSV-1 infects epithelial cells and neuronal cells and exhibits cytotoxicity due to its cytopathic effects on these cells. If the replication of the virus occurs in tumor cells, but not normal cells, the virus may be used as an antitumor agent. Therefore, HSV-1 genes have been modified by genetic engineering, and in vitro and in vivo studies with the oncolytic virus have demonstrated its efficiency against head and neck cancer including oral cancer. The oncolytic abilities of other viruses such as adenovirus and reovirus have also been demonstrated. In clinical trials, HSV-1 is the top runner and is now available for the treatment of patients with advanced melanoma. Thus, melanoma in the oral cavity is the target of oncolytic HSV-1. Oncolytic virotherapy is a hopeful and realistic modality for the treatment of oral cancer.

  9. Pediatric cancer gone viral. Part I: strategies for utilizing oncolytic herpes simplex virus-1 in children

    Directory of Open Access Journals (Sweden)

    Timothy P Cripe

    Full Text Available Progress for improving outcomes in pediatric patients with solid tumors remains slow. In addition, currently available therapies are fraught with numerous side effects, often causing significant life-long morbidity for long-term survivors. The use of viruses to kill tumor cells based on their increased vulnerability to infection is gaining traction, with several viruses moving through early and advanced phase clinical testing. The prospect of increased efficacy and decreased toxicity with these agents is thus attractive for pediatric cancer. In part I of this two-part review, we focus on strategies for utilizing oncolytic engineered herpes simplex virus (HSV to target pediatric malignancies. We discuss mechanisms of action, routes of delivery, and the role of preexisting immunity on antitumor efficacy. Challenges to maximizing oncolytic HSV in children are examined, and we highlight how these may be overcome through various arming strategies. We review the preclinical and clinical evidence demonstrating safety of a variety of oncolytic HSVs. In Part II, we focus on the antitumor efficacy of oncolytic HSV in pediatric tumor types, pediatric clinical advances made to date, and future prospects for utilizing HSV in pediatric patients with solid tumors.

  10. Silk-elastin-like protein polymer matrix for intraoperative delivery of an oncolytic vaccinia virus.

    Science.gov (United States)

    Price, Daniel L; Li, Pingdong; Chen, Chun-Hao; Wong, Danni; Yu, Zhenkun; Chen, Nanhai G; Yu, Yong A; Szalay, Aladar A; Cappello, Joseph; Fong, Yuman; Wong, Richard J

    2016-02-01

    Oncolytic viral efficacy may be limited by the penetration of the virus into tumors. This may be enhanced by intraoperative application of virus immediately after surgical resection. Oncolytic vaccinia virus GLV-1h68 was delivered in silk-elastin-like protein polymer (SELP) in vitro and in vivo in anaplastic thyroid carcinoma cell line 8505c in nude mice. GLV-1h68 in SELP infected and lysed anaplastic thyroid cancer cells in vitro equally as effectively as in phosphate-buffered saline (PBS), and at 1 week retains a thousand fold greater infectious plaque-forming units. In surgical resection models of residual tumor, GLV-1h68 in SELP improves tumor control and shows increased viral β-galactosidase expression as compared to PBS. The use of SELP matrix for intraoperative oncolytic viral delivery protects infectious viral particles from degradation, facilitates sustained viral delivery and transgene expression, and improves tumor control. Such optimization of methods of oncolytic viral delivery may enhance therapeutic outcomes. © 2014 Wiley Periodicals, Inc.

  11. 77 FR 22333 - Prospective Grant of Exclusive License: Development of Oncolytic Viral Cancer Therapies

    Science.gov (United States)

    2012-04-13

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Prospective Grant of Exclusive License: Development of Oncolytic Viral Cancer Therapies AGENCY: National Institutes of Health... administration of the recombinant virus to a human or animal subject, the foreign gene is expressed in vivo to...

  12. A novel mobile dual-wavelength laser altimetry system for improved site-specific Nitrogen fertilizer applications

    Science.gov (United States)

    Eitel, J.; Magney, T. S.; Vierling, L. A.; Brown, T. T.; Huggins, D. R.

    2012-12-01

    Reducing fertilizer inputs while maintaining yield would increase farmer's profits and similarly lessen the adverse environmental effects of production agriculture. The development of technologies that allow precise, site-specific application of Nitrogen (N) fertilizer has thus been an important research goal over the past decades. Remote sensing of foliar crop properties and function with tractor-mountable optical sensors has thought to be useful to optimize N fertilizer applications. However, on-the-go sensing of foliar crop properties and function has proven difficult, particularly during early crop growth stages when fertilizer decisions are often made. This difficulty arises from the fact that the spectral signal measured by on-the-go sensors is dominated by soil reflectance during early crop growth stages. Here, we present the basic principles behind a novel, dual-wavelength, tractor mountable laser altimetry system that measures the laser return intensity of the reflected green and red laser light. The green (532 nm) and the red (660 nm) wavelength combination allows calculation of a modified Photochemical Reflectance Index (mPRI) that have shown to be sensitive to both crop function and foliar chemistry. The small field of view of the laser points (diameter: 4 mm) combined with its high sampling rate (1000 points sec-1) allows vegetation returns to be isolated from ground returns by using simple thresholds. First tests relating foliar N of winter wheat (Triticum aestivum L.) with laser derived mPRI are promising (r2 = 0.72). Further research is needed to test the relationship between laser derived spectral indices and crop function.

  13. Treatment of medulloblastoma with oncolytic measles viruses expressing the angiogenesis inhibitors endostatin and angiostatin

    International Nuclear Information System (INIS)

    Hutzen, Brian; Bid, Hemant Kumar; Houghton, Peter J; Pierson, Christopher R; Powell, Kimerly; Bratasz, Anna; Raffel, Corey; Studebaker, Adam W

    2014-01-01

    Medulloblastoma is the most common type of pediatric brain tumor. Although numerous factors influence patient survival rates, more than 30% of all cases will ultimately be refractory to conventional therapies. Current standards of care are also associated with significant morbidities, giving impetus for the development of new treatments. We have previously shown that oncolytic measles virotherapy is effective against medulloblastoma, leading to significant prolongation of survival and even cures in mouse xenograft models of localized and metastatic disease. Because medulloblastomas are known to be highly vascularized tumors, we reasoned that the addition of angiogenesis inhibitors could further enhance the efficacy of oncolytic measles virotherapy. Toward this end, we have engineered an oncolytic measles virus that express a fusion protein of endostatin and angiostatin, two endogenous and potent inhibitors of angiogenesis. Oncolytic measles viruses encoding human and mouse variants of a secretable endostatin/angiostatin fusion protein were designed and rescued according to established protocols. These viruses, known as MV-hE:A and MV-mE:A respectively, were then evaluated for their anti-angiogenic potential and efficacy against medulloblastoma cell lines and orthotopic mouse models of localized disease. Medulloblastoma cells infected by MV-E:A readily secrete endostatin and angiostatin prior to lysis. The inclusion of the endostatin/angiostatin gene did not negatively impact the measles virus’ cytotoxicity against medulloblastoma cells or alter its growth kinetics. Conditioned media obtained from these infected cells was capable of inhibiting multiple angiogenic factors in vitro, significantly reducing endothelial cell tube formation, viability and migration compared to conditioned media derived from cells infected by a control measles virus. Mice that were given a single intratumoral injection of MV-E:A likewise showed reduced numbers of tumor-associated blood

  14. Dual specificity phosphatase 6 deficiency is associated with impaired systemic glucose tolerance and reversible weight retardation in mice.

    Directory of Open Access Journals (Sweden)

    Katrin Pfuhlmann

    Full Text Available Here, we aimed to investigate the potential role of DUSP6, a dual specificity phosphatase, that specifically inactivates extracellular signal-regulated kinase (ERK, for the regulation of body weight and glucose homeostasis. We further assessed whether metabolic challenges affect Dusp6 expression in selected brain areas or white adipose tissue. Hypothalamic Dusp6 mRNA levels remained unchanged in chow-fed lean vs. high fat diet (HFD fed obese C57Bl/6J mice, and in C57Bl/6J mice undergoing prolonged fasting or refeeding with fat free diet (FFD or HFD. Similarly, Dusp6 expression levels were unchanged in selected brain regions of Lepob mice treated with 1 mg/kg of leptin for 6 days, compared to pair-fed or saline-treated Lepob controls. Dusp6 expression levels remained unaltered in vitro in primary adipocytes undergoing differentiation, but were increased in eWAT of HFD-fed obese C57Bl/6J mice, compared to chow-fed lean controls. Global chow-fed DUSP6 KO mice displayed reduced body weight and lean mass and slightly increased fat mass at a young age, which is indicative for early-age weight retardation. Subsequent exposure to HFD led to a significant increase in lean mass and body weight in DUSP6 deficient mice, compared to WT controls. Nevertheless, after 26 weeks of high-fat diet exposure, we observed comparable body weight, fat and lean mass in DUSP6 WT and KO mice, suggesting overall normal susceptibility to develop obesity. In line with the increased weight gain to compensate for early-age weight retardation, HFD-fed DUSP6 KO displayed increased expression levels of anabolic genes involved in lipid and cholesterol metabolism in the epididymal white adipose tissue (eWAT, compared to WT controls. Glucose tolerance was perturbed in both chow-fed lean or HFD-fed obese DUSP6 KO, compared to their respective WT controls. Overall, our data indicate that DUSP6 deficiency has limited impact on the regulation of energy metabolism, but impairs systemic

  15. Sensitivity and specificity of simultaneously acquired (dual channel) radiogallium and Tc-99m-HDP in painful hip and knee prosthetic joints

    International Nuclear Information System (INIS)

    Skarzynski, J.J.; Sziklas, J.J.; Rosenberg, R.J.; Rich, D.A.; Spencer, R.P.

    1985-01-01

    Differentiation of prosthetic loosening from infection, by use of sequential bone and radiogallium imaging, has been discussed in the literature. The authors investigated simultaneous (2 channel) imaging of Ga-67 and Tc-99m-HDP in multiviews, in order to assess the parameter of Tc-99m-Ga-67 incongruity. Acquisition of data was carried out 2 days after 5 mCi of Ga-67 citrate IV and 2 hours after 8 mCi of Tc-99m-HDP. Dual data channels were used to insure perfect superimposition of the images and to reduce total imaging time. Normalized bone images were taken, then subtracted from those of Ga-67, by means of progressive weighting factors. A total of 68 studies were carried out on 43 patients. Exams involved both knee and hip prostheses, in population with 63% of the patients over age 60 years. Time from placement of the prosthesis to the dual radionuclide exam was within 2 years in 48% and within 5 years in 78%. Sensitivity was 0.88 and specificity 0.89. Using information on the follow-up dual channel studies, 40/43 cases were correctly identified (93%). Dual channel radionuclide imaging offers a readily available and accurate means of differentiating infection from loosening of hip or knee prostheses

  16. Dual Mode Fluorophore-Doped Nickel Nitrilotriacetic Acid-Modified Silica Nanoparticles Combine Histidine-Tagged Protein Purification with Site-Specific Fluorophore Labeling

    OpenAIRE

    Kim, Sung Hoon; Jeyakumar, M.; Katzenellenbogen, John A.

    2007-01-01

    We present the first example of a fluorophore-doped nickel chelate surface- modified silica nanoparticle that functions in a dual mode, combining histidine-tagged protein purification with site-specific fluorophore labeling. Tetramethylrhodamine (TMR)-doped silica nanoparticles, estimated to contain 700–900 TMRs per ca. 23-nm particle, were surface modified with nitrilotriacetic acid (NTA), producing TMR-SiO2-NTA-Ni+2. Silica-embedded TMR retains very high quantum yield, is resistant to quenc...

  17. Toward a Molecular Understanding of the Interaction of Dual Specificity Phosphatases with Substrates: Insights from Structure-Based Modeling and High Throughput Screening

    OpenAIRE

    Bakan, Ahmet; Lazo, John S; Wipf, Peter; Brummond, Kay M; Bahar, Ivet

    2008-01-01

    Dual-specificity phosphatases (DSPs) are important, but poorly understood, cell signaling enzymes that remove phosphate groups from tyrosine and serine/threonine residues on their substrate. Deregulation of DSPs has been implicated in cancer, obesity, diabetes, inflammation, and Alzheimer’s disease. Due to their biological and biomedical significance, DSPs have increasingly become the subject of drug discovery high-throughput screening (HTS) and focused compound library development efforts. P...

  18. Expression of DAI by an oncolytic vaccinia virus boosts the immunogenicity of the virus and enhances antitumor immunity

    Directory of Open Access Journals (Sweden)

    Mari Hirvinen

    2016-01-01

    Full Text Available In oncolytic virotherapy, the ability of the virus to activate the immune system is a key attribute with regard to long-term antitumor effects. Vaccinia viruses bear one of the strongest oncolytic activities among all oncolytic viruses. However, its capacity for stimulation of antitumor immunity is not optimal, mainly due to its immunosuppressive nature. To overcome this problem, we developed an oncolytic VV that expresses intracellular pattern recognition receptor DNA-dependent activator of IFN-regulatory factors (DAI to boost the innate immune system and to activate adaptive immune cells in the tumor. We showed that infection with DAI-expressing VV increases expression of several genes related to important immunological pathways. Treatment with DAI-armed VV resulted in significant reduction in the size of syngeneic melanoma tumors in mice. When the mice were rechallenged with the same tumor, DAI-VV-treated mice completely rejected growth of the new tumor, which indicates immunity established against the tumor. We also showed enhanced control of growth of human melanoma tumors and elevated levels of human T-cells in DAI-VV-treated mice humanized with human peripheral blood mononuclear cells. We conclude that expression of DAI by an oncolytic VV is a promising way to amplify the vaccine potency of an oncolytic vaccinia virus to trigger the innate—and eventually the long-lasting adaptive immunity against cancer.

  19. Promoting Preservice Teachers' Dual Self-Regulation Roles as Learners and as Teachers: Effects of Generic vs. Specific Prompts

    Science.gov (United States)

    Kramarski, Bracha; Kohen, Zehavit

    2017-01-01

    Researchers have recently suggested that teachers must undertake important dual self-regulation roles if they want to become effective at improving their students' self-regulation. First, teachers need to become proficient at self-regulated learning (SRL) themselves, and then teachers need to learn explicitly how to proactively teach SRL -- termed…

  20. Macromolecular bipill of gemcitabine and methotrexate facilitates tumor-specific dual drug therapy with higher benefit-to-risk ratio

    DEFF Research Database (Denmark)

    Das, Manasmita; Jain, Roopal; Agrawal, Ashish Kumar

    2014-01-01

    -PEG-MTX conjugate over all other pharmaceutical preparations including free drugs, physical mixture of GEM and MTX, and PEGylated GEM/MTX. Toxicity studies in tumor bearing rats as well as healthy mice corroborated that dual drug conjugation is an effective means to synergize the therapeutic indices of potential...

  1. Inhibitors of dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) exert a strong anti-herpesviral activity.

    Science.gov (United States)

    Hutterer, Corina; Milbradt, Jens; Hamilton, Stuart; Zaja, Mirko; Leban, Johann; Henry, Christophe; Vitt, Daniel; Steingruber, Mirjam; Sonntag, Eric; Zeitträger, Isabel; Bahsi, Hanife; Stamminger, Thomas; Rawlinson, William; Strobl, Stefan; Marschall, Manfred

    2017-07-01

    Infection with human cytomegalovirus (HCMV) is a serious medical problem, particularly in immunocompromised individuals and neonates. The success of (val)ganciclovir therapy is hampered by low drug compatibility and induction of viral resistance. A novel strategy of antiviral treatment is based on the exploitation of cell-directed signaling, e. g. pathways with a known relevance for carcinogenesis and tumor drug development. Here we describe a principle for putative antiviral drugs based on targeting dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs). DYRKs constitute an evolutionarily conserved family of protein kinases with key roles in the control of cell proliferation and differentiation. Members of the DYRK family are capable of phosphorylating a number of substrate proteins, including regulators of the cell cycle, e.g. DYRK1B can induce cell cycle arrest, a critical step for the regulation of HCMV replication. Here we provide first evidence for a critical role of DYRKs during viral replication and the high antiviral potential of DYRK inhibitors (SC84227, SC97202 and SC97208, Harmine and AZ-191). Using established replication assays for laboratory and clinically relevant strains of HCMV, concentration-dependent profiles of inhibition were obtained. Mean inhibitory concentrations (EC50) of 0.98 ± 0.08 μM/SC84227, 0.60 ± 0.02 μM/SC97202, 6.26 ± 1.64 μM/SC97208, 0.71 ± 0.019 μM/Harmine and 0.63 ± 0.23 μM/AZ-191 were determined with HCMV strain AD169-GFP for the infection of primary human fibroblasts. A first analysis of the mode of antiviral action suggested a block of viral replication at the early-late stage of HCMV gene expression. Moreover, rhesus macaque cytomegalovirus (RhCMV), varicella-zoster virus (VZV) and herpes simplex virus (HSV-1) showed a similarly high sensitivity to these compounds. Thus, we conclude that DYRK signaling represents a promising target pathway for the development of novel anti

  2. Immunogenicity of oncolytic vaccinia viruses JX-GFP and TG6002 in a human melanoma in vitro model: studying immunogenic cell death, dendritic cell maturation and interaction with cytotoxic T lymphocytes

    Directory of Open Access Journals (Sweden)

    Heinrich B

    2017-05-01

    Full Text Available B Heinrich,1 J Klein,1 M Delic,1 K Goepfert,1 V Engel,1 L Geberzahn,1 M Lusky,2 P Erbs,2 X Preville,3 M Moehler1 1First Department of Internal Medicine, University Medical Center Mainz, Mainz, Germany; 2Transgene SA, Illkirch-Graffenstaden, 3Amoneta Diagnostics, Huningue, France Abstract: Oncolytic virotherapy is an emerging immunotherapeutic modality for cancer treatment. Oncolytic viruses with genetic modifications can further enhance the oncolytic effects on tumor cells and stimulate antitumor immunity. The oncolytic vaccinia viruses JX-594-GFP+/hGM-CSF (JX-GFP and TG6002 are genetically modified by secreting granulocyte-macrophage colony-stimulating factor (GM-CSF or transforming 5-fluorocytosine (5-FC into 5-fluorouracil (5-FU. We compared their properties to kill tumor cells and induce an immunogenic type of cell death in a human melanoma cell model using SK29-MEL melanoma cells. Their influence on human immune cells, specifically regarding the activation of dendritic cells (DCs and the interaction with the autologous cytotoxic T lymphocyte (CTL clone, was investigated. Melanoma cells were infected with either JX-GFP or TG6002 alone or in combination with 5-FC and 5-FU. The influence of viral infection on cell viability followed a time- and multiplicity of infection dependent manner. Combination of virus treatment with 5-FU resulted in stronger reduction of cell viability. TG6002 in combination with 5-FC did not significantly strengthen the reduction of cell viability in this setting. Expression of calreticulin and high mobility group 1 protein (HMGB1, markers of immunogenic cell death (ICD, could be detected after viral infection. Accordingly, DC maturation was noted after viral oncolysis. DCs presented stronger expression of activation and maturation markers. The autologous CTL clone IVSB expressed the activation marker CD69, but viral treatment failed to enhance cytotoxicity marker. In summary, vaccinia viruses JX-GFP and TG6002 lyse

  3. Dual-mode fluorophore-doped nickel nitrilotriacetic acid-modified silica nanoparticles combine histidine-tagged protein purification with site-specific fluorophore labeling.

    Science.gov (United States)

    Kim, Sung Hoon; Jeyakumar, M; Katzenellenbogen, John A

    2007-10-31

    We present the first example of a fluorophore-doped nickel chelate surface-modified silica nanoparticle that functions in a dual mode, combining histidine-tagged protein purification with site-specific fluorophore labeling. Tetramethylrhodamine (TMR)-doped silica nanoparticles, estimated to contain 700-900 TMRs per ca. 23 nm particle, were surface modified with nitrilotriacetic acid (NTA), producing TMR-SiO2-NTA-Ni2+. Silica-embedded TMR retains very high quantum yield, is resistant to quenching by buffer components, and is modestly quenched and only to a certain depth (ca. 2 nm) by surface-attached Ni2+. When exposed to a bacterial lysate containing estrogen receptor alpha ligand binding domain (ERalpha) as a minor component, these beads showed very high specificity binding, enabling protein purification in one step. The capacity and specificity of these beads for binding a his-tagged protein were characterized by electrophoresis, radiometric counting, and MALDI-TOF MS. ERalpha, bound to TMR-SiO2-NTA-Ni++ beads in a site-specific manner, exhibited good activity for ligand binding and for ligand-induced binding to coactivators in solution FRET experiments and protein microarray fluorometric and FRET assays. This dual-mode type TMR-SiO2-NTA-Ni2+ system represents a powerful combination of one-step histidine-tagged protein purification and site-specific labeling with multiple fluorophore species.

  4. Oncorine, the World First Oncolytic Virus Medicine and its Update in China.

    Science.gov (United States)

    Liang, Min

    2018-01-01

    The oncolytic viruses now hold a promise of new therapeutic strategy for cancer. Its concept has inspired a wave of commercial research and development activities for the products of this category in China since 1998. The first commercialized oncolytic virus product in the world, Oncorine (H101), developed by Shanghai Sunway Biotech Co., Ltd since 1999, was approved by Chinese SFDA in November, 2005 for nasopharyngeal carcinoma in combination with chemotherapy after the phase III clinical trial, and finally acquired GMP certificate in August, 2006. This review introduces how Oncorine was successfully developed in China, and how the Chinese market responded after it was launched into the market in 2006. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Combinatorial Effects of VEGFR Kinase Inhibitor Axitinib and Oncolytic Virotherapy in Mouse and Human Glioblastoma Stem-Like Cell Models.

    Science.gov (United States)

    Saha, Dipongkor; Wakimoto, Hiroaki; Peters, Cole W; Antoszczyk, Slawomir J; Rabkin, Samuel D; Martuza, Robert L

    2018-03-29

    Purpose: Glioblastoma (GBM), a fatal brain cancer, contains a subpopulation of GBM stem-like cells (GSCs) that contribute to resistance to current therapy. Angiogenesis also plays a key role in GBM progression. Therefore, we developed a strategy to target the complex GBM microenvironment, including GSCs and tumor vasculature. Experimental Design: We evaluated the cytotoxic effects of VEFGR tyrosine kinase inhibitor (TKI) axitinib in vitro and then tested antitumor efficacy of axitinib in combination with oncolytic herpes simplex virus (oHSV) expressing antiangiogenic cytokine murine IL12 (G47Δ-mIL12) in two orthotopic GSC-derived GBM models: patient-derived recurrent MGG123 GSCs, forming vascular xenografts in immunodeficient mice; and mouse 005 GSCs, forming syngeneic tumors in immunocompetent mice. Results: GSCs form endothelial-like tubes and were sensitive to axitinib. G47Δ-mIL12 significantly improved survival, as did axitinib, while dual combinations further extended survival significantly compared with single therapies alone in both models. In MGG123 tumors, axitinib was effective only at high doses (50 mg/kg), alone and in combination with G47Δ-mIL12, and this was associated with greatly decreased vascularity, increased macrophage infiltration, extensive tumor necrosis, and PDGFR/ERK pathway inhibition. In the mouse 005 model, antiglioma activity, after single and combination therapy, was only observed in immunocompetent mice and not the T-cell-deficient athymic mice. Interestingly, immune checkpoint inhibition did not improve efficacy. Conclusions: Systemic TKI (axitinib) beneficially combines with G47Δ-mIL12 to enhance antitumor efficacy in both immunodeficient and immunocompetent orthotopic GBM models. Our results support further investigation of TKIs in combination with oHSV for GBM treatment. Clin Cancer Res; 1-14. ©2018 AACR. ©2018 American Association for Cancer Research.

  6. Reovirus FAST Protein Enhances Vesicular Stomatitis Virus Oncolytic Virotherapy in Primary and Metastatic Tumor Models

    Directory of Open Access Journals (Sweden)

    Fabrice Le Boeuf

    2017-09-01

    Full Text Available The reovirus fusion-associated small transmembrane (FAST proteins are the smallest known viral fusogens (∼100–150 amino acids and efficiently induce cell-cell fusion and syncytium formation in multiple cell types. Syncytium formation enhances cell-cell virus transmission and may also induce immunogenic cell death, a form of apoptosis that stimulates immune recognition of tumor cells. These properties suggest that FAST proteins might serve to enhance oncolytic virotherapy. The oncolytic activity of recombinant VSVΔM51 (an interferon-sensitive vesicular stomatitis virus [VSV] mutant encoding the p14 FAST protein (VSV-p14 was compared with a similar construct encoding GFP (VSV-GFP in cell culture and syngeneic BALB/c tumor models. Compared with VSV-GFP, VSV-p14 exhibited increased oncolytic activity against MCF-7 and 4T1 breast cancer spheroids in culture and reduced primary 4T1 breast tumor growth in vivo. VSV-p14 prolonged survival in both primary and metastatic 4T1 breast cancer models, and in a CT26 metastatic colon cancer model. As with VSV-GFP, VSV-p14 preferentially replicated in vivo in tumors and was cleared rapidly from other sites. Furthermore, VSV-p14 increased the numbers of activated splenic CD4, CD8, natural killer (NK, and natural killer T (NKT cells, and increased the number of activated CD4 and CD8 cells in tumors. FAST proteins may therefore provide a multi-pronged approach to improving oncolytic virotherapy via syncytium formation and enhanced immune stimulation.

  7. Sensitivity of C6 Glioma Cells Carrying the Human Poliovirus Receptor to Oncolytic Polioviruses.

    Science.gov (United States)

    Sosnovtseva, A O; Lipatova, A V; Grinenko, N F; Baklaushev, V P; Chumakov, P M; Chekhonin, V P

    2016-10-01

    A humanized line of rat C6 glioma cells expressing human poliovirus receptor was obtained and tested for the sensitivity to oncolytic effects of vaccine strains of type 1, 2, and 3 polioviruses. Presentation of the poliovirus receptor on the surface of C6 glioma cells was shown to be a necessary condition for the interaction of cells with polioviruses, but insufficient for complete poliovirus oncolysis.

  8. Proof-of-principle that a decoy virus protects oncolytic measles virus against neutralizing antibodies

    OpenAIRE

    Xu C; Goß AV; Dorneburg C; Debatin KM; Wei J; Beltinger C

    2018-01-01

    Chun Xu,1,2,* Annika Verena Goß,1,* Carmen Dorneburg,1 Klaus-Michael Debatin,1 Jiwu Wei,2 Christian Beltinger1 1Department of Pediatrics and Adolescent Medicine, Section of Experimental Pediatric Oncology, University Medical Center Ulm, Ulm, Germany; 2Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, China *These authors contributed equally to this work Background: Attenuated oncolytic measles virus (OMV) is a promising antitumor agent in early-phase cl...

  9. Exploring metal artifact reduction using dual-energy CT with pre-metal and post-metal implant cadaver comparison: are implant specific protocols needed?

    Science.gov (United States)

    Wellenberg, Ruud H H; Donders, Johanna C E; Kloen, Peter; Beenen, Ludo F M; Kleipool, Roeland P; Maas, Mario; Streekstra, Geert J

    2017-08-25

    To quantify and optimize metal artifact reduction using virtual monochromatic dual-energy CT for different metal implants compared to non-metal reference scans. Dual-energy CT scans of a pair of human cadaver limbs were acquired before and after implanting a titanium tibia plate, a stainless-steel tibia plate and a titanium intramedullary nail respectively. Virtual monochromatic images were analyzed from 70 to 190 keV. Region-of-interest (ROI), used to determine fluctuations and inaccuracies in CT numbers of soft tissues and bone, were placed in muscle, fat, cortical bone and intramedullary tibia canal. The stainless-steel implant resulted in more pronounced metal artifacts compared to both titanium implants. CT number inaccuracies in 70 keV reference images were minimized at 130, 180 and 190 keV for the titanium tibia plate, stainless-steel tibia plate and titanium intramedullary nail respectively. Noise, measured as the standard deviation of pixels within a ROI, was minimized at 130, 150 and 140 keV for the titanium tibia plate, stainless-steel tibia plate and titanium intramedullary nail respectively. Tailoring dual-energy CT protocols using implant specific virtual monochromatic images minimizes fluctuations and inaccuracies in CT numbers in bone and soft tissues compared to non-metal reference scans.

  10. Targeting an Oncolytic Influenza A Virus to Tumor Tissue by Elastase

    Directory of Open Access Journals (Sweden)

    Irina Kuznetsova

    2017-12-01

    Full Text Available Oncolytic viruses are currently established as a novel type of immunotherapy. The challenge is to safely target oncolytic viruses to tumors. Previously, we have generated influenza A viruses (IAVs containing deletions in the viral interferon antagonist. Those deletions have attenuated the virus in normal tissue but allowed replication in tumor cells. IAV entry is mediated by hemagglutinin (HA, which needs to be activated by a serine protease, for example, through trypsin. To further target the IAV to tumors, we have changed the trypsin cleavage site to an elastase cleavage site. We chose this cleavage site because elastase is expressed in the tumor microenvironment. Moreover, the exchange of the cleavage site previously has been shown to attenuate viral growth in lungs. Newly generated elastase-activated influenza viruses (AE viruses grew to similar titers in tumor cells as the trypsin-activated counterparts (AT viruses. Intratumoral injection of AE viruses into syngeneic B16f1 melanoma-derived tumors in mice reduced tumor growth similar to AT viruses and had a better therapeutic effect in heterologous human PANC-1-derived tumors. Therefore, the introduction of the attenuation marker “elastase cleavage site” in viral HA allows for safe, effective oncolytic virus therapy.

  11. A novel, polymer-coated oncolytic measles virus overcomes immune suppression and induces robust antitumor activity

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    Kaname Nosaki

    2016-01-01

    Full Text Available Although various therapies are available to treat cancers, including surgery, chemotherapy, and radiotherapy, cancer has been the leading cause of death in Japan for the last 30 years, and new therapeutic modalities are urgently needed. As a new modality, there has recently been great interest in oncolytic virotherapy, with measles virus being a candidate virus expected to show strong antitumor effects. The efficacy of virotherapy, however, was strongly limited by the host immune response in previous clinical trials. To enhance and prolong the antitumor activity of virotherapy, we combined the use of two newly developed tools: the genetically engineered measles virus (MV-NPL and the multilayer virus-coating method of layer-by-layer deposition of ionic polymers. We compared the oncolytic effects of this polymer-coated MV-NPL with the naked MV-NPL, both in vitro and in vivo. In the presence of anti-MV neutralizing antibodies, the polymer-coated virus showed more enhanced oncolytic activity than did the naked MV-NPL in vitro. We also examined antitumor activities in virus-treated mice. Complement-dependent cytotoxicity and antitumor activities were higher in mice treated with polymer-coated MV-NPL than in mice treated with the naked virus. This novel, polymer-coated MV-NPL is promising for clinical cancer therapy in the future.

  12. Preclinical evaluation of oncolytic vaccinia virus for therapy of canine soft tissue sarcoma.

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    Ivaylo Gentschev

    Full Text Available Virotherapy using oncolytic vaccinia virus (VACV strains is one promising new strategy for canine cancer therapy. In this study we describe the establishment of an in vivo model of canine soft tissue sarcoma (CSTS using the new isolated cell line STSA-1 and the analysis of the virus-mediated oncolytic and immunological effects of two different Lister VACV LIVP1.1.1 and GLV-1h68 strains against CSTS. Cell culture data demonstrated that both tested VACV strains efficiently infected and destroyed cells of the canine soft tissue sarcoma line STSA-1. In addition, in our new canine sarcoma tumor xenograft mouse model, systemic administration of LIVP1.1.1 or GLV-1h68 viruses led to significant inhibition of tumor growth compared to control mice. Furthermore, LIVP1.1.1 mediated therapy resulted in almost complete tumor regression and resulted in long-term survival of sarcoma-bearing mice. The replication of the tested VACV strains in tumor tissues led to strong oncolytic effects accompanied by an intense intratumoral infiltration of host immune cells, mainly neutrophils. These findings suggest that the direct viral oncolysis of tumor cells and the virus-dependent activation of tumor-associated host immune cells could be crucial parts of anti-tumor mechanism in STSA-1 xenografts. In summary, the data showed that both tested vaccinia virus strains and especially LIVP1.1.1 have great potential for effective treatment of CSTS.

  13. Targeting Poxvirus Decapping Enzymes and mRNA Decay to Generate an Effective Oncolytic Virus

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    Hannah Burgess

    2018-03-01

    Full Text Available Through the action of two virus-encoded decapping enzymes (D9 and D10 that remove protective caps from mRNA 5′-termini, Vaccinia virus (VACV accelerates mRNA decay and limits activation of host defenses. D9- or D10-deficient VACV are markedly attenuated in mice and fail to counter cellular double-stranded RNA-responsive innate immune effectors, including PKR. Here, we capitalize upon this phenotype and demonstrate that VACV deficient in either decapping enzyme are effective oncolytic viruses. Significantly, D9- or D10-deficient VACV displayed anti-tumor activity against syngeneic mouse tumors of different genetic backgrounds and human hepatocellular carcinoma xenografts. Furthermore, D9- and D10-deficient VACV hyperactivated the host anti-viral enzyme PKR in non-tumorigenic cells compared to wild-type virus. This establishes a new genetic platform for oncolytic VACV development that is deficient for a major pathogenesis determinant while retaining viral genes that support robust productive replication like those required for nucleotide metabolism. It further demonstrates how VACV mutants unable to execute a fundamental step in virus-induced mRNA decay can be unexpectedly translated into a powerful anti-tumor therapy. Keywords: oncolytic virus, mRNA decay, decapping

  14. Novel therapeutic strategies in human malignancy: combining immunotherapy and oncolytic virotherapy

    Directory of Open Access Journals (Sweden)

    Sampath P

    2015-06-01

    Full Text Available Padma Sampath, Steve H Thorne Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA Abstract: Results from randomized clinical trials over the last several years have finally begun to demonstrate the potential of oncolytic viral therapies to treat a variety of cancers. One reason for these successes has been the realization that this platform is most effective when considered primarily as an immunotherapy. Cancer immunotherapy has also made dramatic strides recently with antibodies capable of blocking immune checkpoint inhibitors and adoptive T-cell therapies, notably CAR T-cells, leading a panel of novel and highly clinically effective therapies. It is clear therefore that an understanding of how and when these complementary approaches can most effectively be combined offers the real hope of moving beyond simply treating the disease and toward starting to talk about curative therapies. In this review we discuss approaches to combining these therapeutic platforms, both through engineering the viral vectors to more beneficially interact with the host immune response during therapy, as well as through the direct combinations of different therapeutics. This primarily, but not exclusively focuses on strains of oncolytic vaccinia virus. Some of the results reported to date, primarily in pre-clinical models but also in early clinical trials, are dramatic and hold great promise for the future development of similar therapies and their translation into cancer therapies. Keywords: oncolytic virus, CAR T-cell, adoptive cell therapy, immune checkpoint inhibitor 

  15. Imaging characteristics, tissue distribution, and spread of a novel oncolytic vaccinia virus carrying the human sodium iodide symporter.

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    Dana Haddad

    Full Text Available INTRODUCTION: Oncolytic viruses show promise for treating cancer. However, to assess therapy and potential toxicity, a noninvasive imaging modality is needed. This study aims to determine the in vivo biodistribution, and imaging and timing characteristics of a vaccinia virus, GLV-1h153, encoding the human sodium iodide symporter (hNIS. METHODS: GLV-1h153 was modified from GLV-1h68 to encode the hNIS gene. Timing of cellular uptake of radioiodide (131I in human pancreatic carcinoma cells PANC-1 was assessed using radiouptake assays. Viral biodistribution was determined in nude mice bearing PANC-1 xenografts, and infection in tumors confirmed histologically and optically via Green Fluorescent Protein (GFP and bioluminescence. Timing characteristics of enhanced radiouptake in xenografts were assessed via (124I-positron emission tomography (PET. Detection of systemic administration of virus was investigated with both (124I-PET and 99m-technecium gamma-scintigraphy. RESULTS: GLV-1h153 successfully facilitated time-dependent intracellular uptake of (131I in PANC-1 cells with a maximum uptake at 24 hours postinfection (P<0.05. In vivo, biodistribution profiles revealed persistence of virus in tumors 5 weeks postinjection at 10(9 plaque-forming unit (PFU/gm tissue, with the virus mainly cleared from all other major organs. Tumor infection by GLV-1h153 was confirmed via optical imaging and histology. GLV-1h153 facilitated imaging virus replication in tumors via PET even at 8 hours post radiotracer injection, with a mean %ID/gm of 3.82 ± 0.46 (P<0.05 2 days after intratumoral administration of virus, confirmed via tissue radiouptake assays. One week post systemic administration, GLV-1h153-infected tumors were detected via (124I-PET and 99m-technecium-scintigraphy. CONCLUSION: GLV-1h153 is a promising oncolytic agent against pancreatic cancer with a promising biosafety profile. GLV-1h153 facilitated time-dependent hNIS-specific radiouptake in pancreatic

  16. The combination of i-leader truncation and gemcitabine improves oncolytic adenovirus efficacy in an immunocompetent model.

    Science.gov (United States)

    Puig-Saus, C; Laborda, E; Rodríguez-García, A; Cascalló, M; Moreno, R; Alemany, R

    2014-02-01

    Adenovirus (Ad) i-leader protein is a small protein of unknown function. The C-terminus truncation of the i-leader protein increases Ad release from infected cells and cytotoxicity. In the current study, we use the i-leader truncation to enhance the potency of an oncolytic Ad. In vitro, an i-leader truncated oncolytic Ad is released faster to the supernatant of infected cells, generates larger plaques, and is more cytotoxic in both human and Syrian hamster cell lines. In mice bearing human tumor xenografts, the i-leader truncation enhances oncolytic efficacy. However, in a Syrian hamster pancreatic tumor model, which is immunocompetent and less permissive to human Ad, antitumor efficacy is only observed when the i-leader truncated oncolytic Ad, but not the non-truncated version, is combined with gemcitabine. This synergistic effect observed in the Syrian hamster model was not seen in vitro or in immunodeficient mice bearing the same pancreatic hamster tumors, suggesting a role of the immune system in this synergism. These results highlight the interest of the i-leader C-terminus truncation because it enhances the antitumor potency of an oncolytic Ad and provides synergistic effects with gemcitabine in the presence of an immune competent system.

  17. DYRK1A (Dual-Specificity Tyrosine-Phosphorylated and -Regulated Kinase 1A: A Gene with Dosage Effect During Development and Neurogenesis

    Directory of Open Access Journals (Sweden)

    M. Dierssen

    2006-01-01

    Full Text Available DYRKs (dual-specificity tyrosine-regulated kinases are an emerging family of evolutionarily conserved dual-specificity kinases that play key roles in cell proliferation, survival, and development. The research in the last years suggests a relevant conserved function during neuronal development, related to proliferation and/or differentiation for DYRK1A. It is expressed in neural progenitor cells and has been proposed to participate in the signaling mechanisms that regulate dendrite differentiation. In Drosophila, disruption of the homolog minibrain gene results in flies with reduced neuroblast proliferation, decreased numbers of central brain neurons, and learning/memory deficits. Knockout DYRK1A mice are embryonic lethal, and heterozygotes show decreased viability and region-specific reductions in brain size. In humans, DYRK1A has been proposed to be involved in the neurodevelopmental alterations associated with Down syndrome. The large number of protein interaction and putative substrates described for DYRK1A suggest multiple pathways and functions to be involved in its developmental function. This review focuses on the functional role that DYRK1A plays in brain development.

  18. Oncolytic measles virus enhances antitumour responses of adoptive CD8+NKG2D+ cells in hepatocellular carcinoma treatment.

    Science.gov (United States)

    Chen, Aiping; Zhang, Yonghui; Meng, Gang; Jiang, Dengxu; Zhang, Hailin; Zheng, Meihong; Xia, Mao; Jiang, Aiqin; Wu, Junhua; Beltinger, Christian; Wei, Jiwu

    2017-07-12

    There is an urgent need for novel effective treatment for hepatocellular carcinoma (HCC). Oncolytic viruses (OVs) not only directly lyse malignant cells, but also induce potent antitumour immune responses. The potency and precise mechanisms of antitumour immune activation by attenuated measles virus remain unclear. In this study, we investigated the potency of the measles virus vaccine strain Edmonston (MV-Edm) in improving adoptive CD8 + NKG2D + cells for HCC treatment. We show that MV-Edm-infected HCC enhanced the antitumour activity of CD8 + NKG2D + cells, mediated by at least three distinct mechanisms. First, MV-Edm infection compelled HCC cells to express the specific NKG2D ligands MICA/B, which may contribute to the activation of CD8 + NKG2D + cells. Second, MV-Edm-infected HCC cells stimulated CD8 + NKG2D + cells to express high level of FasL resulting in enhanced induction of apoptosis. Third, intratumoural administration of MV-Edm enhanced infiltration of intravenously injected CD8 + NKG2D + cells. Moreover, we found that MV-Edm and adoptive CD8 + NKG2D + cells, either administered alone or combined, upregulated the immune suppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in HCC. Elimination of IDO1 by fludarabine enhanced antitumour responses. Taken together, our data provide a novel and clinically relevant strategy for treatment of HCC.

  19. Dual specific oral tolerance induction using interferon gamma for IgE-mediated anaphylactic food allergy and the dissociation of local skin allergy and systemic oral allergy: tolerance or desensitization?

    Science.gov (United States)

    Noh, G; Jang, E H

    2014-01-01

    Specific oral tolerance induction (SOTI) for IgE-mediated food allergy (IFA) can be successfully achieved using interfero gamma (classic SOTI). In this study, a tolerable dose was introduced during tolerance induction with interferon gamma (dual SOTI), and its effectiveness was evaluated. The study population comprised 25 IFA patients. Blood samples were taken for analysis, including complete blood count with differential counts of eosinophils, serum total IgE levels, and specific IgE for allergenic foods. Skin prick tests were conducted with the allergens. Oral food challenges were performed to diagnose IFA. Ten patients received dual SOTI, 5 received classic SOTI, 5 received SOTI without interferon gamma (original SOTI), and 5 were not treated (controls). Patients treated with dual SOTI and classic SOTI using interferon gamma became tolerant to the allergenic food. The tolerable dose was introduced successfully in dual SOTI. It was difficult to proceed with the same dosing protocol used for classic SOTI in cases treated with original SOTI. Following dual SOTI, the systemic reaction to oral intake subsided, but the local skin reaction to contact with the allergenic food persisted. Dual SOTI is an improved protocol for SOTI using interferon gamma for IFA.The local skin reaction and systemic reaction to oral intake were dissociated following dual SOTI. In cases of food allergy, tolerance appears to result from desensitization to allergens.

  20. Sensitivity and Specificity of Dual-Isotope 99mTc-Tetrofosmin and 123I Sodium Iodide Single Photon Emission Computed Tomography (SPECT) in Hyperparathyroidism.

    Science.gov (United States)

    Sommerauer, Michael; Graf, Carmen; Schäfer, Niklaus; Huber, Gerhard; Schneider, Paul; Wüthrich, Rudolf; Schmid, Christoph; Steinert, Hans

    2015-01-01

    Despite recommendations for 99mTc-tetrofosmin dual tracer imaging for hyperparathyroidism in current guidelines, no report was published on dual-isotope 99mTc-tetrofosmin and 123I sodium iodide single-photon-emission-computed-tomography (SPECT). We evaluated diagnostic accuracy and the impact of preoperative SPECT on the surgical procedures and disease outcomes. Analysis of 70 consecutive patients with primary hyperparathyroidism and 20 consecutive patients with tertiary hyperparathyroidism. Imaging findings were correlated with surgical results. Concomitant thyroid disease, pre- and postoperative laboratory measurements, histopathological results, type and duration of surgery were assessed. In primary hyperparathyroidism, SPECT had a sensitivity of 80% and a positive predictive value of 93% in patient-based analysis. Specificity was 99% in lesion-based analysis. Patients with positive SPECT elicit higher levels of parathyroid hormone and higher weight of resected parathyroids than SPECT-negative patients. Duration of parathyroid surgery was on average, approximately 40 minutes shorter in SPECT-positive than in SPECT-negative patients (89 ± 46 vs. 129 ± 41 minutes, p = 0.006); 86% of SPECT-positive and 50% of SPECT-negative patients had minimal invasive surgery (p = 0.021). SPECT had lower sensitivity (60%) in patients with tertiary hyperparathyroidism; however, 90% of these patients had multiple lesions and all of these patients had bilateral lesions. Dual-isotope SPECT with 99mTc-tetrofosmin and 123I sodium iodide has a high diagnostic value in patients with primary hyperparathyroidism and allows for saving of operation time. Higher levels of parathyroid hormone and higher glandular weight facilitated detection of parathyroid lesion. Diagnostic accuracy of preoperative imaging was lower in patients with tertiary hyperparathyroidism.

  1. Radiation dose of cardiac dual-source CT: The effect of tailoring the protocol to patient-specific parameters

    International Nuclear Information System (INIS)

    Alkadhi, Hatem; Stolzmann, Paul; Scheffel, Hans; Desbiolles, Lotus; Baumueller, Stephan; Plass, Andre; Genoni, Michele; Marincek, Borut; Leschka, Sebastian

    2008-01-01

    Objective: To determine the radiation doses and image quality of different dual-source computed tomography coronary angiography (CTCA) protocols tailored to the heart rate (HR) and body mass index (BMI) of the patients. Materials and methods: Two hundred consecutive patients (68 women; mean age 61 ± 9 years) underwent either helical CTCA with retrospective ECG-gating or sequential CT with prospective ECG-triggering: 50 patients (any BMI, any HR) were examined with a standard, non-tailored protocol (helical CTCA, 120 kV, 330 mAs), whereas the other 150 patients were examined with a tailored protocol: 40 patients (group A, BMI ≤ 25 kg/sqm, HR ≤ 70 bpm) with sequential CTCA (100 kV, 190 mAs ref ), 43 patients (group B, BMI ≤ 25 kg/sqm, HR > 70 bpm) with helical CTCA (100 kV, 220 mAs), 28 patients (group C, BMI > 25 kg/sqm, HR ≤ 70 bpm) with sequential CTCA (120 kV, 330 mAs ref ), and 39 patients (group D, BMI > 25 kg/sqm, HR > 70 bpm) with helical CTCA (120 kV, 330 mAs). The effective radiation dose estimates were calculated from the dose-length-product for each patient. Image quality was classified as being diagnostic or non-diagnostic in each coronary segment. Results: Image quality was diagnostic in 2403/2460 (98%) and non-diagnostic in 57/2460 (2%) of all coronary segments. No significant differences in image quality were found among all five CTCA protocols (p = 0.78). The non-tailored helical CTCA protocol was associated with a radiation dose of 9.0 ± 1.0 mSv, being significantly higher compared to that using sequential CTCA (group A: 1.3 ± 0.3 mSv, p 70 bpm (group D: 8.5 ± 0.9 mSv, p = 0.51). Conclusions: Dual-source CTCA is associated with radiation doses ranging between 1.3 and 9.0 mSv, depending on the protocol used. Tailoring of the CTCA protocol to the HR and BMI of the individual patient results in dose reductions of up to 86%, while maintaining a diagnostic image quality of the examination

  2. Adaptive T cell responses induced by oncolytic Herpes Simplex Virus-granulocyte macrophage-colony-stimulating factor therapy expanded by dendritic cell and cytokine-induced killer cell adoptive therapy.

    Science.gov (United States)

    Ren, Jun; Gwin, William R; Zhou, Xinna; Wang, Xiaoli; Huang, Hongyan; Jiang, Ni; Zhou, Lei; Agarwal, Pankaj; Hobeika, Amy; Crosby, Erika; Hartman, Zachary C; Morse, Michael A; H Eng, Kevin; Lyerly, H Kim

    2017-01-01

    Purpose : Although local oncolytic viral therapy (OVT) may enhance tumor lysis, antigen release, and adaptive immune responses, systemic antitumor responses post-therapy are limited. Adoptive immunotherapy with autologous dendritic cells (DC) and cytokine-induced killer cells (DC-CIK) synergizes with systemic therapies. We hypothesized that OVT with Herpes Simplex Virus-granulocyte macrophage-colony-stimulating factor (HSV-GM-CSF) would induce adaptive T cell responses that could be expanded systemically with sequential DC-CIK therapy. Patients and Methods : We performed a pilot study of intratumoral HSV-GM-CSF OVT followed by autologous DC-CIK cell therapy. In addition to safety and clinical endpoints, we monitored adaptive T cell responses by quantifying T cell receptor (TCR) populations in pre-oncolytic therapy, post-oncolytic therapy, and after DC-CIK therapy. Results : Nine patients with advanced malignancy were treated with OVT (OrienX010), of whom seven experienced stable disease (SD). Five of the OVT treated patients underwent leukapheresis, generation, and delivery of DC-CIKs, and two had SD, whereas three progressed. T cell receptor sequencing of TCR β sequences one month after OVT therapy demonstrates a dynamic TCR repertoire in response to OVT therapy in the majority of patients with the systematic expansion of multiple T cell clone populations following DC-CIK therapy. This treatment was well tolerated and long-term event free and overall survival was observed in six of the nine patients. Conclusions : Strategies inducing the local activation of tumor-specific immune responses can be combined with adoptive cellular therapies to expand the adaptive T cell responses systemically and further studies are warranted.

  3. A next-generation dual-recombinase system for time and host specific targeting of pancreatic cancer

    Science.gov (United States)

    Schachtler, Christina; Zukowska, Magdalena; Eser, Stefan; Feyerabend, Thorsten B.; Paul, Mariel C.; Eser, Philipp; Klein, Sabine; Lowy, Andrew M.; Banerjee, Ruby; Yang, Fangtang; Lee, Chang-Lung; Moding, Everett J.; Kirsch, David G.; Scheideler, Angelika; Alessi, Dario R.; Varela, Ignacio; Bradley, Allan; Kind, Alexander; Schnieke, Angelika E.; Rodewald, Hans-Reimer; Rad, Roland; Schmid, Roland M.; Schneider, Günter; Saur, Dieter

    2014-01-01

    Genetically engineered mouse models (GEMMs) have dramatically improved our understanding of tumor evolution and therapeutic resistance. However, sequential genetic manipulation of gene expression and targeting of the host is almost impossible using conventional Cre-loxP–based models. We have developed an inducible dual-recombinase system by combining flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies to improve GEMMs of pancreatic cancer. This enables investigation of multistep carcinogenesis, genetic manipulation of tumor subpopulations (such as cancer stem cells), selective targeting of the tumor microenvironment and genetic validation of therapeutic targets in autochthonous tumors on a genome-wide scale. As a proof of concept, we performed tumor cell–autonomous and nonautonomous targeting, recapitulated hallmarks of human multistep carcinogenesis, validated genetic therapy by 3-phosphoinositide-dependent protein kinase inactivation as well as cancer cell depletion and show that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are dispensable for tumor formation. PMID:25326799

  4. A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer.

    Science.gov (United States)

    Schönhuber, Nina; Seidler, Barbara; Schuck, Kathleen; Veltkamp, Christian; Schachtler, Christina; Zukowska, Magdalena; Eser, Stefan; Feyerabend, Thorsten B; Paul, Mariel C; Eser, Philipp; Klein, Sabine; Lowy, Andrew M; Banerjee, Ruby; Yang, Fangtang; Lee, Chang-Lung; Moding, Everett J; Kirsch, David G; Scheideler, Angelika; Alessi, Dario R; Varela, Ignacio; Bradley, Allan; Kind, Alexander; Schnieke, Angelika E; Rodewald, Hans-Reimer; Rad, Roland; Schmid, Roland M; Schneider, Günter; Saur, Dieter

    2014-11-01

    Genetically engineered mouse models (GEMMs) have dramatically improved our understanding of tumor evolution and therapeutic resistance. However, sequential genetic manipulation of gene expression and targeting of the host is almost impossible using conventional Cre-loxP-based models. We have developed an inducible dual-recombinase system by combining flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies to improve GEMMs of pancreatic cancer. This enables investigation of multistep carcinogenesis, genetic manipulation of tumor subpopulations (such as cancer stem cells), selective targeting of the tumor microenvironment and genetic validation of therapeutic targets in autochthonous tumors on a genome-wide scale. As a proof of concept, we performed tumor cell-autonomous and nonautonomous targeting, recapitulated hallmarks of human multistep carcinogenesis, validated genetic therapy by 3-phosphoinositide-dependent protein kinase inactivation as well as cancer cell depletion and show that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are dispensable for tumor formation.

  5. Dual Recognition Strategy for Specific and Sensitive Detection of Bacteria Using Aptamer-Coated Magnetic Beads and Antibiotic-Capped Gold Nanoclusters.

    Science.gov (United States)

    Cheng, Dan; Yu, Mengqun; Fu, Fei; Han, Weiye; Li, Gan; Xie, Jianping; Song, Yang; Swihart, Mark T; Song, Erqun

    2016-01-05

    Food poisoning and infectious diseases caused by pathogenic bacteria such as Staphylococcus aureus (SA) are serious public health concerns. A method of specific, sensitive, and rapid detection of such bacteria is essential and important. This study presents a strategy that combines aptamer and antibiotic-based dual recognition units with magnetic enrichment and fluorescent detection to achieve specific and sensitive quantification of SA in authentic specimens and in the presence of much higher concentrations of other bacteria. Aptamer-coated magnetic beads (Apt-MB) were employed for specific capture of SA. Vancomycin-stabilized fluorescent gold nanoclusters (AuNCs@Van) were prepared by a simple one-step process and used for sensitive quantification of SA in the range of 32-10(8) cfu/mL with the detection limit of 16 cfu/mL via a fluorescence intensity measurement. And using this strategy, about 70 cfu/mL of SA in complex samples (containing 3 × 10(8) cfu/mL of other different contaminated bacteria) could be successfully detected. In comparison to prior studies, the developed strategy here not only simplifies the preparation procedure of the fluorescent probes (AuNCs@Van) to a great extent but also could sensitively quantify SA in the presence of much higher concentrations of other bacteria directly with good accuracy. Moreover, the aptamer and antibiotic used in this strategy are much less expensive and widely available compared to common-used antibodies, making it cost-effective. This general aptamer- and antibiotic-based dual recognition strategy, combined with magnetic enrichment and fluorescent detection of trace bacteria, shows great potential application in monitoring bacterial food contamination and infectious diseases.

  6. Estimating pathway-specific contributions to biodegradation in aquifers based on dual isotope analysis: Theoretical analysis and reactive transport simulations

    NARCIS (Netherlands)

    Centler, F.; Heße, F.; Thullner, M.

    2013-01-01

    At field sites with varying redox conditions, different redox-specific microbial degradation pathways contribute to total contaminant degradation. The identification of pathway-specific contributions to total contaminant removal is of high practical relevance, yet difficult to achieve with current

  7. Knockdown of dual specificity phosphatase 4 enhances the chemosensitivity of MCF-7 and MCF-7/ADR breast cancer cells to doxorubicin

    International Nuclear Information System (INIS)

    Liu, Yu; Du, Feiya; Chen, Wei; Yao, Minya; Lv, Kezhen; Fu, Peifen

    2013-01-01

    Background: Breast cancer is the major cause of cancer-related deaths in females world-wide. Doxorubicin-based therapy has limited efficacy in breast cancer due to drug resistance, which has been shown to be associated with the epithelial-to-mesenchymal transition (EMT). However, the molecular mechanisms linking the EMT and drug resistance in breast cancer cells remain unclear. Dual specificity phosphatase 4 (DUSP4), a member of the dual specificity phosphatase family, is associated with cellular proliferation and differentiation; however, its role in breast cancer progression is controversial. Methods: We used cell viability assays, Western blotting and immunofluorescent staining, combined with siRNA interference, to evaluate chemoresistance and the EMT in MCF-7 and adriamycin-resistant MCF-7/ADR breast cancer cells, and investigate the underlying mechanisms. Results: Knockdown of DUSP4 significantly increased the chemosensitivity of MCF-7 and MCF-7/ADR breast cancer cells to doxorubicin, and MCF-7/ADR cells which expressed high levels of DUSP4 had a mesenchymal phenotype. Furthermore, knockdown of DUSP4 reversed the EMT in MCF-7/ADR cells, as demonstrated by upregulation of epithelial biomarkers and downregulation of mesenchymal biomarkers, and also increased the chemosensitivity of MCF-7/ADR cells to doxorubicin. Conclusions: DUSP4 might represent a potential drug target for inhibiting drug resistance and regulating the process of the EMT during the treatment of breast cancer. - Highlights: • We used different technologies to prove our conclusion. • DUSP4 knockdown increased doxorubicin chemosensitivity in breast cancer cells. • DUSP4 is a potential target for combating drug resistance in breast cancer. • DUSP4 is a potential target for regulating the EMT in breast cancer

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

    Directory of Open Access Journals (Sweden)

    Catherine Dold

    2016-01-01

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

  9. Cyclophosphamide increases transgene expression mediated by an oncolytic adenovirus in glioma-bearing mice monitored by bioluminescence imaging

    NARCIS (Netherlands)

    Lamfers, Martine L. M.; Fulci, Giulia; Gianni, Davide; Tang, Yi; Kurozumi, Kazuhiko; Kaur, Balveen; Moeniralm, Sharif; Saeki, Yoshinaga; Carette, Jan E.; Weissleder, Ralph; Vandertop, W. Peter; van Beusechem, Victor W.; Dirven, Clemens M. F.; Chiocca, E. Antonio

    2006-01-01

    Approaches to improve the oncolytic potency of replication-competent adenoviruses include the insertion of therapeutic transgenes into the viral genome. Little is known about the levels and duration of in vivo transgene expression by cells infected with such "armed" viruses. Using a tumor-selective

  10. Pediatric cancer gone viral. Part II: potential clinical application of oncolytic herpes simplex virus-1 in children

    Directory of Open Access Journals (Sweden)

    Gregory K Friedman

    Full Text Available Oncolytic engineered herpes simplex viruses (HSVs possess many biologic and functional attributes that support their use in clinical trials in children with solid tumors. Tumor cells, in an effort to escape regulatory mechanisms that would impair their growth and progression, have removed many mechanisms that would have protected them from virus infection and eventual virus-mediated destruction. Viruses engineered to exploit this weakness, like mutant HSV, can be safely employed as tumor cell killers, since normal cells retain these antiviral strategies. Many preclinical studies and early phase trials in adults demonstrated that oncolytic HSV can be safely used and are highly effective in killing tumor cells that comprise pediatric malignancies, without generating the toxic side effects of nondiscriminatory chemotherapy or radiation therapy. A variety of engineered viruses have been developed and tested in numerous preclinical models of pediatric cancers and initial trials in patients are underway. In Part II of this review series, we examine the preclinical evidence to support the further advancement of oncolytic HSV in the pediatric population. We discuss clinical advances made to date in this emerging era of oncolytic virotherapy.

  11. Ex Vivo Oncolytic Virotherapy with Myxoma Virus Arms Multiple Allogeneic Bone Marrow Transplant Leukocytes to Enhance Graft versus Tumor

    NARCIS (Netherlands)

    Lilly, Cameron L.; Villa, Nancy Y.; Lemos de Matos, Ana; Ali, Haider M.; Dhillon, Jess-Karan S.; Hofland, Tom; Rahman, Masmudur M.; Chan, Winnie; Bogen, Bjarne; Cogle, Christopher; McFadden, Grant

    2017-01-01

    Allogeneic stem cell transplant-derived T cells have the potential to seek and eliminate sites of residual cancer that escaped primary therapy. Oncolytic myxoma virus (MYXV) exhibits potent anti-cancer efficacy against human cancers like multiple myeloma (MM) and can arm transplant-derived T cells

  12. Cap-dependent translational control of oncolytic measles virus infection in malignant mesothelioma.

    Science.gov (United States)

    Jacobson, Blake A; Sadiq, Ahad A; Tang, Shaogeng; Jay-Dixon, Joe; Patel, Manish R; Drees, Jeremy; Sorenson, Brent S; Russell, Stephen J; Kratzke, Robert A

    2017-09-08

    Malignant mesothelioma has a poor prognosis for which there remains an urgent need for successful treatment approaches. Infection with the Edmonston vaccine strain (MV-Edm) derivative of measles virus results in lysis of cancer cells and has been tested in clinical trials for numerous tumor types including mesothelioma. Many factors play a role in MV-Edm tumor cell selectivity and cytopathic activity while also sparing non-cancerous cells. The MV-Edm receptor CD46 (cluster of differentiation 46) was demonstrated to be significantly higher in mesothelioma cells than in control cells. In contrast, mesothelioma cells are not reliant upon the alternative MV-Edm receptor nectin-4 for entry. MV-Edm treatment of mesothelioma reduced cell viability and also invoked apoptotic cell death. Forced expression of eIF4E or translation stimulation following IGF-I (insulin-like growth factor 1) exposure strengthened the potency of measles virus oncolytic activity. It was also shown that repression of cap-dependent translation by treatment with agents [4EASO, 4EGI-1] that suppress host cell translation or by forcing cells to produce an activated repressor protein diminishes the strength of oncolytic viral efficacy.

  13. Treatment of colon cancer with oncolytic herpes simplex virus in preclinical models.

    Science.gov (United States)

    Yang, H; Peng, T; Li, J; Wang, Y; Zhang, W; Zhang, P; Peng, S; Du, T; Li, Y; Yan, Q; Liu, B

    2016-05-01

    Cancer stem cells (CSCs), which are a rare population in any type of cancer, including colon cancer, are tumorigenic and responsible for cancer recurrence and metastasis. CSCs have been isolated from a number of different solid tumors recently, although the isolation of CSCs in colon cancer is still challenging. We cultured colon cancer cells in stem cell medium to obtain colonosphere cells. These cells possessed the characteristics of CSCs, with a high capacity of tumorigenicity, migration and invasion in vitro and in vivo. The isolation and identification of CSCs have provided new targets for the therapeutics. Oncolytic herpes simplex viruses (oHSV) are an effective strategy for killing colon cancer cells in preclinical models. Here, we examined the efficacy of an oncolytic herpes simplex virus type 2 (oHSV2) in killing colon cancer cells and colon cancer stem-like cells (CSLCs). oHSV2 was found to be highly cytotoxic to the adherent and sphere cells in vitro, and oHSV2 treatment in vivo significantly inhibited tumor growth. This study demonstrates that oHSV2 is effective against colon cancer cells and colon CSLCs and could be a promising strategy for treating colon cancer patients.

  14. Generation of an adenovirus-parvovirus chimera with enhanced oncolytic potential.

    Science.gov (United States)

    El-Andaloussi, Nazim; Bonifati, Serena; Kaufmann, Johanna K; Mailly, Laurent; Daeffler, Laurent; Deryckère, François; Nettelbeck, Dirk M; Rommelaere, Jean; Marchini, Antonio

    2012-10-01

    In this study, our goal was to generate a chimeric adenovirus-parvovirus (Ad-PV) vector that combines the high-titer and efficient gene transfer of adenovirus with the anticancer potential of rodent parvovirus. To this end, the entire oncolytic PV genome was inserted into a replication-defective E1- and E3-deleted Ad5 vector genome. As we found that parvoviral NS expression inhibited Ad-PV chimera production, we engineered the parvoviral P4 early promoter, which governs NS expression, by inserting into its sequence tetracycline operator elements. As a result of these modifications, P4-driven expression was blocked in the packaging T-REx-293 cells, which constitutively express the tetracycline repressor, allowing high-yield chimera production. The chimera effectively delivered the PV genome into cancer cells, from which fully infectious replication-competent parvovirus particles were generated. Remarkably, the Ad-PV chimera exerted stronger cytotoxic activities against various cancer cell lines, compared with the PV and Ad parental viruses, while being still innocuous to a panel of tested healthy primary human cells. This Ad-PV chimera represents a novel versatile anticancer agent which can be subjected to further genetic manipulations in order to reinforce its enhanced oncolytic capacity through arming with transgenes or retargeting into tumor cells.

  15. A double-regulated oncolytic adenovirus with improved safety for adenocarcinoma therapy

    International Nuclear Information System (INIS)

    Wei, Na; Fan, Jun Kai; Gu, Jin Fa; He, Ling Feng; Tang, Wen Hao; Cao, Xin; Liu, Xin Yuan

    2009-01-01

    Safety and efficiency are equally important to be considered in developing oncolytic adenovirus. Previously, we have reported that ZD55, an oncolytic adenovirus with the deletion of E1B-55K gene, exhibited potent antitumor activity. In this study, to improve the safety of ZD55, we utilized MUC1 promoter to replace the native promoter of E1A on the basis of ZD55, and generated a double-regulated adenovirus, named MUD55. Our data demonstrated that the expression of early and late genes of MUD55 was both reduced in MUC1-negative cells, resulting in its stricter glandular-tumor selective progeny production. The cytopathic effect of MUD55 was about 10-fold lower than mono-regulated adenovirus ZD55 or Ad.MUC1 in normal cells and not obviously attenuated in glandular tumor cells. Moreover, MUD55 showed the least liver toxicity when administrated by intravenous injection in nude mice. These results indicate that MUD55 could be a promising candidate for the treatment of adenocarcinoma.

  16. High titer oncolytic measles virus production process by integration of dielectric spectroscopy as online monitoring system.

    Science.gov (United States)

    Grein, Tanja A; Loewe, Daniel; Dieken, Hauke; Salzig, Denise; Weidner, Tobias; Czermak, Peter

    2018-05-01

    Oncolytic viruses offer new hope to millions of patients with incurable cancer. One promising class of oncolytic viruses is Measles virus, but its broad administration to cancer patients is currently hampered by the inability to produce the large amounts of virus needed for treatment (10 10 -10 12 virus particles per dose). Measles virus is unstable, leading to very low virus titers during production. The time of infection and time of harvest are therefore critical parameters in a Measles virus production process, and their optimization requires an accurate online monitoring system. We integrated a probe based on dielectric spectroscopy (DS) into a stirred tank reactor to characterize the Measles virus production process in adherent growing Vero cells. We found that DS could be used to monitor cell adhesion on the microcarrier and that the optimal virus harvest time correlated with the global maximum permittivity signal. In 16 independent bioreactor runs, the maximum Measles virus titer was achieved approximately 40 hr after the permittivity maximum. Compared to an uncontrolled Measles virus production process, the integration of DS increased the maximum virus concentration by more than three orders of magnitude. This was sufficient to achieve an active Measles virus concentration of > 10 10 TCID 50 ml -1 . © 2017 Wiley Periodicals, Inc.

  17. Newly Characterized Murine Undifferentiated Sarcoma Models Sensitive to Virotherapy with Oncolytic HSV-1 M002

    Directory of Open Access Journals (Sweden)

    Eric K. Ring

    2017-12-01

    Full Text Available Despite advances in conventional chemotherapy, surgical techniques, and radiation, outcomes for patients with relapsed, refractory, or metastatic soft tissue sarcomas are dismal. Survivors often suffer from lasting morbidity from current treatments. New targeted therapies with less toxicity, such as those that harness the immune system, and immunocompetent murine sarcoma models to test these therapies are greatly needed. We characterized two new serendipitous murine models of undifferentiated sarcoma (SARC-28 and SARC-45 and tested their sensitivity to virotherapy with oncolytic herpes simplex virus 1 (HSV-1. Both models expressed high levels of the primary HSV entry molecule nectin-1 (CD111 and were susceptible to killing by interleukin-12 (IL-12 producing HSV-1 M002 in vitro and in vivo. M002 resulted in a significant intratumoral increase in effector CD4+ and CD8+ T cells and activated monocytes, and a decrease in myeloid-derived suppressor cells (MDSCs in immunocompetent mice. Compared to parent virus R3659 (no IL-12 production, M002 resulted in higher CD8:MDSC and CD8:T regulatory cell (Treg ratios, suggesting that M002 creates a more favorable immune tumor microenvironment. These data provide support for clinical trials targeting sarcomas with oncolytic HSV-1. These models provide an exciting opportunity to explore combination therapies for soft tissue sarcomas that rely on an intact immune system to reach full therapeutic potential.

  18. Cancer-Targeted Oncolytic Adenoviruses for Modulation of the Immune System.

    Science.gov (United States)

    Cerullo, Vincenzo; Capasso, Cristian; Vaha-Koskela, Markus; Hemminki, Otto; Hemminki, Akseli

    2018-01-01

    Adenovirus is one of the most commonly used vectors for gene therapy and it is the first approved virus-derived drug for treatment of cancer. As an oncolytic agent, it can induce lysis of infected cells, but it can also engage the immune system, promoting activation and maturation of antigen- presenting cells (APCs). In essence, oncolysis combined with the associated immunostimulatory actions result in a "personalized in situ vaccine" for each patient. In order to take full advantage of these features, we should try to understand how adenovirus interacts with the immune system, what are the receptors involved in triggering subsequent signals and which kind of responses they elicit. Tackling these questions will give us further insight in how to manipulate adenovirus-mediated immune responses for enhancement of anti-tumor efficacy. In this review, we first highlight how oncolytic adenovirus interacts with the innate immune system and its receptors such as Toll-like receptors, nucleotide-binding and oligomerization domain (NOD)- like receptors and other immune sensors. Then we describe the effect of these interactions on the adaptive immune system and its cells, especially B and T lymphocytes. Finally, we summarize the most significant preclinical and clinical results in the field of gene therapy where researchers have engineered adenovirus to manipulate the host immune system by expressing cytokines and signalingmediators. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Oncolytic Viral Therapy and the Immune System: A Double-Edged Sword Against Cancer.

    Science.gov (United States)

    Marelli, Giulia; Howells, Anwen; Lemoine, Nicholas R; Wang, Yaohe

    2018-01-01

    Oncolytic viral therapy is a new promising strategy against cancer. Oncolytic viruses (OVs) can replicate in cancer cells but not in normal cells, leading to lysis of the tumor mass. Beside this primary effect, OVs can also stimulate the immune system. Tumors are an immuno-suppressive environment in which the immune system is silenced in order to avoid the immune response against cancer cells. The delivery of OVs into the tumor wakes up the immune system so that it can facilitate a strong and durable response against the tumor itself. Both innate and adaptive immune responses contribute to this process, producing an immune response against tumor antigens and facilitating immunological memory. However, viruses are recognized by the immune system as pathogens and the consequent anti-viral response could represent a big hurdle for OVs. Finding a balance between anti-tumor and anti-viral immunity is, under this new light, a priority for researchers. In this review, we provide an overview of the various ways in which different components of the immune system can be allied with OVs. We have analyzed the different immune responses in order to highlight the new and promising perspectives leading to increased anti-tumor response and decreased immune reaction to the OVs.

  20. The potential application of a transcriptionally regulated oncolytic herpes simplex virus for human cancer therapy

    Science.gov (United States)

    Miao, L; Fraefel, C; Sia, K C; Newman, J P; Mohamed-Bashir, S A; Ng, W H; Lam, P Y P

    2014-01-01

    Background: Emerging studies have shown the potential benefit of arming oncolytic viruses with therapeutic genes. However, most of these therapeutic genes are placed under the regulation of ubiquitous viral promoters. Our goal is to generate a safer yet potent oncolytic herpes simplex virus type-1 (HSV-1) for cancer therapy. Methods: Using bacterial artificial chromosome (BAC) recombineering, a cell cycle-regulatable luciferase transgene cassette was replaced with the infected cell protein 6 (ICP6) coding region (encoded for UL39 or large subunit of ribonucleotide reductase) of the HSV-1 genome. These recombinant viruses, YE-PC8, were further tested for its proliferation-dependent luciferase gene expression. Results: The ability of YE-PC8 to confer proliferation-dependent transgene expression was demonstrated by injecting similar amount of viruses into the tumour-bearing region of the brain and the contralateral normal brain parenchyma of the same mouse. The results showed enhanced levels of luciferase activities in the tumour region but not in the normal brain parenchyma. Similar findings were observed in YE-PC8-infected short-term human brain patient-derived glioma cells compared with normal human astrocytes. intratumoural injection of YE-PC8 viruses resulted in 77% and 80% of tumour regression in human glioma and human hepatocellular carcinoma xenografts, respectively. Conclusion: YE-PC8 viruses confer tumour selectivity in proliferating cells and may be developed further as a feasible approach to treat human cancers. PMID:24196790

  1. High treatment efficacy by dual targeting of Burkitt's lymphoma xenografted mice with a {sup 177}Lu-based CD22-specific radioimmunoconjugate and rituximab

    Energy Technology Data Exchange (ETDEWEB)

    Weber, Tobias; Boetticher, Benedikt; Keller, Armin; Schlegelmilch, Anne; Jaeger, Dirk; Krauss, Juergen [Heidelberg University Hospital, Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg (Germany); Mier, Walter; Kraemer, Susanne; Leotta, Karin [Heidelberg University Hospital, Department of Nuclear Medicine, Heidelberg (Germany); Sauter, Max; Haberkorn, Uwe [Heidelberg University Hospital, Department of Nuclear Medicine, Heidelberg (Germany); German Cancer Research Center (DKFZ), Clinical Cooperation Unit Nuclear Medicine, Heidelberg (Germany); Grosse-Hovest, Ludger [University of Tuebingen, Department of Immunology, Tuebingen (Germany); Arndt, Michaela A.E. [Heidelberg University Hospital, Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg (Germany); German Cancer Research Center (DKFZ), Immunotherapy Program, National Center for Tumor Diseases, Heidelberg (Germany)

    2016-03-15

    Dual-targeted therapy has been shown to be a promising treatment option in recurrent and/or refractory B-cell non-Hodgkin's lymphoma (B-NHL). We generated radioimmunoconjugates (RICs) comprising either a novel humanized anti-CD22 monoclonal antibody, huRFB4, or rituximab, and the low-energy β-emitter {sup 177}Lu. Both RICs were evaluated as single agents in a human Burkitt's lymphoma xenograft mouse model. To increase the therapeutic efficacy of the anti-CD22 RIC, combination therapy with unlabelled anti-CD20 rituximab was explored. The binding activity of CHX-A''-DTPA-conjugated antibodies to target cells was analysed by flow cytometry. To assess tumour targeting of {sup 177}Lu-labelled antibodies, in vivo biodistribution experiments were performed. For radioimmunotherapy (RIT) studies, non-obese diabetic recombination activating gene-1 (NOD-Rag1{sup null}) interleukin-2 receptor common gamma chain (IL2r γ {sup null}) null mice (NRG mice) were xenografted subcutaneously with Raji Burkitt's lymphoma cells. {sup 177}Lu-conjugated antibodies were administered at a single dose of 9.5 MBq per mouse. For dual-targeted therapy, rituximab was injected at weekly intervals (0.5 - 1.0 mg). Tumour accumulation of RICs was monitored by planar scintigraphy. Conjugation of CHX-A''-DTPA resulted in highly stable RICs with excellent antigen-binding properties. Biodistribution experiments revealed higher tumour uptake of the {sup 177}Lu-labelled anti-CD22 IgG than of {sup 177}Lu-labelled rituximab. Treatment with {sup 177}Lu-conjugated huRFB4 resulted in increased tumour growth inhibition and significantly longer survival than treatment with {sup 177}Lu-conjugated rituximab. The therapeutic efficacy of the anti-CD22 RIC could be markedly enhanced by combination with unlabelled rituximab. These findings suggest that dual targeting with {sup 177}Lu-based CD22-specific RIT in combination with rituximab is a promising new treatment option for

  2. Assessment of the Na/I symporter as a reporter gene to visualize oncolytic adenovirus propagation in peritoneal tumours

    International Nuclear Information System (INIS)

    Merron, Andrew; McNeish, Iain A.; Baril, Patrick; Tran, Lucile; Vassaux, Georges; Martin-Duque, Pilar; Vieja, Antonio de la; Briat, Arnaud; Harrington, Kevin J.

    2010-01-01

    In vivo imaging of the spread of oncolytic viruses using the Na/I symporter (NIS) has been proposed. Here, we assessed whether the presence of NIS in the viral genome affects the therapeutic efficacy of the oncolytic adenovirus dl922-947 following intraperitoneal administration, in a mouse model of peritoneal ovarian carcinoma. We generated AdAM7, a dl922-947 oncolytic adenovirus encoding the NIS coding sequence. Iodide uptake, NIS expression, infectivity and cell-killing activity of AdAM7, as well as that of relevant controls, were determined in vitro. In vivo, the propagation of this virus in the peritoneal cavity of tumour-bearing mice was determined using SPECT/CT imaging and its therapeutic efficacy was evaluated. In vitro infection of ovarian carcinoma IGROV-1 cells with ADAM7 led to functional expression of NIS. However, the insertion of NIS into the viral genome resulted in a loss of efficacy of the virus in terms of replication and cytotoxicity. In vivo, on SPECT/CT imaging AdAM7 was only detectable in the peritoneal cavity of animals bearing peritoneal ovarian tumours for up to 5 days after intraperitoneal administration. Therapeutic experiments in vivo demonstrated that AdAM7 is as potent as its NIS-negative counterpart. This study demonstrated that despite the detrimental effect observed in vitro, insertion of the reporter gene NIS in an oncolytic adenovirus did not affect its therapeutic efficacy in vivo. We conclude that NIS is a highly relevant reporter gene to monitor the fate of oncolytic adenovectors in live subjects. (orig.)

  3. Assessment of the Na/I symporter as a reporter gene to visualize oncolytic adenovirus propagation in peritoneal tumours

    Energy Technology Data Exchange (ETDEWEB)

    Merron, Andrew; McNeish, Iain A. [Queen Mary' s School of Medicine and Dentistry, Centre for Molecular Oncology, Institute of Cancer, London (United Kingdom); Baril, Patrick; Tran, Lucile; Vassaux, Georges [CHU Hotel Dieu, INSERM, Nantes (France); CHU de Nantes, Institut des Maladies de l' Appareil Digestif, Nantes (France); Martin-Duque, Pilar [Instituto Aragones de Ciencias de la Salud, Zaragoza (Spain); Vieja, Antonio de la [Instituto de Investigaciones Biomedicas, Madrid (Spain); Briat, Arnaud [INSERM U877, Grenoble (France); Harrington, Kevin J. [Chester Beatty Laboratories, Institute of Cancer Research, London (United Kingdom)

    2010-07-15

    In vivo imaging of the spread of oncolytic viruses using the Na/I symporter (NIS) has been proposed. Here, we assessed whether the presence of NIS in the viral genome affects the therapeutic efficacy of the oncolytic adenovirus dl922-947 following intraperitoneal administration, in a mouse model of peritoneal ovarian carcinoma. We generated AdAM7, a dl922-947 oncolytic adenovirus encoding the NIS coding sequence. Iodide uptake, NIS expression, infectivity and cell-killing activity of AdAM7, as well as that of relevant controls, were determined in vitro. In vivo, the propagation of this virus in the peritoneal cavity of tumour-bearing mice was determined using SPECT/CT imaging and its therapeutic efficacy was evaluated. In vitro infection of ovarian carcinoma IGROV-1 cells with ADAM7 led to functional expression of NIS. However, the insertion of NIS into the viral genome resulted in a loss of efficacy of the virus in terms of replication and cytotoxicity. In vivo, on SPECT/CT imaging AdAM7 was only detectable in the peritoneal cavity of animals bearing peritoneal ovarian tumours for up to 5 days after intraperitoneal administration. Therapeutic experiments in vivo demonstrated that AdAM7 is as potent as its NIS-negative counterpart. This study demonstrated that despite the detrimental effect observed in vitro, insertion of the reporter gene NIS in an oncolytic adenovirus did not affect its therapeutic efficacy in vivo. We conclude that NIS is a highly relevant reporter gene to monitor the fate of oncolytic adenovectors in live subjects. (orig.)

  4. Quantitative characterization of conformational-specific protein-DNA binding using a dual-spectral interferometric imaging biosensor

    Science.gov (United States)

    Zhang, Xirui; Daaboul, George G.; Spuhler, Philipp S.; Dröge, Peter; Ünlü, M. Selim

    2016-03-01

    DNA-binding proteins play crucial roles in the maintenance and functions of the genome and yet, their specific binding mechanisms are not fully understood. Recently, it was discovered that DNA-binding proteins recognize specific binding sites to carry out their functions through an indirect readout mechanism by recognizing and capturing DNA conformational flexibility and deformation. High-throughput DNA microarray-based methods that provide large-scale protein-DNA binding information have shown effective and comprehensive analysis of protein-DNA binding affinities, but do not provide information of DNA conformational changes in specific protein-DNA complexes. Building on the high-throughput capability of DNA microarrays, we demonstrate a quantitative approach that simultaneously measures the amount of protein binding to DNA and nanometer-scale DNA conformational change induced by protein binding in a microarray format. Both measurements rely on spectral interferometry on a layered substrate using a single optical instrument in two distinct modalities. In the first modality, we quantitate the amount of binding of protein to surface-immobilized DNA in each DNA spot using a label-free spectral reflectivity technique that accurately measures the surface densities of protein and DNA accumulated on the substrate. In the second modality, for each DNA spot, we simultaneously measure DNA conformational change using a fluorescence vertical sectioning technique that determines average axial height of fluorophores tagged to specific nucleotides of the surface-immobilized DNA. The approach presented in this paper, when combined with current high-throughput DNA microarray-based technologies, has the potential to serve as a rapid and simple method for quantitative and large-scale characterization of conformational specific protein-DNA interactions.DNA-binding proteins play crucial roles in the maintenance and functions of the genome and yet, their specific binding mechanisms are

  5. Synthesis and in vitro evaluation of an antiangiogenic cancer-specific dual-targeting 177Lu-Au-nanoradiopharmaceutical

    International Nuclear Information System (INIS)

    Gonzalez-Ruiz, Abraham; Ferro-Flores, Guillermina; Azorin-Vega, Erika; Ocampo-Garcia, Blanca; Maria Ramirez, Flor de; Santos-Cuevas, Clara; Luna-Gutierrez, Myrna; Leon-Rodriguez, Luis De; Isaac-Olive, Keila; Morales-Avila, Enrique

    2017-01-01

    The aim of this research was to synthesize and chemically characterize a cancer-specific 177 Lu-Au-nanoradiopharmaceutical based on gold nanoparticles (NPs), the nuclear localization sequence (NLS)-Arg-Gly-Asp peptide and an aptamer (HS-pentyl-pegaptanib) to target both the α(v)β(3) integrin and the vascular endothelial growth factor (VEGF) overexpressed in the tumor neovasculature, as well as to evaluate by the tube formation assay, the nanosystem capability to inhibit angiogenesis. 177 Lu-NP-RGD-NLS-Aptamer was obtained with a radiochemical purity of 99 ± 1%. Complete inhibition of tube formation (angiogenesis) was demonstrated when endothelial cells (EA.hy926), cultured in a 3D-extracellular matrix support, were treated with the developed nanosystem. (author)

  6. The structure of bradyzoite-specific enolase from Toxoplasma gondii reveals insights into its dual cytoplasmic and nuclear functions

    Energy Technology Data Exchange (ETDEWEB)

    Ruan, Jiapeng [Northwestern University, 320 E. Superior Street, Morton 7-601, Chicago, IL 60611 (United States); Mouveaux, Thomas [Université Lille Nord de France, (France); Light, Samuel H.; Minasov, George; Anderson, Wayne F. [Northwestern University, 320 E. Superior Street, Morton 7-601, Chicago, IL 60611 (United States); Tomavo, Stanislas [Université Lille Nord de France, (France); Ngô, Huân M., E-mail: h-ngo@northwestern.edu [Northwestern University, 320 E. Superior Street, Morton 7-601, Chicago, IL 60611 (United States); BrainMicro LLC, 21 Pendleton Street, New Haven, CT 06511 (United States)

    2015-03-01

    The second crystal structure of a parasite protein preferentially enriched in the brain cyst of T. gondii has been solved at 2.75 Å resolution. Bradyzoite enolase 1 is reported to have differential functions as a glycolytic enzyme and a transcriptional regulator in bradyzoites. In addition to catalyzing a central step in glycolysis, enolase assumes a remarkably diverse set of secondary functions in different organisms, including transcription regulation as documented for the oncogene c-Myc promoter-binding protein 1. The apicomplexan parasite Toxoplasma gondii differentially expresses two nuclear-localized, plant-like enolases: enolase 1 (TgENO1) in the latent bradyzoite cyst stage and enolase 2 (TgENO2) in the rapidly replicative tachyzoite stage. A 2.75 Å resolution crystal structure of bradyzoite enolase 1, the second structure to be reported of a bradyzoite-specific protein in Toxoplasma, captures an open conformational state and reveals that distinctive plant-like insertions are located on surface loops. The enolase 1 structure reveals that a unique residue, Glu164, in catalytic loop 2 may account for the lower activity of this cyst-stage isozyme. Recombinant TgENO1 specifically binds to a TTTTCT DNA motif present in the cyst matrix antigen 1 (TgMAG1) gene promoter as demonstrated by gel retardation. Furthermore, direct physical interactions of both nuclear TgENO1 and TgENO2 with the TgMAG1 gene promoter are demonstrated in vivo using chromatin immunoprecipitation (ChIP) assays. Structural and biochemical studies reveal that T. gondii enolase functions are multifaceted, including the coordination of gene regulation in parasitic stage development. Enolase 1 provides a potential lead in the design of drugs against Toxoplasma brain cysts.

  7. SERS Assay for Copper(II) Ions Based on Dual Hot-Spot Model Coupling with MarR Protein: New Cu2+-Specific Biorecognition Element.

    Science.gov (United States)

    Wang, Yulong; Su, Zhenhe; Wang, Limin; Dong, Jinbo; Xue, Juanjuan; Yu, Jiao; Wang, Yuan; Hua, Xiude; Wang, Minghua; Zhang, Cunzheng; Liu, Fengquan

    2017-06-20

    We have developed a rapid and ultrasensitive surface-enhanced Raman scattering (SERS) assay for Cu 2+ detection using the multiple antibiotic resistance regulator (MarR) as specific bridging molecules in a SERS hot-spot model. In the assay, Cu 2+ induces formation of MarR tetramers, which provide Au nanoparticle (NP)-AuNP bridges, resulting in the formation of SERS hot spots. 4-Mercaptobenzoic acid (4-MBA) was used as a Raman reporter. The addition of Cu 2+ increased the Raman intensity of 4-MBA. Use of a dual hot-spot signal-amplification strategy based on AuNP-AgNP heterodimers combined through antigen-antibody reactions increased the sensitivity of the sensing platform by 50-fold. The proposed method gave a linear response for Cu 2+ detection in the range of 0.5-1000 nM, with a detection limit of 0.18 nM, which is 5 orders of magnitude lower than the U.S. Environmental Protection Agency limit for Cu 2+ in drinking water (20 μM). In addition, all analyses can be completed in less than 15 min. The high sensitivity, high specificity, and rapid detection capacity of the SERS assay therefore provide a combined advantage over current assays.

  8. Reduction of virion-associated σ1 fibers on oncolytic reovirus variants promotes adaptation toward tumorigenic cells.

    Science.gov (United States)

    Mohamed, Adil; Teicher, Carmit; Haefliger, Sarah; Shmulevitz, Maya

    2015-04-01

    adaptation toward cancer cells and away from conditions that mimic natural routes of infection. Specifically, we found that reovirus particles with fewer molecules of the cell attachment protein σ1 became more infectious toward transformed cells. Reduced σ1 levels conferred a benefit to incoming particles only, resulting in an earlier depletion of σ1 and a higher probability of establishing productive infection. Conversely, reovirus variants with fewer σ1 molecules showed reduced stability and infectivity and distinct disassembly when exposed to conditions that mimic natural intestinal proteolysis. These findings support a model where the mode of infection dictates the precise optimum of reovirus structure and provide a molecular rationale for considering alternative reovirus structures during oncolytic therapy. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  9. Exploring metal artifact reduction using dual-energy CT with pre-metal and post-metal implant cadaver comparison: are implant specific protocols needed?

    NARCIS (Netherlands)

    Wellenberg, Ruud H. H.; Donders, Johanna C. E.; Kloen, Peter; Beenen, Ludo F. M.; Kleipool, Roeland P.; Maas, Mario; Streekstra, Geert J.

    2017-01-01

    To quantify and optimize metal artifact reduction using virtual monochromatic dual-energy CT for different metal implants compared to non-metal reference scans. Dual-energy CT scans of a pair of human cadaver limbs were acquired before and after implanting a titanium tibia plate, a stainless-steel

  10. Dual-Specificity Phosphatase 4 Overexpression in Cells Prevents Hypoxia/Reoxygenation-Induced Apoptosis via the Upregulation of eNOS

    Science.gov (United States)

    Dougherty, Julie A.; Kilbane Myers, Joanna; Khan, Mahmood; Angelos, Mark G.; Chen, Chun-An

    2017-01-01

    Mitogen-activated protein kinases (MAPKs) signaling cascades regulate several cellular functions, including differentiation, proliferation, survival, and apoptosis. The duration and magnitude of phosphorylation of these MAPKs are decisive determinants of their physiological functions. Dual-specificity phosphatases exert kinetic control over these signaling cascades. Previously, we demonstrated that DUSP4−/− hearts sustain a larger infarct and have poor functional recovery, when isolated hearts were subjected to ischemia/reperfusion. Uncontrolled p38 activation and upregulation of Nox4 expression are the main effectors for this functional alteration. Here, dual-specificity phosphatase 4 (DUSP4) overexpression in endothelial cells was used to investigate the role of DUSP4 on the modulation of reactive oxygen species (ROS) generation and vascular function, when cells were subjected to hypoxia/reoxygenation (H/R) insult. Immunostaining with cleaved caspase-3 revealed that DUSP4 overexpression prevents caspase-3 activation and apoptosis after H/R. The beneficial effects occur via modulating p38 activity, increased NO bioavailability, and reduced oxidative stress. More importantly, DUSP4 overexpression upregulates eNOS protein expression (1.62 ± 0.33 versus 0.65 ± 0.16) during H/R-induced stress. NO is a critical small molecule involved in regulating vascular tone, vascular growth, platelet aggregation, and modulation of inflammation. The level of NO generation determined using DAF-2 fluorescence demonstrated that DUSP4 overexpression augments NO production and thus improves vascular function. The level of superoxide generated from cells after being subjected to H/R was determined using dihydroethidium-HPLC method. The results suggested that DUSP4 overexpression in cells decreases H/R-induced superoxide generation (1.56 ± 0.14 versus 1.19 ± 0.05) and thus reduces oxidant stress. This also correlates with the reduction in the total protein S

  11. Dual effect of fetal bovine serum on early development depends on stage-specific reactive oxygen species demands in pigs.

    Directory of Open Access Journals (Sweden)

    Seong-Eun Mun

    Full Text Available Despite the application of numerous supplements to improve in vitro culture (IVC conditions of mammalian cells, studies regarding the effect of fetal bovine serum (FBS on mammalian early embryogenesis, particularly in relation to redox homeostasis, are lacking. Herein, we demonstrated that early development of in vitro-produced (IVP porcine embryos highly depends on the combination of FBS supplementation timing and embryonic reactive oxygen species (ROS requirements. Interestingly, FBS significantly reduced intracellular ROS levels in parthenogenetically activated (PA embryos regardless of the developmental stage. However, the beneficial effect of FBS on early embryogenesis was found only during the late phase (IVC 4-6 days treatment group. In particular, developmental competence parameters, such as blastocyst formation rate, cellular survival, total cell number and trophectoderm proportion, were markedly increased by FBS supplementation during the late IVC phase. In addition, treatment with FBS elevated antioxidant transcript levels during the late IVC phase. In contrast, supplementation with FBS during the entire period (1-6 days or during the early IVC phase (1-2 days greatly impaired the developmental parameters. Consistent with the results from PA embryos, the developmental competence of in vitro fertilization (IVF or somatic cell nuclear transfer (SCNT embryos were markedly improved by treatment with FBS during the late IVC phase. Moreover, the embryonic stage-specific effects of FBS were reversed by the addition of an oxidant and were mimicked by treatment with an antioxidant. These findings may increase our understanding of redox-dependent early embryogenesis and contribute to the large-scale production of high-quality IVP embryos.

  12. Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer

    Directory of Open Access Journals (Sweden)

    Prestwich Robin

    2011-06-01

    Full Text Available Abstract Background Reovirus type 3 Dearing (T3D has demonstrated oncolytic activity in vitro, in in vivo murine models and in early clinical trials. However the true potential of oncolytic viruses may only be realized fully in combination with other modalities such as chemotherapy, targeted therapy and radiotherapy. In this study, we examine the oncolytic activity of reovirus T3D and chemotherapeutic agents against human prostate cancer cell lines, with particular focus on the highly metastatic cell line PC3 and the chemotherapeutic agent docetaxel. Docetaxel is the standard of care for metastatic prostate cancer and acts by disrupting the normal process of microtubule assembly and disassembly. Reoviruses have been shown to associate with microtubules and may require this association for efficient viral replication. Methods The effects of reovirus and chemotherapy on in vitro cytotoxicity were investigated in PC3 and Du 145 cells and the interactions between agents were assessed by combination index analysis. An Annexin V/propidium iodide fluorescence-activated cell sorting-based assay was used to determine mode of cell death. The effects of reovirus and docetaxel administered as single agent or combination therapy were tested in vivo in a murine model. The effects of docetaxel and reovirus, alone and together, on microtubule stabilisation were investigated by Western blot analysis. Results Variable degrees of synergistic cytotoxicity were observed in PC3 and Du 145 cells exposed to live reovirus and several chemotherapy agents. Combination of reovirus infection with docetaxel exposure led to increased late apoptotic/necrotic cell populations. Reovirus/docetaxel combined therapy led to reduced tumour growth and increased survival in a PC3 tumour bearing mouse model. Microtubule stabilization was enhanced in PC3 cells treated with reovirus/docetaxel combined therapy compared to other reovirus/chemotherapy combinations. Conclusions The co

  13. The dual specificity PI3K/mTOR inhibitor PKI-587 displays efficacy against T-cell acute lymphoblastic leukemia (T-ALL).

    Science.gov (United States)

    Gazi, Mohiuddin; Moharram, Sausan A; Marhäll, Alissa; Kazi, Julhash U

    2017-04-28

    Although significant improvements have been made in the treatment of acute lymphoblastic leukemia (ALL), there is a substantial subset of high-risk T-cell ALL (T-ALL) patients with relatively poor prognosis. Like in other leukemia types, alterations of the PI3K/mTOR pathway are predominant in ALL which is also responsible for treatment failure and relapse. In this study, we show that relapsed T-ALL patients display an enrichment of the PI3K/mTOR pathway. Using a panel of inhibitors targeting multiple components of the PI3K/mTOR pathway, we observed that the dual-specific PI3K/mTOR inhibitor PKI-587 was the most selective inhibitor for T-ALL cells dependent on the PI3K/mTOR pathway. Furthermore, we observed that PKI-587 blocked proliferation and colony formation of T-ALL cell lines. Additionally, PKI-587 selectively abrogated PI3K/mTOR signaling without affecting MAPK signaling both in in vitro and in vivo. Inhibition of the PI3K/mTOR pathway using PKI-587 delayed tumor progression, reduced tumor load and enhanced the survival rate in immune-deficient mouse xenograft models without inducing weight loss in the inhibitor treated mice. This preclinical study shows beneficial effects of PKI-587 on T-ALL that warrants further investigation in the clinical setting. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Dual-specificity tyrosine-regulated kinase 2 is a suppressor and potential prognostic marker for liver metastasis of colorectal cancer.

    Science.gov (United States)

    Ito, Daisuke; Yogosawa, Satomi; Mimoto, Rei; Hirooka, Shinichi; Horiuchi, Takashi; Eto, Ken; Yanaga, Katsuhiko; Yoshida, Kiyotsugu

    2017-08-01

    Colorectal cancer is a common cancer and a leading cause of cancer-related death worldwide. The liver is a dominant metastatic site for patients with colorectal cancer. Molecular mechanisms that allow colorectal cancer cells to form liver metastases are largely unknown. Activation of epithelial-mesenchymal transition is the key step for metastasis of cancer cells. We recently reported that dual-specificity tyrosine-regulated kinase 2 (DYRK2) controls epithelial-mesenchymal transition in breast cancer and ovarian serous adenocarcinoma. The aim of this study is to clarify whether DYRK2 regulates liver metastases of colorectal cancer. We show that the ability of cell invasion and migration was abrogated in DYRK2-overexpressing cells. In an in vivo xenograft model, liver metastatic lesions were markedly diminished by ectopic expression of DYRK2. Furthermore, we found that patients whose liver metastases expressed low DYRK2 levels had significantly worse overall and disease-free survival. Given the findings that DYRK2 regulates cancer cell metastasis, we concluded that the expression status of DYRK2 could be a predictive marker for liver metastases of colorectal cancer. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  15. Crystal Structure of Human Dual-Specificity Tyrosine-Regulated Kinase 3 Reveals New Structural Features and Insights into its Auto-phosphorylation.

    Science.gov (United States)

    Kim, Kuglae; Cha, Jeong Seok; Cho, Yong-Soon; Kim, Hoyoung; Chang, Nienping; Kim, Hye-Jung; Cho, Hyun-Soo

    2018-04-07

    Dual-specificity tyrosine-regulated kinases (DYRKs) auto-phosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues. The auto-phosphorylation occurs intramolecularly and is a one-off event. DYRK3 is selectively expressed at a high level in hematopoietic cells and attenuates erythroblast development, leading to anemia. In the present study, we determined the crystal structure of the mature form of human DYRK3 in complex with harmine, an ATP competitive inhibitor. The crystal structure revealed a phosphorylation site, residue S350, whose phosphorylation increases the stability of DYRK3 and enhances its kinase activity. In addition, our structural and biochemical assays suggest that the N-terminal auto-phosphorylation accessory domain stabilizes the DYRK3 protein, followed by auto-phosphorylation of the tyrosine of the activation loop, which is important for kinase activity. Finally, our docking analysis provides information for the design of novel and potent therapeutics to treat anemia. Copyright © 2018 Elsevier Ltd. All rights reserved.

  16. Increased suppression of oncolytic adenovirus carrying mutant k5 on colorectal tumor

    International Nuclear Information System (INIS)

    Fan Junkai; Xiao Tian; Gu Jinfa; Wei Na; He Lingfeng; Ding Miao; Liu Xinyuan

    2008-01-01

    Angiogenesis plays a key role in the development of a wide variety of malignant tumors. The approach of targeting antiangiogenesis has become an important field of cancer gene therapy. In this study, the antiangiogenesis protein K5 (the kringle 5 of human plasminogen) has been mutated by changing leucine71 to arginine to form mK5. Then the ZD55-mK5, which is an oncolytic adenovirus expressing mK5, was constructed. It showed stronger inhibition on proliferation of human umbilical vein endothelial cell. Moreover, in tube formation and embryonic chorioallantoic membrane assay, ZD55-mK5 exhibited more effective antiangiogenesis than ZD55-K5. In addition, ZD55-mK5 generated obvious suppression on the growth of colorectal tumor xenografts and prolonged the life span of nude mice. These results indicate that ZD55-mK5 is a potent agent for inhibiting the tumor angiogenesis and tumor growth

  17. Characterization of the Antiglioma Effect of the Oncolytic Adenovirus VCN-01.

    Directory of Open Access Journals (Sweden)

    Beatriz Vera

    Full Text Available Despite the recent advances in the development of antitumor therapies, the prognosis for patients with malignant gliomas remains dismal. Therapy with tumor-selective viruses is emerging as a treatment option for this devastating disease. In this study we characterize the anti-glioma effect of VCN-01, an improved hyaluronidase-armed pRB-pathway-selective oncolytic adenovirus that has proven safe and effective in the treatment of several solid tumors. VCN-01 displayed a significant cytotoxic effect on glioma cells in vitro. In vivo, in two different orthotopic glioma models, a single intra-tumoral administration of VCN-01 increased overall survival significantly and led to long-term survivors free of disease.

  18. Combination of Vaccine-Strain Measles and Mumps Viruses Enhances Oncolytic Activity against Human Solid Malignancies.

    Science.gov (United States)

    Son, Ho Anh; Zhang, LiFeng; Cuong, Bui Khac; Van Tong, Hoang; Cuong, Le Duy; Hang, Ngo Thu; Nhung, Hoang Thi My; Yamamoto, Naoki; Toan, Nguyen Linh

    2018-02-07

    Oncolytic measles and mumps viruses (MeV, MuV) have a potential for anti-cancer treatment. We examined the anti-tumor activity of MeV, MuV, and MeV-MuV combination (MM) against human solid malignancies (HSM). MeV, MuV, and MM targeted and significantly killed various cancer cell lines of HSM but not normal cells. MM demonstrated a greater anti-tumor effect and prolonged survival in a human prostate cancer xenograft tumor model compared to MeV and MuV. MeV, MuV, and MM significantly induced the expression of immunogenic cell death markers and enhanced spleen-infiltrating immune cells. In conclusion, MM combination significantly improves the treatment of human solid malignancies.

  19. p21 promotes oncolytic adenoviral activity in ovarian cancer and is a potential biomarker

    Directory of Open Access Journals (Sweden)

    Lockley Michelle

    2010-07-01

    Full Text Available Abstract The oncolytic adenovirus dl922-947 replicates selectively within and lyses cells with a dysregulated Rb pathway, a finding seen in > 90% human cancers. dl922-947 is more potent than wild type adenovirus and the E1B-deletion mutant dl1520 (Onyx-015. We wished to determine which host cell factors influence cytotoxicity. SV40 large T-transformed MRC5-VA cells are 3-logs more sensitive to dl922-947 than isogenic parental MRC5 cells, confirming that an abnormal G1/S checkpoint increases viral efficacy. The sensitivity of ovarian cancer cells to dl922-947 varied widely: IC50 values ranged from 51 (SKOV3ip1 to 0.03 pfu/cell (TOV21G. Cells sensitive to dl922-947 had higher S phase populations and supported earlier E1A expression. Cytotoxicity correlated poorly with both infectivity and replication, but well with expression of p21 by microarray and western blot analyses. Matched p21+/+ and -/- Hct116 cells confirmed that p21 influences dl922-947 activity in vitro and in vivo. siRNA-mediated p21 knockdown in sensitive TOV21G cells decreases E1A expression and viral cytotoxicity, whilst expression of p21 in resistant A2780CP cells increases virus activity in vitro and in intraperitoneal xenografts. These results highlight that host cell factors beyond simple infectivity can influence the efficacy of oncolytic adenoviruses. p21 expression may be an important biomarker of response in clinical trials.

  20. Current good manufacturing practice production of an oncolytic recombinant vesicular stomatitis viral vector for cancer treatment.

    Science.gov (United States)

    Ausubel, L J; Meseck, M; Derecho, I; Lopez, P; Knoblauch, C; McMahon, R; Anderson, J; Dunphy, N; Quezada, V; Khan, R; Huang, P; Dang, W; Luo, M; Hsu, D; Woo, S L C; Couture, L

    2011-04-01

    Vesicular stomatitis virus (VSV) is an oncolytic virus currently being investigated as a promising tool to treat cancer because of its ability to selectively replicate in cancer cells. To enhance the oncolytic property of the nonpathologic laboratory strain of VSV, we generated a recombinant vector [rVSV(MΔ51)-M3] expressing murine gammaherpesvirus M3, a secreted viral chemokine-binding protein that binds to a broad range of mammalian chemokines with high affinity. As previously reported, when rVSV(MΔ51)-M3 was used in an orthotopic model of hepatocellular carcinoma (HCC) in rats, it suppressed inflammatory cell migration to the virus-infected tumor site, which allowed for enhanced intratumoral virus replication leading to increased tumor necrosis and substantially prolonged survival. These encouraging results led to the development of this vector for clinical translation in patients with HCC. However, a scalable current Good Manufacturing Practice (cGMP)-compliant manufacturing process has not been described for this vector. To produce the quantities of high-titer virus required for clinical trials, a process that is amenable to GMP manufacturing and scale-up was developed. We describe here a large-scale (50-liter) vector production process capable of achieving crude titers on the order of 10(9) plaque-forming units (PFU)/ml under cGMP. This process was used to generate a master virus seed stock and a clinical lot of the clinical trial agent under cGMP with an infectious viral titer of approximately 2 × 10(10) PFU/ml (total yield, 1 × 10(13) PFU). The lot has passed all U.S. Food and Drug Administration-mandated release testing and will be used in a phase 1 clinical translational trial in patients with advanced HCC.

  1. Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway

    International Nuclear Information System (INIS)

    Twigger, Katie; Coffey, Matt; Thompson, Brad; Jebar, Adel; Errington, Fiona; Melcher, Alan A; Vile, Richard G; Pandha, Hardev S; Harrington, Kevin J; Roulstone, Victoria; Kyula, Joan; Karapanagiotou, Eleni M; Syrigos, Konstantinos N; Morgan, Richard; White, Christine; Bhide, Shreerang; Nuovo, Gerard

    2012-01-01

    Reovirus exploits aberrant signalling downstream of Ras to mediate tumor-specific oncolysis. Since ~90% squamous cell carcinomas of the head and neck (SCCHN) over-express EGFR and SCCHN cell lines are sensitive to oncolytic reovirus, we conducted a detailed analysis of the effects of reovirus in 15 head and neck cancer cell lines. Both pre- and post-entry events were studied in an attempt to define biomarkers predictive of sensitivity/resistance to reovirus. In particular, we analysed the role of EGFR/Ras signalling in determining virus-mediated cytotoxicity in SCCHN. To test whether EGFR pathway activity was predictive of increased sensitivity to reovirus, correlative analyses between reoviral IC50 by MTT assay and EGFR levels by western blot and FACS were conducted. Inhibition or stimulation of EGFR signalling were analysed for their effect on reoviral oncolysis by MTT assay, and viral growth by TCID50 assay. We next analysed the effects of inhibiting signalling downstream of Ras, by specific inhibitors of p38MAPK, PI3-K or MEK, on reoviral killing examined by MTT assay. The role of PKR in reoviral killing was also determined by blockade of PKR using 2-aminopurine and assaying for cell survival by MTT assay. The apoptotic response of SCCHN to reovirus was examined by western blot analysis of caspase 3 cleavage. Correlative analyses between reoviral sensitivity and EGFR levels revealed no association. Intermediate sub-viral and core particles showed the same infectivity/cytotoxicity as intact reovirus. Therefore, sensitivity was not determined by cell entry. In 4 cell lines, oncolysis and viral growth were both unaffected by inhibition or stimulation of EGFR signalling. Inhibition of signalling downstream of Ras did not abrogate reoviral oncolysis and, in addition, modulation of PKR using 2-aminopurine did not alter reovirus sensitivity in resistant cell lines. Caspase 3 cleavage was not detected in infected cells and oncolysis was observed in pan

  2. Sex- and age-specific percentiles of body composition indices for Chinese adults using dual-energy X-ray absorptiometry.

    Science.gov (United States)

    Xiao, Zeyu; Guo, Bin; Gong, Jian; Tang, Yongjin; Shang, Jingjie; Cheng, Yong; Xu, Hao

    2017-10-01

    The aims of the study were to develop sex- and age-specific percentiles for lean mass index (LMI), appendicular LMI (aLMI), fat mass index (FMI), and body fat distribution indices in Chinese adults using dual-energy X-ray absorptiometry (DXA), and to compare those indices with those of other ethnicities using the US NHANES data. Whole-body and regional lean mass and fat mass (FM) were measured using DXA in 5688 healthy males (n = 1693) and females (n = 3995) aged 20-90 years. Body fat distribution indices were expressed as % fat trunk/% fat legs, trunk/appendicular FM ratio (FMR), and android/gynoid FMR. Percentile curves of LMI, aLMI, FMI, and body fat distribution indices were obtained by the Lambda-Mu-Sigma method. The aLMI and LMI were negatively associated with age, decreasing from the fifth decade for males, but were not associated with age in females. Females had more total FM than males, whereas males had greater central adiposity (% fat trunk/% fat legs ratio, trunk/appendicular FMR, and android/gynoid FMR) than females. Moreover, FMI and body fat distribution indices consistently increased with age in both sexes, especially in women. In comparison with white, black, and Mexican populations in the USA, Chinese adults had lower total FM, but had greater central adiposity (% fat trunk/% fat legs ratio and trunk/appendicular FMR). Additionally, older white and Mexican populations showed greater decreases for aLMI and LMI than their Chinese counterparts. We present the sex- and age-specific percentiles for aLMI, LMI, FMI, and body fat distribution indices by DXA in Chinese adults, which may refine the individual assessment of the nutritional status of Chinese adults.

  3. E4orf1 Limits the Oncolytic Potential of the E1B-55K Deletion Mutant Adenovirus▿

    Science.gov (United States)

    Thomas, Michael A.; Broughton, Robin S.; Goodrum, Felicia D.; Ornelles, David A.

    2009-01-01

    Clinical trials have shown oncolytic adenoviruses to be tumor selective with minimal toxicity toward normal tissue. The virus ONYX-015, in which the gene encoding the early region 1B 55-kDa (E1B-55K) protein is deleted, has been most effective when used in combination with either chemotherapy or radiation therapy. Therefore, improving the oncolytic nature of tumor-selective adenoviruses remains an important objective for improving this form of cancer therapy. Cells infected during the G1 phase of the cell cycle with the E1B-55K deletion mutant virus exhibit a reduced rate of viral late protein synthesis, produce fewer viral progeny, and are less efficiently killed than cells infected during the S phase. Here we demonstrate that the G1 restriction imposed on the E1B-55K deletion mutant virus is due to the viral oncogene encoded by open reading frame 1 of early region 4 (E4orf1). E4orf1 has been reported to signal through the phosphatidylinositol 3′-kinase pathway leading to the activation of Akt, mTOR, and p70 S6K. Evidence presented here shows that E4orf1 may also induce the phosphorylation of Akt and p70 S6K in a manner that depends on Rac1 and its guanine nucleotide exchange factor Tiam1. Accordingly, agents that have been reported to disrupt the Tiam1-Rac1 interaction or to prevent phosphorylation of the ribosomal S6 kinase partially alleviated the E4orf1 restriction to late viral protein synthesis and enhanced tumor cell killing by the E1B-55K mutant virus. These results demonstrate that E4orf1 limits the oncolytic nature of a conditionally replicating adenovirus such as ONYX-015. The therapeutic value of similar oncolytic adenoviruses may be improved by abrogating E4orf1 function. PMID:19129452

  4. E4orf1 limits the oncolytic potential of the E1B-55K deletion mutant adenovirus.

    Science.gov (United States)

    Thomas, Michael A; Broughton, Robin S; Goodrum, Felicia D; Ornelles, David A

    2009-03-01

    Clinical trials have shown oncolytic adenoviruses to be tumor selective with minimal toxicity toward normal tissue. The virus ONYX-015, in which the gene encoding the early region 1B 55-kDa (E1B-55K) protein is deleted, has been most effective when used in combination with either chemotherapy or radiation therapy. Therefore, improving the oncolytic nature of tumor-selective adenoviruses remains an important objective for improving this form of cancer therapy. Cells infected during the G(1) phase of the cell cycle with the E1B-55K deletion mutant virus exhibit a reduced rate of viral late protein synthesis, produce fewer viral progeny, and are less efficiently killed than cells infected during the S phase. Here we demonstrate that the G(1) restriction imposed on the E1B-55K deletion mutant virus is due to the viral oncogene encoded by open reading frame 1 of early region 4 (E4orf1). E4orf1 has been reported to signal through the phosphatidylinositol 3'-kinase pathway leading to the activation of Akt, mTOR, and p70 S6K. Evidence presented here shows that E4orf1 may also induce the phosphorylation of Akt and p70 S6K in a manner that depends on Rac1 and its guanine nucleotide exchange factor Tiam1. Accordingly, agents that have been reported to disrupt the Tiam1-Rac1 interaction or to prevent phosphorylation of the ribosomal S6 kinase partially alleviated the E4orf1 restriction to late viral protein synthesis and enhanced tumor cell killing by the E1B-55K mutant virus. These results demonstrate that E4orf1 limits the oncolytic nature of a conditionally replicating adenovirus such as ONYX-015. The therapeutic value of similar oncolytic adenoviruses may be improved by abrogating E4orf1 function.

  5. The oncolytic peptide LTX-315 induces cell death and DAMP release by mitochondria distortion in human melanoma cells

    Science.gov (United States)

    Eike, Liv-Marie; Yang, Nannan; Rekdal, Øystein; Sveinbjørnsson, Baldur

    2015-01-01

    Host defense peptides (HDPs) are naturally occurring molecules found in most species, in which they play a significant role in the first line defense against intruding pathogens, and several HDPs have been shown to possess anticancer activity. Structure-activity relationship studies on the HDP bovine lactoferricin revealed a de novo design of a nonamer peptide LTX-315, with oncolytic properties. In the present study, we investigated the oncolytic activity of LTX-315 in human melanoma cells (A375). LTX-315 induced a rapid plasma membrane disruption and cell death within 2 hours. At a low concentration, fluorescence-labeled LTX-315 was internalized and accumulated in cytoplasmic vacuoles in close proximity to the mitochondria. The mitochondrial membrane potential was shown to depolarize as a consequence of LTX-315 treatment and at ultrastructural level, the mitochondria morphology was significantly altered. Release of danger signals (DAMPs) such as ATP, Cytochrome C and HMGB1 into the cell supernatant of cultured cells was evident minutes after peptide treatment. The oncolytic effect of LTX-315 involving perturbation of both the cell membrane and the mitochondria with subsequent release of DAMPs may highlight the ability of LTX-315 to induce complete regression and long-term protective immune responses as previously reported in experimental animal models. PMID:26472184

  6. Dual Regression

    OpenAIRE

    Spady, Richard; Stouli, Sami

    2012-01-01

    We propose dual regression as an alternative to the quantile regression process for the global estimation of conditional distribution functions under minimal assumptions. Dual regression provides all the interpretational power of the quantile regression process while avoiding the need for repairing the intersecting conditional quantile surfaces that quantile regression often produces in practice. Our approach introduces a mathematical programming characterization of conditional distribution f...

  7. Impaired spatial learning strategies and novel object recognition in mice haploinsufficient for the dual specificity tyrosine-regulated kinase-1A (Dyrk1A.

    Directory of Open Access Journals (Sweden)

    Glòria Arqué

    Full Text Available BACKGROUND: Pathogenic aneuploidies involve the concept of dosage-sensitive genes leading to over- and underexpression phenotypes. Monosomy 21 in human leads to mental retardation and skeletal, immune and respiratory function disturbances. Most of the human condition corresponds to partial monosomies suggesting that critical haploinsufficient genes may be responsible for the phenotypes. The DYRK1A gene is localized on the human chromosome 21q22.2 region, and has been proposed to participate in monosomy 21 phenotypes. It encodes a dual-specificity kinase involved in neuronal development and in adult brain physiology, but its possible role as critical haploinsufficient gene in cognitive function has not been explored. METHODOLOGY/PRINCIPAL FINDINGS: We used mice heterozygous for a Dyrk1A targeted mutation (Dyrk1A+/- to investigate the implication of this gene in the cognitive phenotypes of monosomy 21. Performance of Dyrk1A+/- mice was assayed 1/ in a navigational task using the standard hippocampally related version of the Morris water maze, 2/ in a swimming test designed to reveal potential kinesthetic and stress-related behavioral differences between control and heterozygous mice under two levels of aversiveness (25 degrees C and 17 degrees C and 3/ in a long-term novel object recognition task, sensitive to hippocampal damage. Dyrk1A+/- mice showed impairment in the development of spatial learning strategies in a hippocampally-dependent memory task, they were impaired in their novel object recognition ability and were more sensitive to aversive conditions in the swimming test than euploid control animals. CONCLUSIONS/SIGNIFICANCE: The present results are clear examples where removal of a single gene has a profound effect on phenotype and indicate that haploinsufficiency of DYRK1A might contribute to an impairment of cognitive functions and stress coping behavior in human monosomy 21.

  8. Dual-specificity phosphatase 10 controls brown adipocyte differentiation by modulating the phosphorylation of p38 mitogen-activated protein kinase.

    Directory of Open Access Journals (Sweden)

    Hye-Ryung Choi

    Full Text Available Brown adipocytes play an important role in regulating the balance of energy, and as such, there is a strong correlation between obesity and the amount of brown adipose tissue. Although the molecular mechanism underlying white adipocyte differentiation has been well characterized, brown adipocyte differentiation has not been studied extensively. Here, we investigate the potential role of dual-specificity phosphatase 10 (DUSP10 in brown adipocyte differentiation using primary brown preadipocytes.The expression of DUSP10 increased continuously after the brown adipocyte differentiation of mouse primary brown preadipocytes, whereas the phosphorylation of p38 was significantly upregulated at an early stage of differentiation followed by steep downregulation. The overexpression of DUSP10 induced a decrease in the level of p38 phosphorylation, resulting in lower lipid accumulation than that in cells overexpressing the inactive mutant DUSP10. The expression levels of several brown adipocyte markers such as PGC-1α, UCP1, and PRDM16 were also significantly reduced upon the ectopic expression of DUSP10. Furthermore, decreased mitochondrial DNA content was detected in cells expressing DUSP10. The results obtained upon treatment with the p38 inhibitor, SB203580, clearly indicated that the phosphorylation of p38 at an early stage is important in brown adipocyte differentiation. The effect of the p38 inhibitor was partially recovered by DUSP10 knockdown using RNAi.These results suggest that p38 phosphorylation is controlled by DUSP10 expression. Furthermore, p38 phosphorylation at an early stage is critical in brown adipocyte differentiation. Thus, the regulation of DUSP10 activity affects the efficiency of brown adipogenesis. Consequently, DUSP10 can be used as a novel target protein for the regulation of obesity.

  9. Structural Insight into the Critical Role of the N-Terminal Region in the Catalytic Activity of Dual-Specificity Phosphatase 26.

    Directory of Open Access Journals (Sweden)

    Eun-Young Won

    Full Text Available Human dual-specificity phosphatase 26 (DUSP26 is a novel target for anticancer therapy because its dephosphorylation of the p53 tumor suppressor regulates the apoptosis of cancer cells. DUSP26 inhibition results in neuroblastoma cell cytotoxicity through p53-mediated apoptosis. Despite the previous structural studies of DUSP26 catalytic domain (residues 61-211, DUSP26-C, the high-resolution structure of its catalytically active form has not been resolved. In this study, we determined the crystal structure of a catalytically active form of DUSP26 (residues 39-211, DUSP26-N with an additional N-terminal region at 2.0 Å resolution. Unlike the C-terminal domain-swapped dimeric structure of DUSP26-C, the DUSP26-N (C152S monomer adopts a fold-back conformation of the C-terminal α8-helix and has an additional α1-helix in the N-terminal region. Consistent with the canonically active conformation of its protein tyrosine phosphate-binding loop (PTP loop observed in the structure, the phosphatase assay results demonstrated that DUSP26-N has significantly higher catalytic activity than DUSP26-C. Furthermore, size exclusion chromatography-multiangle laser scattering (SEC-MALS measurements showed that DUSP26-N (C152S exists as a monomer in solution. Notably, the crystal structure of DUSP26-N (C152S revealed that the N-terminal region of DUSP26-N (C152S serves a scaffolding role by positioning the surrounding α7-α8 loop for interaction with the PTP-loop through formation of an extensive hydrogen bond network, which seems to be critical in making the PTP-loop conformation competent for phosphatase activity. Our study provides the first high-resolution structure of a catalytically active form of DUSP26, which will contribute to the structure-based rational design of novel DUSP26-targeting anticancer therapeutics.

  10. Complex spatial dynamics of oncolytic viruses in vitro: mathematical and experimental approaches.

    Directory of Open Access Journals (Sweden)

    Dominik Wodarz

    Full Text Available Oncolytic viruses replicate selectively in tumor cells and can serve as targeted treatment agents. While promising results have been observed in clinical trials, consistent success of therapy remains elusive. The dynamics of virus spread through tumor cell populations has been studied both experimentally and computationally. However, a basic understanding of the principles underlying virus spread in spatially structured target cell populations has yet to be obtained. This paper studies such dynamics, using a newly constructed recombinant adenovirus type-5 (Ad5 that expresses enhanced jellyfish green fluorescent protein (EGFP, AdEGFPuci, and grows on human 293 embryonic kidney epithelial cells, allowing us to track cell numbers and spatial patterns over time. The cells are arranged in a two-dimensional setting and allow virus spread to occur only to target cells within the local neighborhood. Despite the simplicity of the setup, complex dynamics are observed. Experiments gave rise to three spatial patterns that we call "hollow ring structure", "filled ring structure", and "disperse pattern". An agent-based, stochastic computational model is used to simulate and interpret the experiments. The model can reproduce the experimentally observed patterns, and identifies key parameters that determine which pattern of virus growth arises. The model is further used to study the long-term outcome of the dynamics for the different growth patterns, and to investigate conditions under which the virus population eliminates the target cells. We find that both the filled ring structure and disperse pattern of initial expansion are indicative of treatment failure, where target cells persist in the long run. The hollow ring structure is associated with either target cell extinction or low-level persistence, both of which can be viewed as treatment success. Interestingly, it is found that equilibrium properties of ordinary differential equations describing the

  11. A dual-immunocytochemical method to localize c-fos protein in specific neurons based on their content of neuropeptides and connectivity

    DEFF Research Database (Denmark)

    Mikkelsen, J D; Larsen, P J; Sørensen, G G

    1994-01-01

    Enhanced expression of the immediate early gene c-fos has been used as a marker of cellular activation in many different neuronal pathways. We wished to determine the neurochemical content and the connectivity of neurons, in which expression of c-fos is induced. For this purpose, a dual...

  12. Probing the Oncolytic and Chemosensitizing Effects of Dihydrotanshinone in an In Vitro Glioblastoma Model.

    Science.gov (United States)

    Kumar, Varun; Radin, Daniel; Leonardi, Donna

    2017-11-01

    Temozolomide is the primary chemotherapeutic agent used to treat glioblastoma. However, many tumors are initially resistant to or develop resistance to temozolomide, mainly due to high levels of O 6 -methylguanine DNA transferase (MGMT) which repairs DNA damage traditionally caused by temozolomide. Dihydrotanshinone (DHT) is extracted from Salvia miltiorrhiza, a Chinese medicinal plant, and has also been shown to have antiproliferative effects on various cancer cell lines. DHT has been to shown to induce apoptosis via induction endoplasmic reticulum stress, that can reportedly sensitize cells to temozolomide. MTS cellular proliferation assays or trypan blue viability assays were used to determine the effects of DHT/temozolomide combinatorial treatment. Enzyme-linked immunosorbent assay (ELISA) was used to determine effects on MGMT and P-glycoprotein levels after singular and combinatorial treatment. DHT had a synergistic oncolytic effect in a MGMT-deficient cell line and a sensitizing effect in a MGMT-expressing cell line. Cytotoxicity due to DHT was shown to be reactive oxygen species-dependent, while the combinatorial effect of DHT and temozolomide synergistically reduced MGMT and P-glycoprotein levels. DHT was shown to augment temozolomide efficacy, indicating that, since DHT can penetrate the blood-brain barrier, temozolomide in combination with DHT may represent a promising therapeutic option for glioblastoma. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  13. Immunotherapeutic Potential of Oncolytic H-1 Parvovirus: Hints of Glioblastoma Microenvironment Conversion towards Immunogenicity.

    Science.gov (United States)

    Angelova, Assia L; Barf, Milena; Geletneky, Karsten; Unterberg, Andreas; Rommelaere, Jean

    2017-12-15

    Glioblastoma, one of the most aggressive primary brain tumors, is characterized by highly immunosuppressive microenvironment. This contributes to glioblastoma resistance to standard treatment modalities and allows tumor growth and recurrence. Several immune-targeted approaches have been recently developed and are currently under preclinical and clinical investigation. Oncolytic viruses, including the autonomous protoparvovirus H-1 (H-1PV), show great promise as novel immunotherapeutic tools. In a first phase I/IIa clinical trial (ParvOryx01), H-1PV was safe and well tolerated when locally or systemically administered to recurrent glioblastoma patients. The virus was able to cross the blood-brain (tumor) barrier after intravenous infusion. Importantly, H-1PV treatment of glioblastoma patients was associated with immunogenic changes in the tumor microenvironment. Tumor infiltration with activated cytotoxic T cells, induction of cathepsin B and inducible nitric oxide (NO) synthase (iNOS) expression in tumor-associated microglia/macrophages (TAM), and accumulation of activated TAM in cluster of differentiation (CD) 40 ligand (CD40L)-positive glioblastoma regions was detected. These are the first-in-human observations of H-1PV capacity to switch the immunosuppressed tumor microenvironment towards immunogenicity. Based on this pilot study, we present a tentative model of H-1PV-mediated modulation of glioblastoma microenvironment and propose a combinatorial therapeutic approach taking advantage of H-1PV-induced microglia/macrophage activation for further (pre)clinical testing.

  14. Histone deacetylase inhibitors improve the replication of oncolytic herpes simplex virus in breast cancer cells.

    Directory of Open Access Journals (Sweden)

    James J Cody

    Full Text Available New therapies are needed for metastatic breast cancer patients. Oncolytic herpes simplex virus (oHSV is an exciting therapy being developed for use against aggressive tumors and established metastases. Although oHSV have been demonstrated safe in clinical trials, a lack of sufficient potency has slowed the clinical application of this approach. We utilized histone deacetylase (HDAC inhibitors, which have been noted to impair the innate antiviral response and improve gene transcription from viral vectors, to enhance the replication of oHSV in breast cancer cells. A panel of chemically diverse HDAC inhibitors were tested at three different doses (LD50 for their ability to modulate the replication of oHSV in breast cancer cells. Several of the tested HDAC inhibitors enhanced oHSV replication at low multiplicity of infection (MOI following pre-treatment of the metastatic breast cancer cell line MDA-MB-231 and the oHSV-resistant cell line 4T1, but not in the normal breast epithelial cell line MCF10A. Inhibitors of class I HDACs, including pan-selective compounds, were more effective for increasing oHSV replication compared to inhibitors that selectively target class II HDACs. These studies demonstrate that select HDAC inhibitors increase oHSV replication in breast cancer cells and provides support for pre-clinical evaluation of this combination strategy.

  15. Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound.

    Science.gov (United States)

    Bazan-Peregrino, Miriam; Rifai, Bassel; Carlisle, Robert C; Choi, James; Arvanitis, Costas D; Seymour, Leonard W; Coussios, Constantin C

    2013-07-10

    Oncolytic viruses (OV) and ultrasound-enhanced drug delivery are powerful novel technologies. OV selectively self-amplify and kill cancer cells but their clinical use has been restricted by limited delivery from the bloodstream into the tumor. Ultrasound has been previously exploited for targeted release of OV in vivo, but its use to induce cavitation, microbubble oscillations, for enhanced OV tumor extravasation and delivery has not been previously reported. By identifying and optimizing the underlying physical mechanism, this work demonstrates that focused ultrasound significantly enhances the delivery and biodistribution of systemically administered OV co-injected with microbubbles. Up to a fiftyfold increase in tumor transgene expression was achieved, without any observable tissue damage. Ultrasound exposure parameters were optimized as a function of tumor reperfusion time to sustain inertial cavitation, a type of microbubble activity, throughout the exposure. Passive detection of acoustic emissions during treatment confirmed inertial cavitation as the mechanism responsible for enhanced delivery and enabled real-time monitoring of successful viral delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. The Explicit Determinations Of Dual Plane Curves And Dual Helices In Terms Of Its Dual Curvature And Dual Torsion

    OpenAIRE

    Lee Jae Won; Choi Jin Ho; Jin Dae Ho

    2014-01-01

    In this paper, we give the explicit determinations of dual plane curves, general dual helices and dual slant helices in terms of its dual curvature and dual torsion as a fundamental theory of dual curves in a dual 3-space

  17. Safety studies on intravenous administration of oncolytic recombinant vesicular stomatitis virus in purpose-bred beagle dogs.

    Science.gov (United States)

    LeBlanc, Amy K; Naik, Shruthi; Galyon, Gina D; Jenks, Nathan; Steele, Mike; Peng, Kah-Whye; Federspiel, Mark J; Donnell, Robert; Russell, Stephen J

    2013-12-01

    VSV-IFNβ-NIS is a novel recombinant oncolytic vesicular stomatitis virus (VSV) with documented efficacy and safety in preclinical murine models of cancer. To facilitate clinical translation of this promising oncolytic therapy in patients with disseminated cancer, we are utilizing a comparative oncology approach to gather data describing the safety and efficacy of systemic VSV-IFNβ-NIS administration in dogs with naturally occurring cancer. In support of this, we executed a dose-escalation study in purpose-bred dogs to determine the maximum tolerated dose (MTD) of systemic VSV-hIFNβ-NIS, characterize the adverse event profile, and describe routes and duration of viral shedding in healthy, immune-competent dogs. The data indicate that an intravenous dose of 10(10) TCID50 is well tolerated in dogs. Expected adverse events were mild to moderate fever, self-limiting nausea and vomiting, lymphopenia, and oral mucosal lesions. Unexpected adverse events included prolongation of partial thromboplastin time, development of bacterial urinary tract infection, and scrotal dermatitis, and in one dog receiving 10(11) TCID50 (10 × the MTD), the development of severe hepatotoxicity and symptoms of shock leading to euthanasia. Viral shedding data indicate that detectable viral genome in blood diminishes rapidly with anti-VSV neutralizing antibodies detectable in blood as early as day 5 postintravenous virus administration. While low levels of viral genome copies were detectable in plasma, urine, and buccal swabs of dogs treated at the MTD, no infectious virus was detectable in plasma, urine, or buccal swabs at any of the doses tested. These studies confirm that VSV can be safely administered systemically in dogs, justifying the use of oncolytic VSV as a novel therapy for the treatment of canine cancer.

  18. A novel combination treatment of armed oncolytic adenovirus expressing IL-12 and GM-CSF with radiotherapy in murine hepatocarcinoma

    International Nuclear Information System (INIS)

    Kim, Wonwoo; Seong, Jinsil; Oh, Hae-Jin; Koom, Woong-Sub; Choi, Kyung-Joo; Yun, Chae-Ok

    2011-01-01

    In this study, a novel combination treatment of armed oncolytic adenovirus expressing interleukin 12 (IL-12) and granulocyte-macrophage colony-stimulating factor (GM-CSF) with radiation was investigated for antitumor and antimetastatic effect in a murine hepatic cancer (HCa-I) model. Tumor bearing syngeneic mice were treated with radiation, armed oncolytic virus Ad-ΔE1Bmt7 (dB7) expressing both IL-12 and GM-CSF (armed dB7), or a combination of both. The adenovirus was administered by intratumoral injection 1 x 10 8 plaque forming units (PFU) per tumor in 50 μl of phosphate buffered saline (PBS) four times every other day. Tumor response to treatment was determined by a tumor growth delay assay. Metastatic potential was evaluated by a lung metastasis model. To understand the underlying mechanism, the level of apoptosis was examined as well as the change in microvessel density and expression of immunological markers: CD4+, CD8+ and Cd11c. The combination of armed dB7 and radiation resulted in significant growth delay of murine hepatic cancer, HCa-1, with an enhancement factor of 4.3. The combination treatment also resulted in significant suppression of lung metastasis. Increase of apoptosis level as well as decrease of microvessel density was shown in the combination treatment, suggesting an underlying mechanism for the enhancement of antitumor effect. Expression of immunological markers: CD4+, CD8+ and Cd11c also increased in the combination treatment. This study showed that a novel combination treatment of radiotherapy with armed oncolytic adenovirus expressing IL-12 and GM-CSF was effective in suppressing primary tumor growth. (author)

  19. Preclinical Testing of an Oncolytic Parvovirus: Standard Protoparvovirus H-1PV Efficiently Induces Osteosarcoma Cell Lysis In Vitro

    OpenAIRE

    Carsten Geiss; Zoltán Kis; Barbara Leuchs; Monika Frank-Stöhr; Jörg R. Schlehofer; Jean Rommelaere; Christiane Dinsart; Jeannine Lacroix

    2017-01-01

    Osteosarcoma is the most frequent malignant disease of the bone. On the basis of early clinical experience in the 1960s with H-1 protoparvovirus (H-1PV) in osteosarcoma patients, this effective oncolytic virus was selected for systematic preclinical testing on various osteosarcoma cell cultures. A panel of five human osteosarcoma cell lines (CAL 72, H-OS, MG-63, SaOS-2, U-2OS) was tested. Virus oncoselectivity was confirmed by infecting non-malignant human neonatal fibroblasts and osteoblasts...

  20. Reliability of Measuring Lumbar Lordosis, Flexion and Extension Using Dual Inclinometer in Healthy Subjects and Patients with Non-Specific Chronic Low Back Pain

    Directory of Open Access Journals (Sweden)

    Samira Garmabi

    2012-07-01

    Full Text Available Objective: Accurate assessment of lumbar range of motion is of great value for both evaluating lumbar functions and monitoring treatment progress. Recent research indicates that there is no general consensus on the most valid and reliable method of measuring spinal range of motion. The purpose of this study was to determine the intra-rater reliability of lumbar flexion and extension measurements (within-day and between-days using the dual inclinometer technique.   Materials & Methods: Lumbar flexion and extension of 22 women (14 healthy and 8 with low back pain, were measured by the same examiner on three occasions. The first two measurements were taken with half an hour apart on the first occasion to assess the within-day reliability and the third measurement was taken one week later to assess the between-days reliability.  Results: Within-day lumbar lordosis, flexion and extension measurements using dual inclinometer technique were shown to be very reliable with high Intraclass Correlation Coefficients (ICC values (ICC were 98%, 77% and 69% for lordosis, flexion and extension measurements, respectively in healthy subjects and 94%, 95% and 69% for lordosis, flexion and extension measurements, respectively in patients group. Between-Days measurements also demonstrated high reliability with the high values of ICC (ICC were 96%, 70% and 67% for lordosis, flexion and extension measurements, in healthy subjects and 91%, 71% and 66% for lordosis, flexion and extension measurements, respectively in patients group. Conclusion: The results indicated that, the dual inclinometer technique appears to be a highly reliable method for measuring lumbar lordosis, flexion and extension and can be used as a reliable tool in the assessment of lumbar range of motion and monitoring therapeutic interventions.

  1. QCD Dual

    DEFF Research Database (Denmark)

    Sannino, Francesco

    2009-01-01

    We uncover a novel solution of the 't Hooft anomaly matching conditions for QCD. Interestingly in the perturbative regime the new gauge theory, if interpreted as a possible QCD dual, predicts the critical number of flavors above which QCD in the nonperturbative regime, develops an infrared stable...

  2. Targeting human breast cancer cells by an oncolytic adenovirus using microRNA-targeting strategy.

    Science.gov (United States)

    Shayestehpour, Mohammad; Moghim, Sharareh; Salimi, Vahid; Jalilvand, Somayeh; Yavarian, Jila; Romani, Bizhan; Mokhtari-Azad, Talat

    2017-08-15

    MicroRNA-targeting strategy is a promising approach that enables oncolytic viruses to replicate in tumor cells but not in normal cells. In this study, we targeted adenoviral replication toward breast cancer cells by inserting ten complementary binding sites for miR-145-5p downstream of E1A gene. In addition, we evaluated the effect of increasing miR-145 binding sites on inhibition of virus replication. Ad5-control and adenoviruses carrying five or ten copies of miR145-5p target sites (Ad5-5miR145T, Ad5-10miR145T) were generated and inoculated into MDA-MB-453, BT-20, MCF-7 breast cancer cell lines and human mammary epithelial cells (HMEpC). Titer of Ad5-10miR145T in HMEpC was significantly lower than Ad5-control titer. Difference between the titer of these two viruses at 12, 24, 36, and 48h after infection was 1.25, 2.96, 3.06, and 3.77 log TCID 50 . No significant difference was observed between the titer of both adenoviruses in MDA-MB-453, BT-20 and MCF-7 cells. The infectious titer of adenovirus containing 10 miR-145 binding sites in HMEpC cells at 24, 36, and 48h post-infection was 1.7, 2.08, and 4-fold, respectively, lower than the titer of adenovirus carrying 5 miR-145 targets. Our results suggest that miR-145-targeting strategy provides selectivity for adenovirus replication in breast cancer cells. Increasing the number of miRNA binding sites within the adenoviral genome confers more selectivity for viral replication in cancer cells. Copyright © 2017. Published by Elsevier B.V.

  3. ATN-224 enhances antitumor efficacy of oncolytic herpes virus against both local and metastatic head and neck squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Ji Young Yoo

    Full Text Available Head and neck squamous cell carcinoma (HNSCC is the sixth most frequent cancer worldwide, and the 5-year survival rates are among the worst of the major cancers. Oncolytic herpes simplex viruses (oHSV have the potential to make a significant impact in the targeted treatment of these patients. Here, we tested antitumor efficacy of RAMBO, an oHSV armed with the antiangiogenic Vstat120, alone and in conjunction with ATN-224, a copper chelator against HNSCC in vitro and in vivo animal models. We found that all tested HNSCC cells responded well to virus treatment and were sensitive to RAMBO-mediated oncolytic destruction. In vivo, RAMBO had a significant antiangiogenic and antitumorigenic effect. Physiologic levels of copper inhibited viral replication and HNSCC cell killing. Chelation of copper using ATN-224 treatment significantly improved serum stability of RAMBO and permitted systemic delivery in HNSCC tumor xenografts models. Furthermore, our results show that the combination of ATN-224 and RAMBO strongly inhibits lung metastases in a mouse model of HNSCC. These findings suggest that combining ATN-224 with RAMBO has potential for clinical trials in both early and advanced HNSCC patients.

  4. Complementary induction of immunogenic cell death by oncolytic parvovirus H-1PV and gemcitabine in pancreatic cancer.

    Science.gov (United States)

    Angelova, Assia L; Grekova, Svitlana P; Heller, Anette; Kuhlmann, Olga; Soyka, Esther; Giese, Thomas; Aprahamian, Marc; Bour, Gaétan; Rüffer, Sven; Cziepluch, Celina; Daeffler, Laurent; Rommelaere, Jean; Werner, Jens; Raykov, Zahari; Giese, Nathalia A

    2014-05-01

    Novel therapies employing oncolytic viruses have emerged as promising anticancer modalities. The cure of particularly aggressive malignancies requires induction of immunogenic cell death (ICD), coupling oncolysis with immune responses via calreticulin, ATP, and high-mobility group box protein B1 (HMGB1) release from dying tumor cells. The present study shows that in human pancreatic cancer cells (pancreatic ductal adenocarcinoma [PDAC] cells n=4), oncolytic parvovirus H-1 (H-1PV) activated multiple interconnected death pathways but failed to induce calreticulin exposure or ATP release. In contrast, H-1PV elevated extracellular HMGB1 levels by 4.0±0.5 times (58%±9% of total content; up to 100 ng/ml) in all infected cultures, whether nondying, necrotic, or apoptotic. An alternative secretory route allowed H-1PV to overcome the failure of gemcitabine to trigger HMGB1 release, without impeding cytotoxicity or other ICD activities of the standard PDAC medication. Such broad resistance of H-1PV-induced HMGB1 release to apoptotic blockage coincided with but was uncoupled from an autocrine interleukin-1β (IL-1β) loop. That and the pattern of viral determinants maintained in gemcitabine-treated cells suggested the activation of an inflammasome/caspase 1 (CASP1) platform alongside DNA detachment and/or nuclear exclusion of HMGB1 during early stages of the viral life cycle. We concluded that H-1PV infection of PDAC cells is signaled through secretion of the alarmin HMGB1 and, besides its own oncolytic effect, might convert drug-induced apoptosis into an ICD process. A transient arrest of cells in the cyclin A1-rich S phase would suffice to support compatibility of proliferation-dependent H-1PV with cytotoxic regimens. These properties warrant incorporation of the oncolytic virus H-1PV, which is not pathogenic in humans, into multimodal anticancer treatments. The current therapeutic concepts targeting aggressive malignancies require an induction of immunogenic cell death

  5. Dual Entwining Structures and Dual Entwined Modules

    OpenAIRE

    Abuhlail, Jawad Y.

    2003-01-01

    In this note we introduce and investigate the concepts of dual entwining structures and dual entwined modules. This generalizes the concepts of dual Doi-Koppinen structures and dual Doi-Koppinen modules introduced (in the infinite case over rings) by the author is his dissertation.

  6. [Dual pathology].

    Science.gov (United States)

    Rougier, A

    2008-05-01

    Dual pathology is defined as the association of two potentially epileptogenic lesions, hippocampal (sclerosis, neuronal loss) and extrahippocampal (temporal or extratemporal). Epileptic activity may be generated by either lesion and the relative importance of every lesion's epileptogenicity conditions the surgical strategy adopted. Most frequently associated with hippocampal sclerosis are cortical dysplasias. The common physiopathology of the two lesions is not clearly established. Extrahippocampal lesions may be undetectable on MRI (microdysgenesis, for example) and ictal discharge patterns may vary among dual pathology patients. The surgical strategy depends on the location of the extrahippocampal lesion and its relative role in seizure generation; however, reported surgical results suggest that simultaneous resection of mesial temporal structures along with the extrahippocampal lesion should be performed.

  7. Dual Diagnosis - Multiple Languages

    Science.gov (United States)

    ... National Library of Medicine Comorbidity or dual diagnosis - Opioid addiction, part 9 - English PDF Comorbidity or dual diagnosis - Opioid addiction, part 9 - español (Spanish) PDF Comorbidity or dual ...

  8. Identification of the ENT1 antagonists dipyridamole and dilazep as amplifiers of oncolytic herpes simplex virus-1 replication.

    Science.gov (United States)

    Passer, Brent J; Cheema, Tooba; Zhou, Bingsen; Wakimoto, Hiroaki; Zaupa, Cecile; Razmjoo, Mani; Sarte, Jason; Wu, Shulin; Wu, Chin-lee; Noah, James W; Li, Qianjun; Buolamwini, John K; Yen, Yun; Rabkin, Samuel D; Martuza, Robert L

    2010-05-15

    Oncolytic herpes simplex virus-1 (oHSV) vectors selectively replicate in tumor cells, where they kill through oncolysis while sparing normal cells. One of the drawbacks of oHSV vectors is their limited replication and spread to neighboring cancer cells. Here, we report the outcome of a high-throughput chemical library screen to identify small-molecule compounds that augment the replication of oHSV G47Delta. Of the 2,640-screened bioactives, 6 compounds were identified and subsequently validated for enhanced G47Delta replication. Two of these compounds, dipyridamole and dilazep, interfered with nucleotide metabolism by potently and directly inhibiting the equilibrative nucleoside transporter-1 (ENT1). Replicative amplification promoted by dipyridamole and dilazep were dependent on HSV mutations in ICP6, the large subunit of ribonucleotide reductase. Our results indicate that ENT1 antagonists augment oHSV replication in tumor cells by increasing cellular ribonucleoside activity. (c)2010 AACR.

  9. Cell-based delivery of oncolytic viruses: a new strategic alliance for a biological strike against cancer.

    Science.gov (United States)

    Power, Anthony T; Bell, John C

    2007-04-01

    Recent years have seen tremendous advances in the development of exquisitely targeted replicating virotherapeutics that can safely destroy malignant cells. Despite this promise, clinical advancement of this powerful and unique approach has been hindered by vulnerability to host defenses and inefficient systemic delivery. However, it now appears that delivery of oncolytic viruses within carrier cells may offer one solution to this critical problem. In this review, we compare the advantages and limitations of the numerous cell lineages that have been investigated as delivery platforms for viral therapeutics, and discuss examples showing how combined cell-virus biotherapeutics can be used to achieve synergistic gains in antitumor activity. Finally, we highlight avenues for future preclinical research that might be taken in order to refine cell-virus biotherapeutics in preparation for human trials.

  10. Treatment of medulloblastoma using an oncolytic measles virus encoding the thyroidal sodium iodide symporter shows enhanced efficacy with radioiodine

    International Nuclear Information System (INIS)

    Hutzen, Brian; Pierson, Christopher R; Russell, Stephen J; Galanis, Evanthia; Raffel, Corey; Studebaker, Adam W

    2012-01-01

    Medulloblastoma is the most common malignant brain tumor of childhood. Although the clinical outcome for medulloblastoma patients has improved significantly, children afflicted with the disease frequently suffer from debilitating side effects related to the aggressive nature of currently available therapy. Alternative means for treating medulloblastoma are desperately needed. We have previously shown that oncolytic measles virus (MV) can selectively target and destroy medulloblastoma tumor cells in localized and disseminated models of the disease. MV-NIS, an oncolytic measles virus that encodes the human thyroidal sodium iodide symporter (NIS), has the potential to deliver targeted radiotherapy to the tumor site and promote a localized bystander effect above and beyond that achieved by MV alone. We evaluated the efficacy of MV-NIS against medulloblastoma cells in vitro and examined their ability to incorporate radioiodine at various timepoints, finding peak uptake at 48 hours post infection. The effects of MV-NIS were also evaluated in mouse xenograft models of localized and disseminated medulloblastoma. Athymic nude mice were injected with D283med-Luc medulloblastoma cells in the caudate putamen (localized disease) or right lateral ventricle (disseminated disease) and subsequently treated with MV-NIS. Subsets of these mice were given a dose of 131 I at 24, 48 or 72 hours later. MV-NIS treatment, both by itself and in combination with 131 I, elicited tumor stabilization and regression in the treated mice and significantly extended their survival times. Mice given 131 I were found to concentrate radioiodine at the site of their tumor implantations. In addition, mice with localized tumors that were given 131 I either 24 or 48 hours after MV-NIS treatment exhibited a significant survival advantage over mice given MV-NIS alone. These data suggest MV-NIS plus radioiodine may be a potentially useful therapy for the treatment of medulloblastoma

  11. Potent efficacy signals from systemically administered oncolytic herpes simplex virus (HSV1716 in hepatocellular carcinoma xenograft models

    Directory of Open Access Journals (Sweden)

    Braidwood L

    2014-10-01

    Full Text Available Lynne Braidwood, Kirsty Learmonth, Alex Graham, Joe Conner Virttu Biologics Ltd, Department of Neurology, Southern General Hospital, Glasgow, UK Abstract: Oncolytic herpes simplex virus (HSV1716, lacking the neurovirulence factor ICP34.5, has highly selective replication competence for cancer cells and has been used in clinical studies of glioma, melanoma, head and neck squamous cell carcinoma, pediatric non-central nervous system solid tumors, and malignant pleural mesothelioma. To date, 88 patients have received HSV1716 and the virus is well tolerated, with selective replication in tumor cells and no spread to surrounding normal tissue. We assessed the potential value of HSV1716 in preclinical studies with two human hepatocellular carcinoma cell lines, HuH7 and HepG2-luc. HSV1716 displayed excellent replication kinetics in vitro in HepG2-luc cells, a cell line engineered to express luciferase, and virus-mediated cell killing correlated with loss of light emissions from the cells. In vivo, the HepG2-luc cells readily formed light-emitting xenografts that were easily visualized by an in vivo imaging system and efficiently eliminated by HSV1716 oncolysis after intratumoral injection. HSV1716 also demonstrated strong efficacy signals in subcutaneous HuH7 xenografts in nude mice after intravenous administration of virus. In the HuH7 model, the intravenously injected virus replicated prolifically immediately after efficient tumor localization, resulting in highly significant reductions in tumor growth and enhanced survival. Our preclinical results demonstrate excellent tumor uptake of HSV1716, with prolific replication and potent oncolysis. These observations warrant a clinical study of HSV1716 in hepatocellular carcinoma. Keywords: oncolytic herpes simplex virus, HSV1716, hepatocellular carcinoma, xenografts, efficacy 

  12. Oncolytic effects of parvovirus H-1 in medulloblastoma are associated with repression of master regulators of early neurogenesis.

    Science.gov (United States)

    Lacroix, Jeannine; Schlund, Franziska; Leuchs, Barbara; Adolph, Kathrin; Sturm, Dominik; Bender, Sebastian; Hielscher, Thomas; Pfister, Stefan M; Witt, Olaf; Rommelaere, Jean; Schlehofer, Jörg R; Witt, Hendrik

    2014-02-01

    Based on extensive pre-clinical studies, the oncolytic parvovirus H-1 (H-1PV) is currently applied to patients with recurrent glioblastoma in a phase I/IIa clinical trial (ParvOryx01, NCT01301430). Cure rates of about 40% in pediatric high-risk medulloblastoma (MB) patients also indicate the need of new therapeutic approaches. In order to prepare a future application of oncolytic parvovirotherapy to MB, the present study preclinically evaluates the cytotoxic efficacy of H-1PV on MB cells in vitro and characterizes cellular target genes involved in this effect. Six MB cell lines were analyzed by whole genome oligonucleotide microarrays after treatment and the results were matched to known molecular and cytogenetic risk factors. In contrast to non-transformed infant astrocytes and neurons, in five out of six MB cell lines lytic H-1PV infection and efficient viral replication could be demonstrated. The cytotoxic effects induced by H-1PV were observed at LD50s below 0.05 p. f. u. per cell indicating high susceptibility. Gene expression patterns in the responsive MB cell lines allowed the identification of candidate target genes mediating the cytotoxic effects of H-1PV. H-1PV induced down-regulation of key regulators of early neurogenesis shown to confer poor prognosis in MB such as ZIC1, FOXG1B, MYC, and NFIA. In MB cell lines with genomic amplification of MYC, expression of MYC was the single gene most significantly repressed after H-1PV infection. H-1PV virotherapy may be a promising treatment approach for MB since it targets genes of functional relevance and induces cell death at very low titers of input virus. Copyright © 2013 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

  13. Treatment of medulloblastoma using an oncolytic measles virus encoding the thyroidal sodium iodide symporter shows enhanced efficacy with radioiodine

    Directory of Open Access Journals (Sweden)

    Hutzen Brian

    2012-11-01

    Full Text Available Abstract Background Medulloblastoma is the most common malignant brain tumor of childhood. Although the clinical outcome for medulloblastoma patients has improved significantly, children afflicted with the disease frequently suffer from debilitating side effects related to the aggressive nature of currently available therapy. Alternative means for treating medulloblastoma are desperately needed. We have previously shown that oncolytic measles virus (MV can selectively target and destroy medulloblastoma tumor cells in localized and disseminated models of the disease. MV-NIS, an oncolytic measles virus that encodes the human thyroidal sodium iodide symporter (NIS, has the potential to deliver targeted radiotherapy to the tumor site and promote a localized bystander effect above and beyond that achieved by MV alone. Methods We evaluated the efficacy of MV-NIS against medulloblastoma cells in vitro and examined their ability to incorporate radioiodine at various timepoints, finding peak uptake at 48 hours post infection. The effects of MV-NIS were also evaluated in mouse xenograft models of localized and disseminated medulloblastoma. Athymic nude mice were injected with D283med-Luc medulloblastoma cells in the caudate putamen (localized disease or right lateral ventricle (disseminated disease and subsequently treated with MV-NIS. Subsets of these mice were given a dose of 131I at 24, 48 or 72 hours later. Results MV-NIS treatment, both by itself and in combination with 131I, elicited tumor stabilization and regression in the treated mice and significantly extended their survival times. Mice given 131I were found to concentrate radioiodine at the site of their tumor implantations. In addition, mice with localized tumors that were given 131I either 24 or 48 hours after MV-NIS treatment exhibited a significant survival advantage over mice given MV-NIS alone. Conclusions These data suggest MV-NIS plus radioiodine may be a potentially useful therapy for

  14. Some properties of dual and approximate dual of fusion frames

    OpenAIRE

    Arefijamaal, Ali Akbar; Neyshaburi, Fahimeh Arabyani

    2016-01-01

    In this paper we extend the notion of approximate dual to fusion frames and present some approaches to obtain dual and approximate alternate dual fusion frames. Also, we study the stability of dual and approximate alternate dual fusion frames.

  15. Improving CART-Cell Therapy of Solid Tumors with Oncolytic Virus-Driven Production of a Bispecific T-cell Engager.

    Science.gov (United States)

    Wing, Anna; Fajardo, Carlos Alberto; Posey, Avery D; Shaw, Carolyn; Da, Tong; Young, Regina M; Alemany, Ramon; June, Carl H; Guedan, Sonia

    2018-05-01

    T cells expressing chimeric antigen receptors (CART) have shown significant promise in clinical trials to treat hematologic malignancies, but their efficacy in solid tumors has been limited. Oncolytic viruses have the potential to act in synergy with immunotherapies due to their immunogenic oncolytic properties and the opportunity of incorporating therapeutic transgenes in their genomes. Here, we hypothesized that an oncolytic adenovirus armed with an EGFR-targeting, bispecific T-cell engager (OAd-BiTE) would improve the outcome of CART-cell therapy in solid tumors. We report that CART cells targeting the folate receptor alpha (FR-α) successfully infiltrated preestablished xenograft tumors but failed to induce complete responses, presumably due to the presence of antigen-negative cancer cells. We demonstrated that OAd-BiTE-mediated oncolysis significantly improved CART-cell activation and proliferation, while increasing cytokine production and cytotoxicity, and showed an in vitro favorable safety profile compared with EGFR-targeting CARTs. BiTEs secreted from infected cells redirected CART cells toward EGFR in the absence of FR-α, thereby addressing tumor heterogeneity. BiTE secretion also redirected CAR-negative, nonspecific T cells found in CART-cell preparations toward tumor cells. The combinatorial approach improved antitumor efficacy and prolonged survival in mouse models of cancer when compared with the monotherapies, and this was the result of an increased BiTE-mediated T-cell activation in tumors. Overall, these results demonstrated that the combination of a BiTE-expressing oncolytic virus with adoptive CART-cell therapy overcomes key limitations of CART cells and BiTEs as monotherapies in solid tumors and encourage its further evaluation in human trials. Cancer Immunol Res; 6(5); 605-16. ©2018 AACR . ©2018 American Association for Cancer Research.

  16. Pancreatic adenocarcinoma upregulated factor (PAUF) confers resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNA receptor-mediated signaling

    Energy Technology Data Exchange (ETDEWEB)

    Kaowinn, Sirichat; Cho, Il-Rae; Moon, Jeong; Jun, Seung Won; Kim, Chang Seok [BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-736 (Korea, Republic of); Kang, Ho Young [Department of Microbiology, Pusan National University, Busan 609-736 (Korea, Republic of); Kim, Manbok [Department of Medical Science, Dankook University College of Medicine, Cheonan 330-714 (Korea, Republic of); Koh, Sang Seok [Department of Biological Sciences, Dong-A University, Busan 604-714 (Korea, Republic of); Chung, Young-Hwa, E-mail: younghc@pusan.ac.kr [BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-736 (Korea, Republic of)

    2015-04-03

    Pancreatic adenocarcinoma upregulated factor (PAUF), a novel oncogene, plays a crucial role in the development of pancreatic cancer, including its metastasis and proliferation. Therefore, PAUF-expressing pancreatic cancer cells could be important targets for oncolytic virus-mediated treatment. Panc-1 cells expressing PAUF (Panc-PAUF) showed relative resistance to parvovirus H-1 infection compared with Panc-1 cells expressing an empty vector (Panc-Vec). Of interest, expression of type I IFN-α receptor (IFNAR) was higher in Panc-PAUF cells than in Panc-Vec cells. Increased expression of IFNAR in turn increased the activation of Stat1 and Tyk2 in Panc-PAUF cells compared with that in Panc-Vec cells. Suppression of Tyk2 and Stat1, which are important downstream molecules for IFN-α signaling, sensitized pancreatic cancer cells to parvovirus H-1-mediated apoptosis. Further, constitutive suppression of PAUF sensitized Bxpc3 pancreatic cancer cells to parvovirus H-1 infection. Taken together, these results suggested that PAUF conferred resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNAR-mediated signaling. - Highlights: • PAUF confers resistance against oncolytic parvovirus H-1 infection. • PAUF enhances the expression of IFNAR in Panc-1 cells. • Increased activation of Tyk2 or Stat1 by PAUF provides resistance to parvovirus H-1-mediated apoptosis. • Constitutive inhibition of PAUF enhances parvovirus H-1-mediated oncolysis of Bxpc3 pancreatic cancer cells.

  17. Pancreatic adenocarcinoma upregulated factor (PAUF) confers resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNA receptor-mediated signaling

    International Nuclear Information System (INIS)

    Kaowinn, Sirichat; Cho, Il-Rae; Moon, Jeong; Jun, Seung Won; Kim, Chang Seok; Kang, Ho Young; Kim, Manbok; Koh, Sang Seok; Chung, Young-Hwa

    2015-01-01

    Pancreatic adenocarcinoma upregulated factor (PAUF), a novel oncogene, plays a crucial role in the development of pancreatic cancer, including its metastasis and proliferation. Therefore, PAUF-expressing pancreatic cancer cells could be important targets for oncolytic virus-mediated treatment. Panc-1 cells expressing PAUF (Panc-PAUF) showed relative resistance to parvovirus H-1 infection compared with Panc-1 cells expressing an empty vector (Panc-Vec). Of interest, expression of type I IFN-α receptor (IFNAR) was higher in Panc-PAUF cells than in Panc-Vec cells. Increased expression of IFNAR in turn increased the activation of Stat1 and Tyk2 in Panc-PAUF cells compared with that in Panc-Vec cells. Suppression of Tyk2 and Stat1, which are important downstream molecules for IFN-α signaling, sensitized pancreatic cancer cells to parvovirus H-1-mediated apoptosis. Further, constitutive suppression of PAUF sensitized Bxpc3 pancreatic cancer cells to parvovirus H-1 infection. Taken together, these results suggested that PAUF conferred resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNAR-mediated signaling. - Highlights: • PAUF confers resistance against oncolytic parvovirus H-1 infection. • PAUF enhances the expression of IFNAR in Panc-1 cells. • Increased activation of Tyk2 or Stat1 by PAUF provides resistance to parvovirus H-1-mediated apoptosis. • Constitutive inhibition of PAUF enhances parvovirus H-1-mediated oncolysis of Bxpc3 pancreatic cancer cells

  18. Oncolytic Herpes Virus rRp450 Shows Efficacy in Orthotopic Xenograft Group 3/4 Medulloblastomas and Atypical Teratoid/Rhabdoid Tumors

    Directory of Open Access Journals (Sweden)

    Adam W. Studebaker

    2017-09-01

    Full Text Available Pediatric brain tumors including medulloblastoma and atypical teratoid/rhabdoid tumor are associated with significant mortality and treatment-associated morbidity. While medulloblastoma tumors within molecular subgroups 3 and 4 have a propensity to metastasize, atypical teratoid/rhabdoid tumors frequently afflict a very young patient population. Adjuvant treatment options for children suffering with these tumors are not only sub-optimal but also associated with many neurocognitive obstacles. A potentially novel treatment approach is oncolytic virotherapy, a developing therapeutic platform currently in early-phase clinical trials for pediatric brain tumors and recently US Food and Drug Administration (FDA-approved to treat melanoma in adults. We evaluated the therapeutic potential of the clinically available oncolytic herpes simplex vector rRp450 in cell lines derived from medulloblastoma and atypical teratoid/rhabdoid tumor. Cells of both tumor types were supportive of virus replication and virus-mediated cytotoxicity. Orthotopic xenograft models of medulloblastoma and atypical teratoid/rhabdoid tumors displayed significantly prolonged survival following a single, stereotactic intratumoral injection of rRp450. Furthermore, addition of the chemotherapeutic prodrug cyclophosphamide (CPA enhanced rRp450’s in vivo efficacy. In conclusion, oncolytic herpes viruses with the ability to bioactivate the prodrug CPA within the tumor microenvironment warrant further investigation as a potential therapy for pediatric brain tumors.

  19. Rapid Generation of Multiple Loci-Engineered Marker-free Poxvirus and Characterization of a Clinical-Grade Oncolytic Vaccinia Virus

    Directory of Open Access Journals (Sweden)

    Zong Sheng Guo

    2017-12-01

    Full Text Available Recombinant poxviruses, utilized as vaccine vectors and oncolytic viruses, often require manipulation at multiple genetic loci in the viral genome. It is essential for viral vectors to possess no adventitious mutations and no (antibiotic selection marker in the final product for human patients in order to comply with the guidance from the regulatory agencies. Rintoul et al. have previously developed a selectable and excisable marker (SEM system for the rapid generation of recombinant vaccinia virus. In the current study, we describe an improved methodology for rapid creation and selection of recombinant poxviruses with multiple genetic manipulations solely based on expression of a fluorescent protein and with no requirement for drug selection that can lead to cellular stress and the risk of adventitious mutations throughout the viral genome. Using this improved procedure combined with the SEM system, we have constructed multiple marker-free oncolytic poxviruses expressing different cytokines and other therapeutic genes. The high fidelity of inserted DNA sequences validates the utility of this improved procedure for generation of therapeutic viruses for human patients. We have created an oncolytic poxvirus expressing human chemokine CCL5, designated as vvDD-A34R-hCCL5, with manipulations at two genetic loci in a single virus. Finally, we have produced and purified this virus in clinical grade for its use in a phase I clinical trial and presented data on initial in vitro characterization of the virus.

  20. Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense

    International Nuclear Information System (INIS)

    Echchgadda, Ibtissam; Chang, Te-Hung; Sabbah, Ahmed; Bakri, Imad; Ikeno, Yuji; Hubbard, Gene B; Chatterjee, Bandana; Bose, Santanu

    2011-01-01

    Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV) is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells. The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNα/β)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The essential role of IFN in restricting infection was further

  1. Production of bioactive soluble interleukin-15 in complex with interleukin-15 receptor alpha from a conditionally-replicating oncolytic HSV-1.

    Directory of Open Access Journals (Sweden)

    David C Gaston

    Full Text Available Oncolytic type-1 herpes simplex viruses (oHSVs lacking the γ134.5 neurovirulence gene are being evaluated for treatment of a variety of malignancies. oHSVs replicate within and directly kill permissive cancer cells. To augment their anti-tumor activity, oHSVs have been engineered to express immunostimulatory molecules, including cytokines, to elicit tumor-specific immune responses. Interleukin-15 (IL-15 holds potential as an immunotherapeutic cytokine because it has been demonstrated to promote both natural killer (NK cell-mediated and CD8(+ T cell-mediated cytotoxicity against cancer cells. The purpose of these studies was to engineer an oHSV producing bioactive IL-15. Two oHSVs were constructed encoding murine (mIL-15 alone (J100 or with the mIL-15 receptor α (mIL-15Rα, J100D to determine whether co-expression of these proteins is required for production of bioactive mIL-15 from oHSV. The following were demonstrated: i both oHSVs retain replication competence and cytotoxicity in permissive tumor cell lines. ii Enhanced production of mIL-15 was detected in cell lysates of neuro-2a cells following J100D infection as compared to J100 infection, suggesting that mIL-15Rα improved mIL-15 production. iii Soluble mIL-15 in complex with mIL-15Rα was detected in supernates from J100D-infected, but not J100-infected, neuro-2a, GL261, and CT-2A cells. These cell lines vary in permissiveness to oHSV replication and cytotoxicity, demonstrating soluble mIL-15/IL-15Rα complex production from J100D was independent of direct oHSV effects. iv The soluble mIL-15/IL-15Rα complex produced by J100D was bioactive, stimulating NK cells to proliferate and reduce the viability of syngeneic GL261 and CT-2A cells. v J100 and J100D were aneurovirulent inasmuch as no neuropathologic effects were documented following direct inoculation into brains of CBA/J mice at up to 1x10(7 plaque forming units. The production of mIL-15/mIL-15Rα from multiple tumor lines, as well

  2. Dual descriptions of supersymmetry breaking

    International Nuclear Information System (INIS)

    Intrilligator, K.; Thomas, S.

    1996-08-01

    Dynamical supersymmetry breaking is considered in models which admit descriptions in terms of electric, confined, or magnetic degrees of freedom in various limits. In this way, a variety of seemingly different theories which break supersymmetry are actually interrelated by confinement or duality. Specific examples are given in which there are two dual descriptions of the supersymmetry breaking ground state

  3. Malignant focal hepatic lesions complicating underlying liver disease: dual-phase contrast-enhanced spiral CT sensitivity and specificity in orthotopic liver transplant patients

    International Nuclear Information System (INIS)

    Mortele, K.J.; De Keukeleire, K.; Praet, M.; Van Vlierberghe, H.; Hemptinne, B. de; Ros, P.R.

    2001-01-01

    The aim of this study was to determine the accuracy of contrast-enhanced biphasic spiral CT as a screening tool in the preoperative evaluation of orthotopic liver transplant (OLT) patients. Spiral-CT examinations were performed before liver transplantation in 53 patients. Scans were retrospectively reviewed and compared with pathologic findings in fresh-sectioned livers. When findings between spiral CT and pathology were discordant, formalized livers were reexamined with lesion-by lesion evaluation. Fresh pathologic evaluation revealed 23 liver lesions (16 HCC, 7 macro-regenerative nodules). Malignancy was identified in 13 of 53 patients (24.5%). Pre-transplantation spiral CT depicted 27 liver lesions (23 HCC, 4 macro-regenerative nodules). Malignancy was suspected in 14 patients (26.4%). In 10 of 53 (18.9%), spiral CT and pathologic evaluation were discordant. Subsequent retrospective pathologic evaluation showed malignancy in 4 additional patients. Spiral CT compared with the retrospective pathologic findings revealed 36 real-negative, 14 real-positive, 0 false-positive, and 3 false-negative patients with malignancy. Sensitivity and specificity of spiral CT in detection of malignancy was 82 and 100%, respectively. Contrast-enhanced biphasic spiral CT is an accurate technique in the evaluation of patients preceding OLT. Routine fresh-sectioned liver pathologic findings are not as sensitive as previously estimated. (orig.)

  4. Activation of the human immune system by chemotherapeutic or targeted agents combined with the oncolytic parvovirus H-1

    International Nuclear Information System (INIS)

    Moehler, Markus; Sieben, Maike; Roth, Susanne; Springsguth, Franziska; Leuchs, Barbara; Zeidler, Maja; Dinsart, Christiane; Rommelaere, Jean; Galle, Peter R

    2011-01-01

    Parvovirus H-1 (H-1PV) infects and lyses human tumor cells including melanoma, hepatoma, gastric, colorectal, cervix and pancreatic cancers. We assessed whether the beneficial effects of chemotherapeutic agents or targeted agents could be combined with the oncolytic and immunostimmulatory properties of H-1PV. Using human ex vivo models we evaluated the biological and immunological effects of H-1PV-induced tumor cell lysis alone or in combination with chemotherapeutic or targeted agents in human melanoma cells +/- characterized human cytotoxic T-cells (CTL) and HLA-A2-restricted dendritic cells (DC). H-1PV-infected MZ7-Mel cells showed a clear reduction in cell viability of >50%, which appeared to occur primarily through apoptosis. This correlated with viral NS1 expression levels and was enhanced by combination with chemotherapeutic agents or sunitinib. Tumor cell preparations were phagocytosed by DC whose maturation was measured according to the treatment administered. Immature DC incubated with H-1PV-induced MZ7-Mel lysates significantly increased DC maturation compared with non-infected or necrotic MZ7-Mel cells. Tumor necrosis factor-α and interleukin-6 release was clearly increased by DC incubated with H-1PV-induced SK29-Mel tumor cell lysates (TCL) and was also high with DC-CTL co-cultures incubated with H-1PV-induced TCL. Similarly, DC co-cultures with TCL incubated with H-1PV combined with cytotoxic agents or sunitinib enhanced DC maturation to a greater extent than cytotoxic agents or sunitinib alone. Again, these combinations increased pro-inflammatory responses in DC-CTL co-cultures compared with chemotherapy or sunitinib alone. In our human models, chemotherapeutic or targeted agents did not only interfere with the pronounced immunomodulatory properties of H-1PV, but also reinforced drug-induced tumor cell killing. H-1PV combined with cisplatin, vincristine or sunitinib induced effective immunostimulation via a pronounced DC maturation, better cytokine

  5. Synergistic antitumor activity of oncolytic reovirus and chemotherapeutic agents in non-small cell lung cancer cells

    Directory of Open Access Journals (Sweden)

    Coffey Matthew C

    2009-07-01

    Full Text Available Abstract Background Reovirus type 3 Dearing strain (ReoT3D has an inherent propensity to preferentially infect and destroy cancer cells. The oncolytic activity of ReoT3D as a single agent has been demonstrated in vitro and in vivo against various cancers, including colon, pancreatic, ovarian and breast cancers. Its human safety and potential efficacy are currently being investigated in early clinical trials. In this study, we investigated the in vitro combination effects of ReoT3D and chemotherapeutic agents against human non-small cell lung cancer (NSCLC. Results ReoT3D alone exerted significant cytolytic activity in 7 of 9 NSCLC cell lines examined, with the 50% effective dose, defined as the initial virus dose to achieve 50% cell killing after 48 hours of infection, ranging from 1.46 ± 0.12 ~2.68 ± 0.25 (mean ± SD log10 pfu/cell. Chou-Talalay analysis of the combination of ReoT3D with cisplatin, gemcitabine, or vinblastine demonstrated strong synergistic effects on cell killing, but only in cell lines that were sensitive to these compounds. In contrast, the combination of ReoT3D and paclitaxel was invariably synergistic in all cell lines tested, regardless of their levels of sensitivity to either agent. Treatment of NSCLC cell lines with the ReoT3D-paclitaxel combination resulted in increased poly (ADP-ribose polymerase cleavage and caspase activity compared to single therapy, indicating enhanced apoptosis induction in dually treated NSCLC cells. NSCLC cells treated with the ReoT3D-paclitaxel combination showed increased proportions of mitotic and apoptotic cells, and a more pronounced level of caspase-3 activation was demonstrated in mitotically arrested cells. Conclusion These data suggest that the oncolytic activity of ReoT3D can be potentiated by taxanes and other chemotherapeutic agents, and that the ReoT3D-taxane combination most effectively achieves synergy through accelerated apoptosis triggered by prolonged mitotic arrest.

  6. Dual antagonists of integrins.

    Science.gov (United States)

    Nadrah, K; Dolenc, M Sollner

    2005-01-01

    The roles of integrins in pathologies have been studied intensively and only partially explained. This has resulted in the development of several nanomolar antagonists to certain integrins. In most cases, the aim was to produce compounds which are highly selective towards specific integrins. This paradigm has recently shifted a little. Targeting two or more integrins with one compound has become a very attractive concept, especially since it has become clear that several severe disorders, such as pathological angiogenesis, cannot be treated just with highly specific integrin antagonists. This review is aimed to elucidate some aspects regarding the design of drugs with dual activity towards integrins. Integrin structure and tissue distribution will first be described, in order to provide the basis for their functions in various pathologies which will follow. Inhibitors of several pairs of integrins will be described.

  7. Generation and characterization of ABT-981, a dual variable domain immunoglobulin (DVD-Ig(TM)) molecule that specifically and potently neutralizes both IL-1α and IL-1β.

    Science.gov (United States)

    Lacy, Susan E; Wu, Chengbin; Ambrosi, Dominic J; Hsieh, Chung-Ming; Bose, Sahana; Miller, Renee; Conlon, Donna M; Tarcsa, Edit; Chari, Ravi; Ghayur, Tariq; Kamath, Rajesh V

    2015-01-01

    Interleukin-1 (IL-1) cytokines such as IL-1α, IL-1β, and IL-1Ra contribute to immune regulation and inflammatory processes by exerting a wide range of cellular responses, including expression of cytokines and chemokines, matrix metalloproteinases, and nitric oxide synthetase. IL-1α and IL-1β bind to IL-1R1 complexed to the IL-1 receptor accessory protein and induce similar physiological effects. Preclinical and clinical studies provide significant evidence for the role of IL-1 in the pathogenesis of osteoarthritis (OA), including cartilage degradation, bone sclerosis, and synovial proliferation. Here, we describe the generation and characterization of ABT-981, a dual variable domain immunoglobulin (DVD-Ig) of the IgG1/k subtype that specifically and potently neutralizes IL-1α and IL-1β. In ABT-981, the IL-1β variable domain resides in the outer domain of the DVD-Ig, whereas the IL-1α variable domain is located in the inner position. ABT-981 specifically binds to IL-1α and IL-1β, and is physically capable of binding 2 human IL-1α and 2 human IL-1β molecules simultaneously. Single-dose intravenous and subcutaneous pharmacokinetics studies indicate that ABT-981 has a half-life of 8.0 to 10.4 d in cynomolgus monkey and 10.0 to 20.3 d in rodents. ABT-981 exhibits suitable drug-like-properties including affinity, potency, specificity, half-life, and stability for evaluation in human clinical trials. ABT-981 offers an exciting new approach for the treatment of OA, potentially addressing both disease modification and symptom relief as a disease-modifying OA drug.

  8. Dual-specificity phosphatase 6 (Dusp6), a negative regulator of FGF2/ERK1/2 signaling, enhances 17β-estradiol-induced cell growth in endometrial adenocarcinoma cell.

    Science.gov (United States)

    Zhang, Hui; Guo, Qiufen; Wang, Chong; Yan, Lei; Fu, Yibing; Fan, Mingjun; Zhao, Xingbo; Li, Mingjiang

    2013-08-25

    Dual-specificity phosphatase 6 (Dusp6) is a negative feedback mechanism of fibroblast growth factors (FGFs)/mitogen-activated protein kinase (MAPK)/ERK1/2 signaling. The aim of this study was to explore the expression of Dusp6 in human endometrial adenocarcinomas and the role of Dusp6 expression in the growth regulation of endometrial adenocarcinoma cell. We found that Dusp6 was over-expressed in human endometrial adenocarcinomas. In Ishikawa cells, plasmid-driven Dusp6 expression efficiently blocked the activity of FGF2-induced MAPK/ERK1/2 signaling. Unexpectedly, Dusp6 expression significantly enhanced the growth of Ishikawa cells. In Dusp6 forced-expression cells, 17β-estradiol stimulation increased the cell growth by all most threefolds. In addition, progesterone treatment reduced the cell growth to about half both in Ishikawa cells with and without forced-Dusp6-expression. Dusp6 over-expression is involved in the pathogenesis and development of human endometrial adenocarcinomas. Dusp6 functions as a negative regulator of FGF2/ERK1/2 signaling but enhances the growth and 17β-estradiol-induced cell growth in endometrial adenocarcinoma cell. Copyright © 2013. Published by Elsevier Ireland Ltd.

  9. Subcellular distribution of cyclin-dependent kinase-like 5 (CDKL5) is regulated through phosphorylation by dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).

    Science.gov (United States)

    Oi, Ami; Katayama, Syouichi; Hatano, Naoya; Sugiyama, Yasunori; Kameshita, Isamu; Sueyoshi, Noriyuki

    2017-01-08

    Cyclin-dependent kinase-like 5 (CDKL5) is a Ser/Thr protein kinase primarily expressed in the central nervous system and is known to cause X-linked neurodevelopmental disorders such as Rett syndrome. However, the mechanisms regulating CDKL5 have not yet been fully clarified. Therefore, in this study, we investigated the protein kinase that directly phosphorylates CDKL5, identifying it as dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), an enzyme binding to and phosphorylating CDKL5. We showed that subcellular distribution of CDKL5 was regulated by its phosphorylation by DYRK1A. In mouse neuroblastoma Neuro2a cells, CDKL5 was localized in both the cytosol and nucleus, whereas DYRK1A showed a typical nuclear localization. When CDKL5 and DYRK1A were co-expressed, the cytosolic localization of CDKL5 was significantly increased. Results of site-directed mutagenesis revealed that the phosphorylation site was Ser-308, in the vicinity of the nuclear localization signal. A mutation mimicking the phosphorylated serine residue by aspartate substitution (S308D) changed CDKL5 localization to the cytosol, whereas the corresponding alanine-substituted analog, CDKL5(S308A), was primarily localized to the nucleus. Taken together, these results strongly suggested that DYRK1A bound to CDKL5 and phosphorylated it on Ser-308, thus interfering with its nuclear localization. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Chemovirotherapy for head and neck squamous cell carcinoma with EGFR-targeted and CD/UPRT-armed oncolytic measles virus.

    Science.gov (United States)

    Zaoui, K; Bossow, S; Grossardt, C; Leber, M F; Springfeld, C; Plinkert, P K; Kalle, C von; Ungerechts, G

    2012-03-01

    First-line treatment of recurrent and/or refractory head and neck squamous cell carcinoma (HNSCC) is based on platinum, 5-fluorouracil (5-FU) and the monoclonal antiEGFR antibody cetuximab. However, in most cases this chemoimmunotherapy does not cure the disease, and more than 50% of HNSCC patients are dying because of local recurrence of the tumors. In the majority of cases, HNSCC overexpress the epidermal growth factor receptor (EGFR), and its presence is associated with a poor outcome. In this study, we engineered an EGFR-targeted oncolytic measles virus (MV), armed with the bifunctional enzyme cytosine deaminase/uracil phosphoribosyltransferase (CD/UPRT). CD/UPRT converts 5-fluorocytosine (5-FC) into the chemotherapeutic 5-FU, a mainstay of HNSCC chemotherapy. This virus efficiently replicates in and lyses primary HNSCC cells in vitro. Arming with CD/UPRT mediates efficient prodrug activation with high bystander killing of non-infected tumor cells. In mice bearing primary HNSCC xenografts, intratumoral administration of MV-antiEGFR resulted in statistically significant tumor growth delay and prolongation of survival. Importantly, combination with 5-FC is superior to virus-only treatment leading to significant tumor growth inhibition. Thus, chemovirotherapy with EGFR-targeted and CD/UPRT-armed MV is highly efficacious in preclinical settings with direct translational implications for a planned Phase I clinical trial of MV for locoregional treatment of HNSCC.

  11. Synergistic combination of valproic acid and oncolytic parvovirus H-1PV as a potential therapy against cervical and pancreatic carcinomas.

    Science.gov (United States)

    Li, Junwei; Bonifati, Serena; Hristov, Georgi; Marttila, Tiina; Valmary-Degano, Séverine; Stanzel, Sven; Schnölzer, Martina; Mougin, Christiane; Aprahamian, Marc; Grekova, Svitlana P; Raykov, Zahari; Rommelaere, Jean; Marchini, Antonio

    2013-10-01

    The rat parvovirus H-1PV has oncolytic and tumour-suppressive properties potentially exploitable in cancer therapy. This possibility is being explored and results are encouraging, but it is necessary to improve the oncotoxicity of the virus. Here we show that this can be achieved by co-treating cancer cells with H-1PV and histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA). We demonstrate that these agents act synergistically to kill a range of human cervical carcinoma and pancreatic carcinoma cell lines by inducing oxidative stress, DNA damage and apoptosis. Strikingly, in rat and mouse xenograft models, H-1PV/VPA co-treatment strongly inhibits tumour growth promoting complete tumour remission in all co-treated animals. At the molecular level, we found acetylation of the parvovirus nonstructural protein NS1 at residues K85 and K257 to modulate NS1-mediated transcription and cytotoxicity, both of which are enhanced by VPA treatment. These results warrant clinical evaluation of H-1PV/VPA co-treatment against cervical and pancreatic ductal carcinomas. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

  12. Safety and biodistribution of a double-deleted oncolytic vaccinia virus encoding CD40 ligand in laboratory Beagles

    Directory of Open Access Journals (Sweden)

    Karoliina Autio

    2014-01-01

    Full Text Available We evaluated adverse events, biodistribution and shedding of oncolytic vaccinia virus encoding CD40 ligand in two Beagles, in preparation for a phase 1 trial in canine cancer patients. Dog 1 received one dose of vaccinia virus and was euthanized 24 hours afterwards, while dog 2 received virus four times once weekly and was euthanized 7 days after that. Dogs were monitored for adverse events and underwent a detailed postmortem examination. Blood, saliva, urine, feces, and organs were collected for virus detection. Dog 1 had mild fever and lethargy while dog 2 experienced a possible seizure 5.5 hours after first virus administration. Viral DNA declined quickly in the blood after virus administration in both dogs but was still detectable 1 week later by quantitative polymerase chain reaction. Only samples taken directly after virus infusion contained infectious virus. Small amounts of viral DNA, but no infectious virus, were detected in a few saliva and urine samples. Necropsies did not reveal any relevant pathological changes and virus DNA was detected mainly in the spleen. The dogs in the study did not have cancer, and thus adverse events could be more common and viral load higher in dogs with tumors which allow viral amplification.

  13. The Oncolytic Virus MG1 Targets and Eliminates Cells Latently Infected With HIV-1: Implications for an HIV Cure.

    Science.gov (United States)

    Ranganath, Nischal; Sandstrom, Teslin S; Burke Schinkel, Stephanie C; Côté, Sandra C; Angel, Jonathan B

    2018-02-14

    Cells latently infected with human immunodeficiency virus (HIV) evade immune- and drug-mediated clearance. These cells harbor intracellular signaling defects, including impairment of the antiviral type I interferon response. Such defects have also been observed in several cancers and have been exploited for the development of therapeutic oncolytic viruses, including the recombinant Maraba virus (MG1). We therefore hypothesized that MG1 would infect and eliminate cells latently infected with HIV-1, while sparing healthy uninfected cells. Preferential infection and elimination by MG1 was first demonstrated in cell lines latently infected with HIV-1. Following this, a reduction in HIV-1 DNA and inducible HIV-1 replication was observed following MG1 infection of latently infected, resting CD4+ T cells generated using an in vitro model of latency. Last, MG1 infection resulted in a reduction in HIV-1 DNA and inducible HIV-1 replication in memory CD4+ T cells isolated from effectively treated, HIV-1-infected individuals. Our results therefore highlight a novel approach to eliminate the latent HIV-1 reservoir. © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

  14. Dual Youla parameterization

    DEFF Research Database (Denmark)

    Niemann, Hans Henrik

    2003-01-01

    A different aspect of using the parameterisation of all systems stabilised by a given controller, i.e. the dual Youla parameterisation, is considered. The relation between system change and the dual Youla parameter is derived in explicit form. A number of standard uncertain model descriptions...... are considered and the relation with the dual Youla parameter given. Some applications of the dual Youla parameterisation are considered in connection with the design of controllers and model/performance validation....

  15. Dual affine isoperimetric inequalities

    Directory of Open Access Journals (Sweden)

    Bin Xiong

    2006-01-01

    Full Text Available We establish some inequalities for the dual -centroid bodies which are the dual forms of the results by Lutwak, Yang, and Zhang. Further, we establish a Brunn-Minkowski-type inequality for the polar of dual -centroid bodies.

  16. DUAL TIMELIKE NORMAL AND DUAL TIMELIKE SPHERICAL CURVES IN DUAL MINKOWSKI SPACE

    OpenAIRE

    ÖNDER, Mehmet

    2009-01-01

    Abstract: In this paper, we give characterizations of dual timelike normal and dual timelike spherical curves in the dual Minkowski 3-space and we show that every dual timelike normal curve is also a dual timelike spherical curve. Keywords: Normal curves, Dual Minkowski 3-Space, Dual Timelike curves. Mathematics Subject Classifications (2000): 53C50, 53C40. DUAL MINKOWSKI UZAYINDA DUAL TIMELIKE NORMAL VE DUAL TIMELIKE KÜRESEL EĞRİLER Özet: Bu çalışmada, dual Minkowski 3-...

  17. Preclinical Testing of an Oncolytic Parvovirus in Ewing Sarcoma: Protoparvovirus H-1 Induces Apoptosis and Lytic Infection In Vitro but Fails to Improve Survival In Vivo.

    Science.gov (United States)

    Lacroix, Jeannine; Kis, Zoltán; Josupeit, Rafael; Schlund, Franziska; Stroh-Dege, Alexandra; Frank-Stöhr, Monika; Leuchs, Barbara; Schlehofer, Jörg R; Rommelaere, Jean; Dinsart, Christiane

    2018-06-03

    About 70% of all Ewing sarcoma (EWS) patients are diagnosed under the age of 20 years. Over the last decades little progress has been made towards finding effective treatment approaches for primarily metastasized or refractory Ewing sarcoma in young patients. Here, in the context of the search for novel therapeutic options, the potential of oncolytic protoparvovirus H-1 (H-1PV) to treat Ewing sarcoma was evaluated, its safety having been proven previously tested in adult cancer patients and its oncolytic efficacy demonstrated on osteosarcoma cell cultures. The effects of viral infection were tested in vitro on four human Ewing sarcoma cell lines. Notably evaluated were effects of the virus on the cell cycle and its replication efficiency. Within 24 h after infection, the synthesis of viral proteins was induced. Efficient H-1PV replication was confirmed in all four Ewing sarcoma cell lines. The cytotoxicity of the virus was determined on the basis of cytopathic effects, cell viability, and cell lysis. These in vitro experiments revealed efficient killing of Ewing sarcoma cells by H-1PV at a multiplicity of infection between 0.1 and 5 plaque forming units (PFU)/cell. In two of the four tested cell lines, significant induction of apoptosis by H-1PV was observed. H-1PV thus meets all the in vitro criteria for a virus to be oncolytic towards Ewing sarcoma. In the first xenograft experiments, however, although an antiproliferative effect of intratumoral H-1PV injection was observed, no significant improvement of animal survival was noted. Future projects aiming to validate parvovirotherapy for the treatment of pediatric Ewing sarcoma should focus on combinatorial treatments and will require the use of patient-derived xenografts and immunocompetent syngeneic animal models.

  18. A NOTCH-sensitive uPAR-regulated oncolytic adenovirus effectively suppresses pancreatic tumor growth and triggers synergistic anticancer effects with gemcitabine and nab-paclitaxel.

    Science.gov (United States)

    Mato-Berciano, Ana; Raimondi, Giulia; Maliandi, Maria Victoria; Alemany, Ramon; Montoliu, Lluis; Fillat, Cristina

    2017-04-04

    Notch signaling pathway is an embryonic program that becomes reactivated in pancreatic cancer and contributes to cancer stem cell (CSC) maintenance. We explored the concept of oncolytic adenoviral activity in response to Notch activation signaling, in the context of a chimeric promoter with uPAR regulatory sequences, as a strategy to drive its activity in neoplastic and CSC. We explored the advantages of a chemo-virotherapy approach based on synergistic combinations. Regulatory sequences recognized by the transcriptional factor CSL upstream a minimal uPAR promoter were engineered in adenoviral vectors and in the oncolytic adenovirus AdNuPARmE1A. Viral response to Notch signaling, and viral potency in cell lines and pancreatic cancer stem cells (PCSC) was tested. Preclinical toxicity and antitumor efficacy in xenografts and Patient-derived xenografts (PDX) mouse models was evaluated, as unimodal or in combination with gemcitabine+nab-paclitaxel. Mechanistic studies were conducted to explore the synergism of combined therapies.We demonstrate that CSL-binding site optimized-engineered sequences respond to Notch activation in AdNuPARmLuc and AdNuPARmE1A. AdNuPARmE1A showed strong lytic effects in pancreatic cancer cell lines and PCSC. AdNuPARmE1A displayed attenuated activity in normal tissues, but robust antitumor effects in xenograft and PDX models, leading to a reduced capacity of treated tumors to form tumorspheres. Chemo-virotherapy treatment enlarged therapeutic response in both tumor models. Synergistic effects of the combination resulted from viral sensitization of apoptotic cell death triggered by chemotherapy.In summary we present a novel effective oncolytic adenovirus, AdNuPARmE1A that reduces PCSC and presents synergistic effects with gemcitabine and nab-paclitaxel, supporting further clinical development.

  19. Preclinical Testing of an Oncolytic Parvovirus in Ewing Sarcoma: Protoparvovirus H-1 Induces Apoptosis and Lytic Infection In Vitro but Fails to Improve Survival In Vivo

    Directory of Open Access Journals (Sweden)

    Jeannine Lacroix

    2018-06-01

    Full Text Available About 70% of all Ewing sarcoma (EWS patients are diagnosed under the age of 20 years. Over the last decades little progress has been made towards finding effective treatment approaches for primarily metastasized or refractory Ewing sarcoma in young patients. Here, in the context of the search for novel therapeutic options, the potential of oncolytic protoparvovirus H-1 (H-1PV to treat Ewing sarcoma was evaluated, its safety having been proven previously tested in adult cancer patients and its oncolytic efficacy demonstrated on osteosarcoma cell cultures. The effects of viral infection were tested in vitro on four human Ewing sarcoma cell lines. Notably evaluated were effects of the virus on the cell cycle and its replication efficiency. Within 24 h after infection, the synthesis of viral proteins was induced. Efficient H-1PV replication was confirmed in all four Ewing sarcoma cell lines. The cytotoxicity of the virus was determined on the basis of cytopathic effects, cell viability, and cell lysis. These in vitro experiments revealed efficient killing of Ewing sarcoma cells by H-1PV at a multiplicity of infection between 0.1 and 5 plaque forming units (PFU/cell. In two of the four tested cell lines, significant induction of apoptosis by H-1PV was observed. H-1PV thus meets all the in vitro criteria for a virus to be oncolytic towards Ewing sarcoma. In the first xenograft experiments, however, although an antiproliferative effect of intratumoral H-1PV injection was observed, no significant improvement of animal survival was noted. Future projects aiming to validate parvovirotherapy for the treatment of pediatric Ewing sarcoma should focus on combinatorial treatments and will require the use of patient-derived xenografts and immunocompetent syngeneic animal models.

  20. Subcellular distribution of cyclin-dependent kinase-like 5 (CDKL5) is regulated through phosphorylation by dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A)

    International Nuclear Information System (INIS)

    Oi, Ami; Katayama, Syouichi; Hatano, Naoya; Sugiyama, Yasunori; Kameshita, Isamu; Sueyoshi, Noriyuki

    2017-01-01

    Cyclin-dependent kinase-like 5 (CDKL5) is a Ser/Thr protein kinase primarily expressed in the central nervous system and is known to cause X-linked neurodevelopmental disorders such as Rett syndrome. However, the mechanisms regulating CDKL5 have not yet been fully clarified. Therefore, in this study, we investigated the protein kinase that directly phosphorylates CDKL5, identifying it as dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), an enzyme binding to and phosphorylating CDKL5. We showed that subcellular distribution of CDKL5 was regulated by its phosphorylation by DYRK1A. In mouse neuroblastoma Neuro2a cells, CDKL5 was localized in both the cytosol and nucleus, whereas DYRK1A showed a typical nuclear localization. When CDKL5 and DYRK1A were co-expressed, the cytosolic localization of CDKL5 was significantly increased. Results of site-directed mutagenesis revealed that the phosphorylation site was Ser-308, in the vicinity of the nuclear localization signal. A mutation mimicking the phosphorylated serine residue by aspartate substitution (S308D) changed CDKL5 localization to the cytosol, whereas the corresponding alanine-substituted analog, CDKL5(S308A), was primarily localized to the nucleus. Taken together, these results strongly suggested that DYRK1A bound to CDKL5 and phosphorylated it on Ser-308, thus interfering with its nuclear localization. - Highlights: • We investigated the mechanism regulating subcellular localization of CDKL5. • DYRK1A was identified as an enzyme that bound to and phosphorylated CDKL5. • The phosphorylation site of CDKL5 was Ser-308, in the vicinity of the NLS. • When DYRK1A was co-expressed, the cytosolic CDKL5 was significantly increased. • In conclusion, DYRK1A regulates CDKL5 localization via phosphorylation on Ser-308.

  1. Low cost technology for the rapid and safe in-house (hospital-based) preparation of dual - radiotherapeutic (Rx) and radiodiagnostic (Dx) - dosage forms of high specific activity 131I-mIBG for clinical application

    International Nuclear Information System (INIS)

    Noronha, O.P.D.; Sonawane, G.A.; Samuel, A.M.

    1998-01-01

    Radioiodinated mIBG is finding increasing utility in nuclear medicine. However, its widespread use in developing countries is precluded by logistic constraints owing to the relative instability of the labelled molecule with respect to time and temp., and high costs. This prompted us to develop a low cost in-house batch process technology that could be used for the small-scale preparation of 131 I-mIBG even in a less equipped hospital-based radiopharmacy. The production of large amounts of 131 I-mIBG for clinical use requires sophisticated infrastructure (a scarce resource) to contain / safeguard against internal and external radiation exposures. We have indigenously designed a semi-automated, self-shielded, remote-controlled and safe microplant + process assemblies using easily accessible and cheap inputs, and developed the complete technology for the rapid and safe production of dual dosage forms of 131 I-mIBG, a radiotherapeutic (R x ) single dosage form of high activity along with 1-3 low activity radiodiagnostics (D x ) as multidosage forms. The radioiodide exchange reaction was effected in the solid / melt phase at 190 deg. C in 1.0 h. The radiolabelling yield was ∼80.0-86.0%, and the radiochemical purity > 99.5% and specific activity of R x /D x =900-1300/60-800 MBq ( x dosage forms at 3 weeks. The dosage forms (especially R x ) were only made against firm patient appointment(s). Thus far we have prepared 14 R x (49.0 GBq) and 70 + 14 batches (43.43 GBq) of (∼150 nos.) D x forms, and used them in 14 and > 1100 patients respectively. (author)

  2. Psychosocial approaches to dual diagnosis.

    Science.gov (United States)

    Drake, R E; Mueser, K T

    2000-01-01

    Recent research elucidates many aspects of the problem of co-occurring substance use disorder (SUD) in patients with severe mental illness, which is often termed dual diagnosis. This paper provides a brief overview of current research on the epidemiology, adverse consequences, and phenomenology of dual diagnosis, followed by a more extensive review of current approaches to services, assessment, and treatment. Accumulating evidence shows that comorbid SUD is quite common among individuals with severe mental illness and that these individuals suffer serious adverse consequences of SUD. The research further suggests that traditional, separate services for individuals with dual disorders are ineffective, and that integrated treatment programs, which combine mental health and substance abuse interventions, offer more promise. In addition to a comprehensive integration of services, successful programs include assessment, assertive case management, motivational interventions for patients who do not recognize the need for substance abuse treatment, behavioral interventions for those who are trying to attain or maintain abstinence, family interventions, housing, rehabilitation, and psychopharmacology. Further research is needed on the organization and financing of dual-diagnosis services and on specific components of the integrated treatment model, such as group treatments, family interventions, and housing approaches.

  3. Prostate-Specific and Tumor-Specific Targeting of an Oncolytic HSV-1 Amplicon/Helper Virus for Prostate Cancer Treatment

    Science.gov (United States)

    2009-11-01

    regulation HSV-1 amplicon and recombinant viruses Molecular cloning Cell culture/gene transfection Xenograft mouse model Histology 20...no herpetic lesions were seen in CMV-ICP4-143T–treated and CMV-ICP4-145T– treated animals, although some gastritis developed 28 days after the viral

  4. Preclinical Testing of an Oncolytic Parvovirus: Standard Protoparvovirus H-1PV Efficiently Induces Osteosarcoma Cell Lysis In Vitro.

    Science.gov (United States)

    Geiss, Carsten; Kis, Zoltán; Leuchs, Barbara; Frank-Stöhr, Monika; Schlehofer, Jörg R; Rommelaere, Jean; Dinsart, Christiane; Lacroix, Jeannine

    2017-10-17

    Osteosarcoma is the most frequent malignant disease of the bone. On the basis of early clinical experience in the 1960s with H-1 protoparvovirus (H-1PV) in osteosarcoma patients, this effective oncolytic virus was selected for systematic preclinical testing on various osteosarcoma cell cultures. A panel of five human osteosarcoma cell lines (CAL 72, H-OS, MG-63, SaOS-2, U-2OS) was tested. Virus oncoselectivity was confirmed by infecting non-malignant human neonatal fibroblasts and osteoblasts used as culture models of non-transformed mesenchymal cells. H-1PV was found to enter osteosarcoma cells and to induce viral DNA replication, transcription of viral genes, and translation to viral proteins. After H-1PV infection, release of infectious viral particles from osteosarcoma cells into the supernatant indicated successful viral assembly and egress. Crystal violet staining revealed progressive cytomorphological changes in all osteosarcoma cell lines. Infection of osteosarcoma cell lines with the standard H-1PV caused an arrest of the cell cycle in the G2 phase, and these lines had a limited capacity for standard H-1PV virus replication. The cytotoxicity of wild-type H-1PV virus towards osteosarcoma cells was compared in vitro with that of two variants, Del H-1PV and DM H-1PV, previously described as fitness variants displaying higher infectivity and spreading in human transformed cell lines of different origins. Surprisingly, wild-type H-1PV displayed the strongest cytostatic and cytotoxic effects in this analysis and thus seems the most promising for the next preclinical validation steps in vivo.

  5. Preclinical Testing of an Oncolytic Parvovirus: Standard Protoparvovirus H-1PV Efficiently Induces Osteosarcoma Cell Lysis In Vitro

    Directory of Open Access Journals (Sweden)

    Carsten Geiss

    2017-10-01

    Full Text Available Osteosarcoma is the most frequent malignant disease of the bone. On the basis of early clinical experience in the 1960s with H-1 protoparvovirus (H-1PV in osteosarcoma patients, this effective oncolytic virus was selected for systematic preclinical testing on various osteosarcoma cell cultures. A panel of five human osteosarcoma cell lines (CAL 72, H-OS, MG-63, SaOS-2, U-2OS was tested. Virus oncoselectivity was confirmed by infecting non-malignant human neonatal fibroblasts and osteoblasts used as culture models of non-transformed mesenchymal cells. H-1PV was found to enter osteosarcoma cells and to induce viral DNA replication, transcription of viral genes, and translation to viral proteins. After H-1PV infection, release of infectious viral particles from osteosarcoma cells into the supernatant indicated successful viral assembly and egress. Crystal violet staining revealed progressive cytomorphological changes in all osteosarcoma cell lines. Infection of osteosarcoma cell lines with the standard H-1PV caused an arrest of the cell cycle in the G2 phase, and these lines had a limited capacity for standard H-1PV virus replication. The cytotoxicity of wild-type H-1PV virus towards osteosarcoma cells was compared in vitro with that of two variants, Del H-1PV and DM H-1PV, previously described as fitness variants displaying higher infectivity and spreading in human transformed cell lines of different origins. Surprisingly, wild-type H-1PV displayed the strongest cytostatic and cytotoxic effects in this analysis and thus seems the most promising for the next preclinical validation steps in vivo.

  6. Ultrasound-induced cavitation enhances the delivery and therapeutic efficacy of an oncolytic virus in an in vitro model.

    Science.gov (United States)

    Bazan-Peregrino, Miriam; Arvanitis, Costas D; Rifai, Bassel; Seymour, Leonard W; Coussios, Constantin-C

    2012-01-30

    We investigated whether ultrasound-induced cavitation at 0.5 MHz could improve the extravasation and distribution of a potent breast cancer-selective oncolytic adenovirus, AdEHE2F-Luc, to tumour regions that are remote from blood vessels. We developed a novel tumour-mimicking model consisting of a gel matrix containing human breast cancer cells traversed by a fluid channel simulating a tumour blood vessel, through which the virus and microbubbles could be made to flow. Ultrasonic pressures were chosen to maximize either broadband emissions, associated with inertial cavitation, or ultraharmonic emissions, associated with stable cavitation, while varying duty cycle to keep the total acoustic energy delivered constant for comparison across exposures. None of the exposure conditions tested affected cell viability in the absence of the adenovirus. When AdEHE2F-Luc was delivered via the vessel, inertial cavitation increased transgene expression in tumour cells by up to 200 times. This increase was not observed in the absence of Coxsackie and Adenovirus Receptor cell expression, discounting sonoporation as the mechanism of action. In the presence of inertial cavitation, AdEHE2F-Luc distribution was greatly improved in the matrix surrounding the vessel, particularly in the direction of the ultrasound beam; this enabled AdEHE2F-Luc to kill up to 80% of cancer cells within the ultrasound focal volume in the gel 24 hours after delivery, compared to 0% in the absence of cavitation. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Construction of Various γ34.5 Deleted Fluorescent-Expressing Oncolytic herpes Simplex type 1 (oHSV) for Generation and Isolation of HSV-Based Vectors

    Science.gov (United States)

    Abdoli, Shahriyar; Roohvand, Farzin; Teimoori-Toolabi, Ladan; Shokrgozar, Mohammad Ali; Bahrololoumi, Mina; Azadmanesh, Kayhan

    2017-07-01

    Oncolytic herpes simplex virus (oHSV)-based vectors lacking γ34.5 gene, are considered as ideal templates to construct efficient vectors for (targeted) cancer gene therapy. Herein, we reported the construction of three single/dually-flourescence labeled and γ34.5-deleted, recombinant HSV-1 vectors for rapid generation and easy selection/isolation of different HSV-Based vectors. Generation of recombinant viruses was performed with conventional homologous recombination methods using green fluorescent protein (GFP) and BleCherry harboring shuttle vectors. Viruses were isolated by direct fluorescence observation and standard plaque purifying methods and confirmed by PCR and sequencing and flow cytometry. XTT and plaque assay titration were performed on Vero, U87MG, and T98 GBM cell lines. We generated three recombinant viruses, HSV-GFP, HSV-GR (Green-Red), and HSV-Red. The HSV-GFP showed two log higher titer (1010 PFU) than wild type (108 PFU). In contrast, HSV-GR and HSV-Red showed one log lower titer (107 PFU) than parental HSV. Cytotoxicity analysis showed that HSV-GR and HSV-Red can lyse target tumor cells at multiplicity of infection of 10 and 1 (Pidentification via fluorescence activated cell sorting. These vectors can also be used for tracing the efficacy of therapeutic agents on target cells, imaging of neural or tumoral cells in vitro/in vivo and as oncolytic agents in cancer therapy.

  8. Combination of the oral histone deacetylase inhibitor resminostat with oncolytic measles vaccine virus as a new option for epi-virotherapeutic treatment of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Benjamin Ruf

    Full Text Available Epigenetic therapies such as histone deacetylase inhibitors (HDACi not only have the capability to decrease tumor cell proliferation and to induce tumor cell death but also to silence antiviral response genes. Here, we investigated whether the combination of an oncolytic measles vaccine virus (MeV with the novel oral HDACi resminostat (Res, being in clinical testing in patients with hepatocellular carcinoma (HCC, results in an enhanced efficacy of this epi-virotherapeutic approach compared to any of the two corresponding monotherapies. When testing a panel of human hepatoma cell lines, we found (i a significantly improved rate of primary infections when using oncolytic MeV under concurrent treatment with resminostat, (ii a boosted cytotoxic effect of the epi-virotherapeutic combination (Res + MeV with enhanced induction of apoptosis, and, quite importantly, (iii an absence of any resminostat-induced impairment of MeV replication and spread. Beyond that, we could also show that (iv resminostat, after hepatoma cell stimulation with exogenous human interferon (IFN-β, is able to prevent the induction of IFN-stimulated genes, such as IFIT-1. This finding outlines the possible impact of resminostat on cellular innate immunity, being instrumental in overcoming resistances to MeV-mediated viral oncolysis. Thus, our results support the onset of epi-virotherapeutic clinical trials in patients exhibiting advanced stages of HCC.

  9. Gene Therapy for Pancreatic Cancer: Specificity, Issues and Hopes.

    Science.gov (United States)

    Rouanet, Marie; Lebrin, Marine; Gross, Fabian; Bournet, Barbara; Cordelier, Pierre; Buscail, Louis

    2017-06-08

    A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments of therapeutic innovations in combination with conventional chemotherapy are needed urgently. Among innovative treatments the gene therapy offers a promising avenue. The present review gives an overview of the general strategy of gene therapy as well as the limitations and stakes of the different experimental in vivo models, expression vectors (synthetic and viral), molecular tools (interference RNA, genome editing) and therapeutic genes (tumor suppressor genes, antiangiogenic and pro-apoptotic genes, suicide genes). The latest developments in pancreatic carcinoma gene therapy are described including gene-based tumor cell sensitization to chemotherapy, vaccination and adoptive immunotherapy (chimeric antigen receptor T-cells strategy). Nowadays, there is a specific development of oncolytic virus therapies including oncolytic adenoviruses, herpes virus, parvovirus or reovirus. A summary of all published and on-going phase-1 trials is given. Most of them associate gene therapy and chemotherapy or radiochemotherapy. The first results are encouraging for most of the trials but remain to be confirmed in phase 2 trials.

  10. Dual Income Taxes

    DEFF Research Database (Denmark)

    Sørensen, Peter Birch

    This paper discusses the principles and practices of dual income taxation in the Nordic countries. The first part of the paper explains the rationale and the historical background for the introduction of the dual income tax and describes the current Nordic tax practices. The second part...... of the paper focuses on the problems of taxing income from small businesses and the issue of corporate-personal tax integration under the dual income tax, considering alternative ways of dealing with these challenges. In the third and final part of the paper, I briefly discuss whether introducing a dual income...

  11. Tumor-specific detection of an optically targeted antibody combined with a quencher-conjugated neutravidin "quencher-chaser": a dual "quench and chase" strategy to improve target to nontarget ratios for molecular imaging of cancer.

    Science.gov (United States)

    Ogawa, Mikako; Kosaka, Nobuyuki; Choyke, Peter L; Kobayashi, Hisataka

    2009-01-01

    In vivo molecular cancer imaging with monoclonal antibodies has great potential not only for cancer detection, but also for cancer characterization. However, the prolonged retention of intravenously injected antibody in the blood causes low target tumor-to-background ratio (TBR). Avidin has been used as a "chase" to clear the unbound, circulating biotinylated antibody and decrease the background signal. Here, we utilize a combined approach of a fluorescence resonance energy transfer (FRET) quenched antibody with an "avidin chase" to increase TBR. Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor type 2 (HER2), was biotinylated and conjugated with the near-infrared (NIR) fluorophore Alexa680 to synthesize Tra-Alexa680-biotin. Next, the FRET quencher, QSY-21, was conjugated to avidin, neutravidin (nAv), or streptavidin (sAv), thus creating Av-QSY21, nAv-QSY21, or sAv-QSY21 as "chasers". The fluorescence was quenched in vitro by binding Tra-Alexa680-biotin to Av-QSY21, nAv-QSY21, or sAv-QSY21. To evaluate if the injection of quencher-conjugated avidin derivatives can improve target TBR by using a dual "quench and chase" strategy, both target (3T3/HER2+) and nontarget (Balb3T3/ZsGreen) tumor-bearing mice were employed. The "FRET quench" effect induced by all the QSY21 avidin-based conjugates reduced but did not totally eliminate background signal from the blood pool. The addition of nAv-QSY21 administration increased target TBR mainly because of the "chase" effect where unbound conjugated antibody was preferentially cleared to the liver. The relatively slow clearance of unbound nAv-QSY21 leads to further reductions in background signal by leaking out of the vascular space and binding to unbound antibodies in the extravascular space of tumors, resulting in decreased nontarget tumor-to-background ratios but increased target TBR due to the "FRET quench" effect, because target-bound antibodies were internalized and could not bind

  12. Tumor Specific Detection of an Optically Targeted Antibody Combined with a Quencher-conjugated Neutravidin “Quencher-Chaser”: A Dual “Quench and Chase” Strategy to Improve Target to Non-target Ratios for Molecular Imaging of Cancer

    Science.gov (United States)

    Ogawa, Mikako; Kosaka, Nobuyuki; Choyke, Peter L; Kobayashi, Hisataka

    2009-01-01

    In vivo molecular cancer imaging with monoclonal antibodies has great potential not only for cancer detection but also for cancer characterization. However, the prolonged retention of intravenously injected antibody in the blood causes low target tumor-to-background ratio (TBR). Avidin has been used as a “chase” to clear the unbound, circulating biotinylated antibody and decrease the background signal. Here, we utilize a combined approach of a Fluorescence Resonance Energy Transfer (FRET) quenched antibody with an “avidin chase” to increase TBR. Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor type 2 (HER2), was biotinylated and conjugated with the near-infrared (NIR) fluorophore Alexa680 to synthesize Tra-Alexa680-biotin. Next, the FRET quencher, QSY-21, was conjugated to avidin, neutravidin (nAv) or streptavidin (sAv), thus creating Av-QSY21, nAv-QSY21 or sAv-QSY21 as “chasers”. The fluorescence was quenched in vitro by binding Tra-Alexa680-biotin to Av-QSY21, nAv-QSY21 or sAv-QSY21. To evaluate if the injection of quencher-conjugated avidin-derivatives can improve target TBR by using a dual “quench and chase” strategy, both target (3T3/HER2+) and non-target (Balb3T3/ZsGreen) tumor bearing mice were employed. The “FRET quench” effect induced by all the QSY21 avidin-based conjugates reduced but did not totally eliminate background signal from the blood pool. The addition of nAv-QSY21 administration increased target TBR mainly due to the “chase” effect where unbound conjugated antibody was preferentially cleared to the liver. The relatively slow clearance of unbound nAv-QSY21 leads to further reductions in background signal by leaking out of the vascular space and binding to unbound antibodies in the extravascular space of tumors resulting in decreased non-target tumor-to-background ratios but increased target TBR due to the “FRET quench” effect because target-bound antibodies were internalized

  13. Dual energy CT: New horizon in medical imaging

    Energy Technology Data Exchange (ETDEWEB)

    Goo, Hyun Woo [Dept. of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Goo, Jin Mo [Dept. of Radiology, Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2017-08-01

    Dual-energy CT has remained underutilized over the past decade probably due to a cumbersome workflow issue and current technical limitations. Clinical radiologists should be made aware of the potential clinical benefits of dual-energy CT over single-energy CT. To accomplish this aim, the basic principle, current acquisition methods with advantages and disadvantages, and various material-specific imaging methods as clinical applications of dual-energy CT should be addressed in detail. Current dual-energy CT acquisition methods include dual tubes with or without beam filtration, rapid voltage switching, dual-layer detector, split filter technique, and sequential scanning. Dual-energy material-specific imaging methods include virtual monoenergetic or monochromatic imaging, effective atomic number map, virtual non-contrast or unenhanced imaging, virtual non-calcium imaging, iodine map, inhaled xenon map, uric acid imaging, automatic bone removal, and lung vessels analysis. In this review, we focus on dual-energy CT imaging including related issues of radiation exposure to patients, scanning and post-processing options, and potential clinical benefits mainly to improve the understanding of clinical radiologists and thus, expand the clinical use of dual-energy CT; in addition, we briefly describe the current technical limitations of dual-energy CT and the current developments of photon-counting detector.

  14. Dual-Energy CT: New Horizon in Medical Imaging.

    Science.gov (United States)

    Goo, Hyun Woo; Goo, Jin Mo

    2017-01-01

    Dual-energy CT has remained underutilized over the past decade probably due to a cumbersome workflow issue and current technical limitations. Clinical radiologists should be made aware of the potential clinical benefits of dual-energy CT over single-energy CT. To accomplish this aim, the basic principle, current acquisition methods with advantages and disadvantages, and various material-specific imaging methods as clinical applications of dual-energy CT should be addressed in detail. Current dual-energy CT acquisition methods include dual tubes with or without beam filtration, rapid voltage switching, dual-layer detector, split filter technique, and sequential scanning. Dual-energy material-specific imaging methods include virtual monoenergetic or monochromatic imaging, effective atomic number map, virtual non-contrast or unenhanced imaging, virtual non-calcium imaging, iodine map, inhaled xenon map, uric acid imaging, automatic bone removal, and lung vessels analysis. In this review, we focus on dual-energy CT imaging including related issues of radiation exposure to patients, scanning and post-processing options, and potential clinical benefits mainly to improve the understanding of clinical radiologists and thus, expand the clinical use of dual-energy CT; in addition, we briefly describe the current technical limitations of dual-energy CT and the current developments of photon-counting detector.

  15. Dual Enrollment Academy Programs

    Science.gov (United States)

    Gonzalez, Nicolas; Chavez, Guadalupe

    2009-01-01

    Dual Enrollment Engineering (DEEA) and Medical Science (DEMSA) Academies are two-year dual enrollment programs for high school students. Students explore engineering and medical careers through college coursework. Students prepare for higher education in engineering and medical fields while completing associate degrees in biology or engineering…

  16. A Dual Egalitarian Solution

    NARCIS (Netherlands)

    Klijn, F.; Slikker, M.; Tijs, S.H.

    2000-01-01

    In this note we introduce an egalitarian solution, called the dual egalitarian solution, that is the natural counterpart of the egalitarian solution of Dutta and Ray (1989).We prove, among others, that for a convex game the egalitarian solution coincides with the dual egalitarian solution for its

  17. Dual Credit Report

    Science.gov (United States)

    Light, Noreen

    2016-01-01

    In 2015, legislation to improve access to dual-credit programs and to reduce disparities in access and completion--particularly for low income and underrepresented students--was enacted. The new law focused on expanding access to College in the High School but acknowledged issues in other dual-credit programs and reinforced the notion that cost…

  18. Dual Credit/Dual Enrollment and Data Driven Policy Implementation

    Science.gov (United States)

    Lichtenberger, Eric; Witt, M. Allison; Blankenberger, Bob; Franklin, Doug

    2014-01-01

    The use of dual credit has been expanding rapidly. Dual credit is a college course taken by a high school student for which both college and high school credit is given. Previous studies provided limited quantitative evidence that dual credit/dual enrollment is directly connected to positive student outcomes. In this study, predictive statistics…

  19. Dual-Energy CT of Rectal Cancer Specimens

    DEFF Research Database (Denmark)

    Al-Najami, Issam; Beets-Tan, Regina G H; Madsen, Gunvor

    2016-01-01

    is represented by a certain effective Z value, which allows for information on its composition. OBJECTIVE: We wanted to standardize a method for dual-energy scanning of rectal specimens to evaluate the sensitivity and specificity of benign versus malignant lymph node differentiation. Histopathological evaluation...... cancer. MAIN OUTCOME MEASURES: We measured accuracy of differentiating benign from malignant lymph nodes by investigating the following: 1) gadolinium, iodine, and water concentrations in lymph nodes; 2) dual-energy ratio; 3) dual-energy index; and 4) effective Z value. RESULTS: Optimal discriminations...... between benign and malignant lymph nodes were obtained using the following cutoff values: 1) effective Z at 7.58 (sensitivity, 100%; specificity, 90%; and accuracy, 93%), 2) dual-energy ratio at 1.0 × 10 (sensitivity, 96%; specificity, 87%; and accuracy, 90%), 3) dual-energy index at 0.03 (sensitivity, 97...

  20. Dual thyroid ectopia

    International Nuclear Information System (INIS)

    Al-Akeely, Mohammed H.

    2003-01-01

    Ectopic thyroid gland is a rare embryological fault of thyroid development .Dual ectopic thyroid is more rare and only 8 cases have been reported in the literature. The author presents a case of dual ectopic thyroid in a 16 year old boy with an anterior red neck mass, which is gradually growing in size particularly in last 2 years. The initial diagnosis was thyroglossal duct cyst. Thyroid function test revealed elevated thyroid-stimulating hormone. Ultrasound of the neck did not show thyroid gland in its normal pre tracheal position. Thyroid scan (Technetium 99)revealed the diagnosis of dual thyroid ectopia(lingual and subhyoid). (author)

  1. Dual energy CT

    DEFF Research Database (Denmark)

    Al-Najami, Issam; Drue, Henrik Christian; Steele, Robert

    2017-01-01

    and inaccurate with existing methods. Dual Energy Computed Tomography (DECT) enables qualitative tissue differentiation by simultaneous scanning with different levels of energy. We aimed to assess the feasibility of DECT in quantifying tumor response to neoadjuvant therapy in loco-advanced rectal cancer. METHODS...... to determine the average quantitative parameters; effective-Z, water- and iodine-concentration, Dual Energy Index (DEI), and Dual Energy Ratio (DER). These parameters were compared to the regression in the resection specimen as measured by the pathologist. RESULTS: Changes in the quantitative parameters...

  2. Dual coil ignition system

    Energy Technology Data Exchange (ETDEWEB)

    Huberts, Garlan J.; Qu, Qiuping; Czekala, Michael Damian

    2017-03-28

    A dual coil ignition system is provided. The dual coil ignition system includes a first inductive ignition coil including a first primary winding and a first secondary winding, and a second inductive ignition coil including a second primary winding and a second secondary winding, the second secondary winding connected in series to the first secondary winding. The dual coil ignition system further includes a diode network including a first diode and a second diode connected between the first secondary winding and the second secondary winding.

  3. An oncolytic adenovirus enhances antiangiogenic and antitumoral effects of a replication-deficient adenovirus encoding endostatin by rescuing its selective replication in nasopharyngeal carcinoma cells

    International Nuclear Information System (INIS)

    Liu, Ran-yi; Zhou, Ling; Zhang, Yan-ling; Huang, Bi-jun; Ke, Miao-la; Chen, Jie-min; Li, Li-xia; Fu, Xiang; Wu, Jiang-xue; Huang, Wenlin

    2013-01-01

    Highlights: •H101 promotes endostatin expression by Ad-Endo via rescuing Ad-Endo replication. •H101 rescued Ad-Endo replication by supplying E1A and E1B19k proteins. •Ad-Endo enhanced the cytotoxicity of H101 in NPC cells. •Ad-Endo and oncolytic Ad H101 have synergistic antitumor effects on NPC. -- Abstract: A replication-deficient adenovirus (Ad) encoding secreted human endostatin (Ad-Endo) has been demonstrated to have promising antiangiogenic and antitumoral effects. The E1B55k-deleted Ad H101 can selectively lyse cancer cells. In this study, we explored the antitumor effects and cross-interactions of Ad-Endo and H101 on nasopharyngeal carcinoma (NPC). The results showed that H101 dramatically promoted endostatin expression by Ad-Endo via rescuing Ad-Endo replication in NPC cells, and the expressed endostatin proteins significantly inhibited the proliferation of human umbilical vein endothelial cells. E1A and E1B19k products are required for the rescuing of H101 to Ad-Endo replication in CNE-1 and CNE-2 cells, but not in C666-1 cells. On the other hand, Ad-Endo enhanced the cytotoxicity of H101 by enhancing Ad replication in NPC cells. The combination of H101 and Ad-Endo significantly inhibited CNE-2 xenografts growth through the increased endostatin expression and Ad replication. These findings indicate that the combination of Ad-Endo gene therapy and oncolytic Ad therapeutics could be promising in comprehensive treatment of NPC

  4. An oncolytic adenovirus enhances antiangiogenic and antitumoral effects of a replication-deficient adenovirus encoding endostatin by rescuing its selective replication in nasopharyngeal carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Ran-yi, E-mail: liuranyi@mail.sysu.edu.cn [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Zhou, Ling [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Zhang, Yan-ling [School of Biotechnology, Southern Medical University, Guangzhou 510515 (China); Huang, Bi-jun; Ke, Miao-la; Chen, Jie-min [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Li, Li-xia [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); General Hospital of Guangzhou Military Command of PLA, Guangzhou 510010 (China); Fu, Xiang; Wu, Jiang-xue [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Huang, Wenlin, E-mail: hwenl@mail.sysu.edu.cn [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Guangdong Provincial Key Laboratory of Tumor-Targeted Drug, Doublle Bioproducts Inc., Guangzhou 510663 (China)

    2013-12-13

    Highlights: •H101 promotes endostatin expression by Ad-Endo via rescuing Ad-Endo replication. •H101 rescued Ad-Endo replication by supplying E1A and E1B19k proteins. •Ad-Endo enhanced the cytotoxicity of H101 in NPC cells. •Ad-Endo and oncolytic Ad H101 have synergistic antitumor effects on NPC. -- Abstract: A replication-deficient adenovirus (Ad) encoding secreted human endostatin (Ad-Endo) has been demonstrated to have promising antiangiogenic and antitumoral effects. The E1B55k-deleted Ad H101 can selectively lyse cancer cells. In this study, we explored the antitumor effects and cross-interactions of Ad-Endo and H101 on nasopharyngeal carcinoma (NPC). The results showed that H101 dramatically promoted endostatin expression by Ad-Endo via rescuing Ad-Endo replication in NPC cells, and the expressed endostatin proteins significantly inhibited the proliferation of human umbilical vein endothelial cells. E1A and E1B19k products are required for the rescuing of H101 to Ad-Endo replication in CNE-1 and CNE-2 cells, but not in C666-1 cells. On the other hand, Ad-Endo enhanced the cytotoxicity of H101 by enhancing Ad replication in NPC cells. The combination of H101 and Ad-Endo significantly inhibited CNE-2 xenografts growth through the increased endostatin expression and Ad replication. These findings indicate that the combination of Ad-Endo gene therapy and oncolytic Ad therapeutics could be promising in comprehensive treatment of NPC.

  5. Dual Syntax for XML Languages

    DEFF Research Database (Denmark)

    Brabrand, Claus; Møller, Anders; Schwartzbach, Michael Ignatieff

    2005-01-01

    XML is successful as a machine processable data interchange format, but it is often too verbose for human use. For this reason, many XML languages permit an alternative more legible non-XML syntax. XSLT stylesheets are often used to convert from the XML syntax to the alternative syntax; however......, such transformations are not reversible since no general tool exists to automatically parse the alternative syntax back into XML. We present XSugar, which makes it possible to manage dual syntax for XML languages. An XSugar specification is built around a context-free grammar that unifies the two syntaxes...

  6. Dual Dynamic Programming - DDP

    International Nuclear Information System (INIS)

    Velasquez Bermudez, Jesus M

    1998-01-01

    Objections are presented to the mathematical formulation of the denominated Dual Dynamic programming-PDD that is the theoretical base of several computational model available for the optimal formulation of interconnected hydrothermal systems

  7. The Potentials for the Use of Single- versus Dual-Purpose Officers in Firms:

    DEFF Research Database (Denmark)

    Theotokas, Ioannis; Wagtmann, Maria Anne

    2010-01-01

    In the article, we will focus on economic issues concerning the favourability of employing dual pur­pose officers, given that national dual-purpose educational programs exist; we will thus delimit us from discussing potential advantages and disadvantages of firm-specific educational investments...... of employing dual-purpose officers....

  8. Identifying HIV-1 dual infections

    Directory of Open Access Journals (Sweden)

    Cornelissen Marion

    2007-09-01

    Full Text Available Abstract Transmission of human immunodeficiency virus (HIV is no exception to the phenomenon that a second, productive infection with another strain of the same virus is feasible. Experiments with RNA viruses have suggested that both coinfections (simultaneous infection with two strains of a virus and superinfections (second infection after a specific immune response to the first infecting strain has developed can result in increased fitness of the viral population. Concerns about dual infections with HIV are increasing. First, the frequent detection of superinfections seems to indicate that it will be difficult to develop a prophylactic vaccine. Second, HIV-1 superinfections have been associated with accelerated disease progression, although this is not true for all persons. In fact, superinfections have even been detected in persons controlling their HIV infections without antiretroviral therapy. Third, dual infections can give rise to recombinant viruses, which are increasingly found in the HIV-1 epidemic. Recombinants could have increased fitness over the parental strains, as in vitro models suggest, and could exhibit increased pathogenicity. Multiple drug resistant (MDR strains could recombine to produce a pan-resistant, transmittable virus. We will describe in this review what is presently known about super- and re-infection among ambient viral infections, as well as the first cases of HIV-1 superinfection, including HIV-1 triple infections. The clinical implications, the impact of the immune system, and the effect of anti-retroviral therapy will be covered, as will as the timing of HIV superinfection. The methods used to detect HIV-1 dual infections will be discussed in detail. To increase the likelihood of detecting a dual HIV-1 infection, pre-selection of patients can be done by serotyping, heteroduplex mobility assays (HMA, counting the degenerate base codes in the HIV-1 genotyping sequence, or surveying unexpected increases in the

  9. Dual-Modality Breast Tomosynthesis1

    OpenAIRE

    Williams, Mark B.; Judy, Patricia G.; Gunn, Spencer; Majewski, Stanislaw

    2010-01-01

    Pilot clinical evaluation of this dual-modality tomosynthesis system suggests that it is a feasible and accurate method with which to detect and diagnose breast cancer and that specificity and positive predictive value can be improved by adding molecular breast imaging tomosynthesis to x-ray tomosynthesis.

  10. Dual Protection and Contraceptive Method Use among Women in ...

    African Journals Online (AJOL)

    USER

    communication about condom use may be specifically helpful in promoting dual method use. ... women, Mafikeng, condom, non-barrier method, sexually transmitted infections. Résumé .... concluded that higher education, being unmarried and.

  11. Self-dual Hopf quivers

    International Nuclear Information System (INIS)

    Huang Hualin; Li Libin; Ye Yu

    2004-07-01

    We study pointed graded self-dual Hopf algebras with a help of the dual Gabriel theorem for pointed Hopf algebras. Quivers of such Hopf algebras are said to be self-dual. An explicit classification of self-dual Hopf quivers is obtained. We also prove that finite dimensional coradically graded pointed self-dual Hopf algebras are generated by group-like and skew-primitive elements as associative algebras. This partially justifies a conjecture of Andruskiewitsch and Schneider and may help to classify finite dimensional self-dual pointed Hopf algebras

  12. Dual Syntax for XML Languages

    DEFF Research Database (Denmark)

    Brabrand, Claus; Møller, Anders; Schwartzbach, Michael Ignatieff

    2005-01-01

    XML is successful as a machine processable data interchange format, but it is often too verbose for human use. For this reason, many XML languages permit an alternative more legible non-XML syntax. XSLT stylesheets are often used to convert from the XML syntax to the alternative syntax; however......, such transformations are not reversible since no general tool exists to automatically parse the alternative syntax back into XML. We present XSugar, which makes it possible to manage dual syntax for XML languages. An XSugar specification is built around a context-free grammar that unifies the two syntaxes...... of a language. Given such a specification, the XSugar tool can translate from alternative syntax to XML and vice versa. Moreover, the tool statically checks that the transformations are reversible and that all XML documents generated from the alternative syntax are valid according to a given XML schema....

  13. Dual source CT imaging

    International Nuclear Information System (INIS)

    Seidensticker, Peter R.; Hofmann, Lars K.

    2008-01-01

    The introduction of Dual Source Computed Tomography (DSCT) in 2005 was an evolutionary leap in the field of CT imaging. Two x-ray sources operated simultaneously enable heart-rate independent temporal resolution and routine spiral dual energy imaging. The precise delivery of contrast media is a critical part of the contrast-enhanced CT procedure. This book provides an introduction to DSCT technology and to the basics of contrast media administration followed by 25 in-depth clinical scan and contrast media injection protocols. All were developed in consensus by selected physicians on the Dual Source CT Expert Panel. Each protocol is complemented by individual considerations, tricks and pitfalls, and by clinical examples from several of the world's best radiologists and cardiologists. This extensive CME-accredited manual is intended to help readers to achieve consistently high image quality, optimal patient care, and a solid starting point for the development of their own unique protocols. (orig.)

  14. Dual Pathology of Mandible.

    Science.gov (United States)

    Rajurkar, Suday G; Deshpande, Mohan D; Kazi, Noaman; Jadhav, Dhanashree; Ranadive, Pallavi; Ingole, Snehal

    2017-01-01

    Aneurysmal Bone cyst (ABC)is a rare benign lesion of the bone which is infrequent in craniofacial region (12%). Rapid growth pattern causing bone expansion and facial asymmetry is a characteristic feature of ABC. Giant cell lesion is another distinct pathological entity. Here we present to you a rare case of dual pathology in an 11 year old female patient who presented with a large expansile lesion in the left hemimandible. All radiographic investigations were suggestive of ABC, aspiration of the lesion resulted in blood aspirate. However only after a histologic examination the dual nature of the lesion was revealed.

  15. Dual phase evolution

    CERN Document Server

    Green, David G; Abbass, Hussein A

    2014-01-01

    This book explains how dual phase evolution operates in all these settings and provides a detailed treatment of the subject. The authors discuss the theoretical foundations for the theory, how it relates to other phase transition phenomena and its advantages in evolutionary computation and complex adaptive systems. The book provides methods and techniques to use this concept for problem solving. Dual phase evolution concerns systems that evolve via repeated phase shifts in the connectivity of their elements. It occurs in vast range of settings, including natural systems (species evolution, landscape ecology, geomorphology), socio-economic systems (social networks) and in artificial systems (annealing, evolutionary computing).

  16. Dual-Mode Combustor

    Science.gov (United States)

    Trefny, Charles J (Inventor); Dippold, Vance F (Inventor)

    2013-01-01

    A new dual-mode ramjet combustor used for operation over a wide flight Mach number range is described. Subsonic combustion mode is usable to lower flight Mach numbers than current dual-mode scramjets. High speed mode is characterized by supersonic combustion in a free-jet that traverses the subsonic combustion chamber to a variable nozzle throat. Although a variable combustor exit aperture is required, the need for fuel staging to accommodate the combustion process is eliminated. Local heating from shock-boundary-layer interactions on combustor walls is also eliminated.

  17. Dual-anticipating, dual and dual-lag synchronization in modulated time-delayed systems

    International Nuclear Information System (INIS)

    Ghosh, Dibakar; Chowdhury, A. Roy

    2010-01-01

    In this Letter, dual synchronization in modulated time delay system using delay feedback controller is proposed. Based on Lyapunov stability theory, we suggest a general method to achieve the dual-anticipating, dual, dual-lag synchronization of time-delayed chaotic systems and we find both its existing and sufficient stability conditions. Numerically it is shown that the dual synchronization is also possible when driving system contain two completely different systems. Effect of parameter mismatch on dual synchronization is also discussed. As an example, numerical simulations for the Mackey-Glass and Ikeda systems are conducted, which is in good agreement with the theoretical analysis.

  18. Brain activations during bimodal dual tasks depend on the nature and combination of component tasks

    Directory of Open Access Journals (Sweden)

    Emma eSalo

    2015-02-01

    Full Text Available We used functional magnetic resonance imaging to investigate brain activations during nine different dual tasks in which the participants were required to simultaneously attend to concurrent streams of spoken syllables and written letters. They performed a phonological, spatial or simple (speaker-gender or font-shade discrimination task within each modality. We expected to find activations associated specifically with dual tasking especially in the frontal and parietal cortices. However, no brain areas showed systematic dual task enhancements common for all dual tasks. Further analysis revealed that dual tasks including component tasks that were according to Baddeley’s model modality atypical, that is, the auditory spatial task or the visual phonological task, were not associated with enhanced frontal activity. In contrast, for other dual tasks, activity specifically associated with dual tasking was found in the left or bilateral frontal cortices. Enhanced activation in parietal areas, however, appeared not to be specifically associated with dual tasking per se, but rather with intermodal attention switching. We also expected effects of dual tasking in left frontal supramodal phonological processing areas when both component tasks required phonological processing and in right parietal supramodal spatial processing areas when both tasks required spatial processing. However, no such effects were found during these dual tasks compared with their component tasks performed separately. Taken together, the current results indicate that activations during dual tasks depend in a complex manner on specific demands of component tasks.

  19. spinning self-dual particles

    International Nuclear Information System (INIS)

    Gamboa, J.; Rivelles, V.O.

    1989-01-01

    Self-dual particles in two-dimensions are presented. They were obtained from chiral boson particle by square root technique. The propagator of spinning self-dual particle is calculated using the BFV formalism. (M.C.K.)

  20. Dual Smarandache Curves and Smarandache Ruled Surfaces

    OpenAIRE

    Tanju KAHRAMAN; Mehmet ÖNDER; H. Hüseyin UGURLU

    2013-01-01

    In this paper, by considering dual geodesic trihedron (dual Darboux frame) we define dual Smarandache curves lying fully on dual unit sphere S^2 and corresponding to ruled surfaces. We obtain the relationships between the elements of curvature of dual spherical curve (ruled surface) x(s) and its dual Smarandache curve (Smarandache ruled surface) x1(s) and we give an example for dual Smarandache curves of a dual spherical curve.

  1. N = 1 dual string pairs and their modular superpotentials

    International Nuclear Information System (INIS)

    Luest, D.

    1998-01-01

    We review the duality between heterotic and F-theory string vacua with N=1 space-time supersymmetry in eight, six and four dimensions. In particular, we discuss two chains of four-dimensional F-theory/heterotic dual string pairs, where F-theory is compactified on certain elliptic Calabi-Yau fourfolds, and the dual heterotic vacua are given by compactifications on elliptic Calabi-Yau threefolds plus the specification of the E 8 x E 8 gauge bundles. We show that the massless spectra of the dual pairs agree by using, for one chain of models, an index formula to count the heterotic bundle moduli and determine the dual F-theory spectra from the Hodge numbers of the fourfolds and of the type IIB base spaces. Moreover as a further check, we demonstrate that for one particular heterotic/F-theory dual pair the N=1 superpotentials are the same. (orig.)

  2. Dual Coding in Children.

    Science.gov (United States)

    Burton, John K.; Wildman, Terry M.

    The purpose of this study was to test the applicability of the dual coding hypothesis to children's recall performance. The hypothesis predicts that visual interference will have a small effect on the recall of visually presented words or pictures, but that acoustic interference will cause a decline in recall of visually presented words and…

  3. Dual beam vidicon digitizer

    International Nuclear Information System (INIS)

    Evans, T.L.

    1976-01-01

    A vidicon waveform digitizer which can simultaneously digitize two independent signals has been developed. Either transient or repetitive waveforms can be digitized with this system. A dual beam oscilloscope is used as the signal input device. The light from the oscilloscope traces is optically coupled to a television camera, where the signals are temporarily stored prior to digitizing

  4. Dual QCD: A review

    International Nuclear Information System (INIS)

    Baker, M.; Ball, J.S.; Zachariasen, F.

    1991-01-01

    We review the attempts to use dual (electric) vector potentials rather than the standard magnetic vector potentials to describe QCD, particularly in the infrared regime. The use of dual potentials is motivated by the fact that in classical electrodynamics, in a medium with a dielectric constant vanishing at small momenta (as is believed to be the case in QCD), electric potentials provide a far more convenient language than do magnetic potentials. To begin with, we outline attempts to construct the QCD Lagrangian in terms of dual potentials and describe the various possibilities, their shortcomings and advantages, which so far exist. We then proceed to use the most attractive (albeit consistent as a field theory only at the tree level) of these Lagrangians in a number of applications. We show that it describes a non-Abelian dual superconductor (so that it automatically confines color), derive the static quark-antiquark potential, and various temperature dependent effects, such as deconfinement and chiral symmetry breaking. (orig.)

  5. Dual completion method

    Energy Technology Data Exchange (ETDEWEB)

    Mamedov, N Ya; Kadymova, K S; Dzhafarov, Sh T

    1963-10-28

    One type of dual completion method utilizes a single tubing string. Through the use of the proper tubing equipment, the fluid from the low-productive upper formation is lifted by utilizing the surplus energy of a submerged pump, which handles the production from the lower stratum.

  6. Dual ionization chamber

    International Nuclear Information System (INIS)

    Mallory, J.; Turlej, Z.

    1981-01-01

    Dual ionization chambers are provided for use with an electronic smoke detector. The chambers are separated by electrically-conductive partition. A single radiation source extends through the partition into both chambers, ionizing the air in each. The mid-point current of the device may be balanced by adjusting the position of the source

  7. Fusion of the BCL9 HD2 domain to E1A increases the cytopathic effect of an oncolytic adenovirus that targets colon cancer cells

    Directory of Open Access Journals (Sweden)

    Pittet Anne-Laure

    2006-10-01

    Full Text Available Abstract Background The Wnt signaling pathway is activated by mutations in the APC and β-catenin genes in many types of human cancer. β-catenin is stabilized by these mutations and activates transcription in part by acting as a bridge between Tcf/LEF proteins and the HD2 domain of the BCL9 coactivator. We have previously described oncolytic adenoviruses with binding sites for Tcf/LEF transcription factors inserted into the early viral promoters. These viruses replicate selectively in cells with activation of the Wnt pathway. To increase the activity of these viruses we have fused the viral transactivator E1A to the BCL9 HD2 domain. Methods Luciferase assays, co-immunoprecipitation and Western blotting, immunofluorescent cell staining and cytopathic effect assays were used to characterize the E1A-HD2 fusion protein and virus in vitro. Growth curves of subcutaneous SW620 colon cancer xenografts were used to characterize the virus in vivo. Results The E1A-HD2 fusion protein binds to β-catenin in vivo and activates a Tcf-regulated luciferase reporter better than wild-type E1A in cells with activated Wnt signaling. Expression of the E1A-HD2 protein promotes nuclear import of β-catenin, mediated by the strong nuclear localization signal in E1A. Tcf-regulated viruses expressing the fusion protein show increased expression of viral proteins and a five-fold increase in cytopathic effect (CPE in colorectal cancer cell lines. There was no change in viral protein expression or CPE in HeLa cells, indicating that E1A-HD2 viruses retain selectivity for cells with activation of the Wnt signaling pathway. Despite increasing the cytopathic effect of the virus in vitro, fusion of the HD2 domain to E1A did not increase the burst size of the virus in vitro or the anti-tumor effect of the virus in an SW620 xenograft model in vivo. Conclusion Despite an increase in the nuclear pool of β-catenin, the effects on viral activity in colon cancer cells were small

  8. Dual Orlicz geominimal surface area

    Directory of Open Access Journals (Sweden)

    Tongyi Ma

    2016-02-01

    Full Text Available Abstract The L p $L_{p}$ -geominimal surface area was introduced by Lutwak in 1996, which extended the important concept of the geominimal surface area. Recently, Wang and Qi defined the p-dual geominimal surface area, which belongs to the dual Brunn-Minkowski theory. In this paper, based on the concept of the dual Orlicz mixed volume, we extend the dual geominimal surface area to the Orlicz version and give its properties. In addition, the isoperimetric inequality, a Blaschke-Santaló type inequality, and the monotonicity inequality for the dual Orlicz geominimal surface areas are established.

  9. Glioma stem cells targeted by oncolytic virus carrying endostatin-angiostatin fusion gene and the expression of its exogenous gene in vitro.

    Science.gov (United States)

    Zhu, Guidong; Su, Wei; Jin, Guishan; Xu, Fujian; Hao, Shuyu; Guan, Fangxia; Jia, William; Liu, Fusheng

    2011-05-16

    The development of the cancer stem cell (CSCs) niche theory has provided a new target for the treatment of gliomas. Gene therapy using oncolytic viral vectors has shown great potential for the therapeutic targeting of CSCs. To explore whether a viral vector carrying an exogenous Endo-Angio fusion gene (VAE) can infect and kill glioma stem cells (GSCs), as well as inhibit their vascular niche in vitro, we have collected surgical specimens of human high-grade glioma (world health organization, WHO Classes III-VI) from which we isolated and cultured GSCs under conditions originally designed for the selective expansion of neural stem cells. Our results demonstrate the following: (1) Four lines of GSCs (isolated from 20 surgical specimens) could grow in suspension, were multipotent, had the ability to self-renew and expressed the neural stem cell markers, CD133 and nestin. (2) VAE could infect GSCs and significantly inhibit their viability. (3) The Endo-Angio fusion gene was expressed in GSCs 48 h after VAE infection and could inhibit the proliferation of human brain microvascular endothelial cells (HBMEC). (4) Residual viable cells lose the ability of self-renewal and adherent differentiation. In conclusion, VAE can significantly inhibit the activity of GSCs in vitro and the expression of exogenous Endo-Angio fusion gene can inhibit HBMEC proliferation. VAE can be used as a novel virus-gene therapy strategy for glioma. Copyright © 2011 Elsevier B.V. All rights reserved.

  10. Toxicology and Biodistribution Studies for MGH2.1, an Oncolytic Virus that Expresses Two Prodrug-activating Genes, in Combination with Prodrugs

    Directory of Open Access Journals (Sweden)

    Kazue Kasai

    2013-01-01

    Full Text Available MGH2.1 is a herpes simplex virus type 1 (HSV1 oncolytic virus that expresses two prodrug-activating transgenes: the cyclophosphamide (CPA-activating cytochrome P4502B1 (CYP2B1 and the CPT11-activating secreted human intestinal carboxylesterase (shiCE. Toxicology and biodistribution of MGH2.1 in the presence/absence of prodrugs was evaluated in mice. MGH2.1 ± prodrugs was cytotoxic to human glioma cells, but not to normal cells. Pharmacokinetically, intracranial MGH2.1 did not significantly alter the metabolism of intraperitoneally (i.p. administered prodrugs in mouse plasma, brain, or liver. MGH2.1 did not induce an acute inflammatory reaction. MGH2.1 DNA was detected in brains of mice inoculated with 108 pfus for up to 60 days. However, only one animal showed evidence of viral gene expression at this time. Expression of virally encoded genes was restricted to brain. Intracranial inoculation of MGH2.1 did not induce lethality at 108 pfus in the absence of prodrugs and at 106 pfus in the presence of prodrugs. This study provides safety and toxicology data justifying a possible clinical trial of intratumoral injection of MGH2.1 with peripheral administration of CPA and/or CPT11 prodrugs in humans with malignant gliomas.

  11. Anti-cancer effect of oncolytic adenovirus-armed shRNA targeting MYCN gene on doxorubicin-resistant neuroblastoma cells.

    Science.gov (United States)

    Li, Yuan; Zhuo, Baobiao; Yin, Yiyu; Han, Tao; Li, Shixian; Li, Zhengwei; Wang, Jian

    2017-09-09

    Chemotherapy is one of the few effective choices for patients with neuroblastoma. However, the development of muti-drug resistance (MDR) to chemotherapy is a major obstacle to the effective treatment of advanced or recurrent neuroblastoma. The muti-drug resistance-associated protein (MRP), which encodes a transmembrane glycoprotein, is a key regulator of MDR. The expression of MRP is a close correlation with MYCN oncogene in neuroblastoma. We have recently shown ZD55-shMYCN (oncolytic virus armed with shRNA against MYCN) can down-regulate MYCN to inhibit tumor cells proliferation and induce apoptosis in neuroblastoma. Here we further report ZD55-shMYCN re-sensitized doxorubicin-resistant cells to doxorubicin (as shown by reduced proliferation, increased apoptosis, and inhibited cell migration), and reduced the in vivo growth rate of neuroblastoma xenografts by down-regulation of MRP expression. Sequential therapy with doxorubicin did not affect the replication of ZD55-shMYCN in doxorubicin-resistant neuroblastoma cells, but decreased the expression of Bcl-2, Bcl-X L , MMP-1. Thus, this synergistic effect of ZD55-shMYCN in combination with doxorubicin provides a novel therapy strategy for doxorubicin-resistant neuroblastoma, and is a promising approach for further clinical development. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Dual Y-Shaped Monopole Antenna for Dual-Band WLAN/WiMAX Operations

    Directory of Open Access Journals (Sweden)

    Huiqing Zhai

    2014-01-01

    Full Text Available A dual-band design of monopole antenna with two coupled Y-shaped strips for WLAN/WiMAX applications is presented. By the introduction of dual Y-shaped strips, two separated impedance bandwidths of 22.4% (3.28~4.10 GHz and 19.2% (4.90~5.94 GHz can be obtained to meet the specifications of the WLAN/WiMAX communication band applications. The proposed antenna is successfully simulated, designed, and measured, demonstrating the matched impedance and good radiation characteristics with an overall dimension of 17.7×26×1 mm3.

  13. Dual photon absorptiometry: Validation of mineral and fat measurements

    International Nuclear Information System (INIS)

    Heymsfield, S.B.; Wang, J.; Sulet, M.; Lichtman, S.; Pierson, R.N. Jr.; Kehayias, J.; Lindsay, R.

    1989-01-01

    Photons passing through human tissue undergo attenuation in relation to the specific chemical substances with which they interact. By selecting two appropriate photon energies and recording their attenuation, the investigator can solve simultaneous equations that subdivide body mass into two components: soft tissue and bone mineral ash. The aim of this paper is to describe and to validate the estimates of body composition derived by dual photon systems. The initial studies largely involved dual photon absorptiometers, although the discussion will also include the more recently developed dual energy x-ray absorptiometers. 13 refs., 7 figs., 4 tabs

  14. Chains of N=2, D=4 heterotic type II duals

    CERN Document Server

    Aldazabal, G; Font, A; Quevedo, Fernando

    1996-01-01

    We report on a search for N=2 heterotic strings that are dual candidates of type II compactifications on Calabi-Yau threefolds described as K3 fibrations. We find many new heterotic duals by using standard orbifold techniques. The associated type II compactifications fall into chains in which the proposed duals are heterotic compactifications related one another by a sequential Higgs mechanism. This breaking in the heterotic side typically involves the sequence SU(4)\\rightarrow SU(3)\\rightarrow SU(2)\\rightarrow 0, while in the type II side the weights of the complex hypersurfaces and the structure of the K3 quotient singularities also follow specific patterns.

  15. Dual Campus High School

    Directory of Open Access Journals (Sweden)

    Carmen P. Mombourquette

    2013-04-01

    Full Text Available September 2010 witnessed the opening of the first complete dual campus high school in Alberta. Catholic Central High School, which had been in existence since 1967 in one building, now offered courses to students on two campuses. The “dual campus” philosophy was adopted so as to ensure maximum program flexibility for students. The philosophy, however, was destined to affect student engagement and staff efficacy as the change in organizational structure, campus locations, and course availability was dramatic. Changing school organizational structure also had the potential of affecting student achievement. A mixed-methods study utilizing engagement surveys, efficacy scales, and interviews with students and teachers was used to ascertain the degree of impact. The results of the study showed that minimal impact occurred to levels of student engagement, minor negative impact to staff efficacy, and a slight increase to student achievement results.

  16. IAEA's dual function

    International Nuclear Information System (INIS)

    1967-01-01

    'A factor of paramount importance is the dual nature of atomic energy, which is reflected in the dual function of the Agency; not only to promote, but also to safeguard the peaceful uses of atomic energy'. In taking the above statement as a theme in his address to the 1474th Plenary Meeting of the United Nations General Assembly (22nd November), the Director General, Dr. Sigvard Eklund, went on to speak of a few of the many areas in which society was feeling the impact of atomic energy. During the discussion which followed his report on the Agency's work nearly all speakers referred to the importance of the safeguards system as well as to positive achievements in developing nuclear potential for peaceful purposes

  17. Dual double field theory

    Energy Technology Data Exchange (ETDEWEB)

    Bergshoeff, Eric A. [Centre for Theoretical Physics, University of Groningen,Nijenborgh 4, 9747 AG Groningen (Netherlands); Hohm, Olaf [Simons Center for Geometry and Physics, Stony Brook University,Stony Brook, NY 11794-3636 (United States); Penas, Victor A. [Centre for Theoretical Physics, University of Groningen,Nijenborgh 4, 9747 AG Groningen (Netherlands); Riccioni, Fabio [INFN - Sezione di Roma, Dipartimento di Fisica, Università di Roma “La Sapienza”,Piazzale Aldo Moro 2, 00185 Roma (Italy)

    2016-06-06

    We present the dual formulation of double field theory at the linearized level. This is a classically equivalent theory describing the duals of the dilaton, the Kalb-Ramond field and the graviton in a T-duality or O(D,D) covariant way. In agreement with previous proposals, the resulting theory encodes fields in mixed Young-tableau representations, combining them into an antisymmetric 4-tensor under O(D,D). In contrast to previous proposals, the theory also requires an antisymmetric 2-tensor and a singlet, which are not all pure gauge. The need for these additional fields is analogous to a similar phenomenon for “exotic' dualizations, and we clarify this by comparing with the dualizations of the component fields. We close with some speculative remarks on the significance of these observations for the full non-linear theory yet to be constructed.

  18. Dual Criteria Decisions

    DEFF Research Database (Denmark)

    Andersen, Steffen; Harrison, Glenn W.; Lau, Morten Igel

    2014-01-01

    The most popular models of decision making use a single criterion to evaluate projects or lotteries. However, decision makers may actually consider multiple criteria when evaluating projects. We consider a dual criteria model from psychology. This model integrates the familiar tradeoffs between...... to the clear role that income thresholds play in such decision making, but does not rule out a role for tradeoffs between risk and utility or probability weighting....

  19. Dual isotope assays

    International Nuclear Information System (INIS)

    Smith, G.F.W.; Stevens, R.A.J.; Jacoby, B.

    1980-01-01

    Dual isotope assays for thyroid function are performed by carrying out a radio-immunoassay for two of thyroxine (T4), tri-iodothyronine (T3), thyroid stimulating hormone (TSH), and thyroxine binding globulin (TBG), by a method wherein a version of one of the thyroid components, preferably T4 or T3 is labelled with Selenium-75 and the version of the other thyroid component is labelled with a different radionuclide, preferably Iodine-125. (author)

  20. Towards a Dual Approach

    DEFF Research Database (Denmark)

    Holli, Anne Maria; Harder, Mette Marie Stæhr

    2016-01-01

    Drawing on insights from state feminism and legislative studies on parliamentary committees, this article develops a dual approach for the comparative analysis of committees on gender equality. Empirically, it compares the standing committees on gender equality in Denmark and Finland, two Nordic...... as measured by legislative outputs and oversight differs, however, in line with differing committee system characteristics: the Finnish committee has more impact on legislative outputs while the Danish committee has more impact on overseeing government....

  1. Dual-Schemata Model

    Science.gov (United States)

    Taniguchi, Tadahiro; Sawaragi, Tetsuo

    In this paper, a new machine-learning method, called Dual-Schemata model, is presented. Dual-Schemata model is a kind of self-organizational machine learning methods for an autonomous robot interacting with an unknown dynamical environment. This is based on Piaget's Schema model, that is a classical psychological model to explain memory and cognitive development of human beings. Our Dual-Schemata model is developed as a computational model of Piaget's Schema model, especially focusing on sensori-motor developing period. This developmental process is characterized by a couple of two mutually-interacting dynamics; one is a dynamics formed by assimilation and accommodation, and the other dynamics is formed by equilibration and differentiation. By these dynamics schema system enables an agent to act well in a real world. This schema's differentiation process corresponds to a symbol formation process occurring within an autonomous agent when it interacts with an unknown, dynamically changing environment. Experiment results obtained from an autonomous facial robot in which our model is embedded are presented; an autonomous facial robot becomes able to chase a ball moving in various ways without any rewards nor teaching signals from outside. Moreover, emergence of concepts on the target movements within a robot is shown and discussed in terms of fuzzy logics on set-subset inclusive relationships.

  2. CFT duals for extreme black holes

    International Nuclear Information System (INIS)

    Hartman, Thomas; Strominger, Andrew; Murata, Keiju; Nishioka, Tatsuma

    2009-01-01

    It is argued that the general four-dimensional extremal Kerr-Newman-AdS-dS black hole is holographically dual to a (chiral half of a) two-dimensional CFT, generalizing an argument given recently for the special case of extremal Kerr. Specifically, the asymptotic symmetries of the near-horizon region of the general extremal black hole are shown to be generated by a Virasoro algebra. Semiclassical formulae are derived for the central charge and temperature of the dual CFT as functions of the cosmological constant, Newton's constant and the black hole charges and spin. We then show, assuming the Cardy formula, that the microscopic entropy of the dual CFT precisely reproduces the macroscopic Bekenstein-Hawking area law. This CFT description becomes singular in the extreme Reissner-Nordstrom limit where the black hole has no spin. At this point a second dual CFT description is proposed in which the global part of the U(1) gauge symmetry is promoted to a Virasoro algebra. This second description is also found to reproduce the area law. Various further generalizations including higher dimensions are discussed.

  3. Synchronous colonic tumours of dual pathology.

    Science.gov (United States)

    Basu, S; Selvachandran, S N; Cade, D

    2001-05-01

    Synchronous colonic tumours of dual pathology are extremely rare. A review of the literature revealed that few cases have been reported to date. Because of their rarity and lack of specific symptoms, preoperative diagnosis is not easy and there is no protocol as yet for the ideal management of these cases. We present such a case which was treated by a combination of surgery and chemotherapy.

  4. Dual-Military Couples, Child Care and Retention

    Science.gov (United States)

    2016-04-01

    ACSC/Williams, Ja Rai A./AY16 1 AIR COMMAND AND STAFF COLLEGE AIR UNIVERSITY Dual-Military Couples, Child Care & Retention...academic research paper are those of the author( s ) and do not reflect the official policy or position of the US government or the Department of Defense...inclusion. A number of Airmen are married to other military members—a phenomenon coined as “dual-military” marriages. Specifically, 11.3% (35,239) of

  5. New Fukui, dual and hyper-dual kernels as bond reactivity descriptors.

    Science.gov (United States)

    Franco-Pérez, Marco; Polanco-Ramírez, Carlos-A; Ayers, Paul W; Gázquez, José L; Vela, Alberto

    2017-06-21

    We define three new linear response indices with promising applications for bond reactivity using the mathematical framework of τ-CRT (finite temperature chemical reactivity theory). The τ-Fukui kernel is defined as the ratio between the fluctuations of the average electron density at two different points in the space and the fluctuations in the average electron number and is designed to integrate to the finite-temperature definition of the electronic Fukui function. When this kernel is condensed, it can be interpreted as a site-reactivity descriptor of the boundary region between two atoms. The τ-dual kernel corresponds to the first order response of the Fukui kernel and is designed to integrate to the finite temperature definition of the dual descriptor; it indicates the ambiphilic reactivity of a specific bond and enriches the traditional dual descriptor by allowing one to distinguish between the electron-accepting and electron-donating processes. Finally, the τ-hyper dual kernel is defined as the second-order derivative of the Fukui kernel and is proposed as a measure of the strength of ambiphilic bonding interactions. Although these quantities have never been proposed, our results for the τ-Fukui kernel and for τ-dual kernel can be derived in zero-temperature formulation of the chemical reactivity theory with, among other things, the widely-used parabolic interpolation model.

  6. Short-versus long-term Dual Antiplatelet therapy after drug-eluting stent implantation in women versus men: A sex-specific patient-level pooled-analysis of six randomized trials.

    Science.gov (United States)

    Sawaya, Fadi J; Morice, Marie-Claude; Spaziano, Marco; Mehran, Roxana; Didier, Romain; Roy, Andrew; Valgimigli, Marco; Kim, Hyo-Soo; Woo Park, Kyung; Hong, Myeong-Ki; Kim, Byeong-Keuk; Jang, Yangsoo; Feres, Fausto; Abizaid, Alexandre; Costa, Ricardo A; Colombo, Antonio; Chieffo, Alaide; Giustino, Gennaro; Stone, Gregg W; Bhatt, Deepak L; Palmerini, Tullio; Gilard, Martine

    2017-02-01

    Whether the efficacy and safety of dual antiplatelet therapy (DAPT) are uniform between sexes is unclear. We sought to compare clinical outcomes between short- (≤6 months) versus long-term (≥1 year) DAPT after drug-eluting stent (DES) placement in women and men. We pooled individual patient data from 6 randomized trials of DAPT (EXCELLENT, OPTIMIZE, PRODIGY, RESET, SECURITY, ITALIC PLUS). The primary outcome was 1-year risk of major adverse cardiac events (MACE). The main secondary outcome was 1-year risk of any bleeding. Out of the 11,473 randomized patients included in the pooled dataset, 3,454 (30%) were females. At 1-year follow-up, women had higher risk of MACE (3.6% vs. 2.8%; P = 0.01) but similar risk of bleeding (1.9% vs. 1.6%; P = 0.16) as compared with men. Compared with long-term DAPT, short-term DAPT was associated with similar rates of MACE in both women (HR 0.88; 95% CI 0.62-1.25) and men (HR 1.25; 95% CI 0.95-1.6; P interaction = 0.08)]. At 1-year follow-up, short-term DAPT was associated with lower rates of bleeding as compared with long-term DAPT in both women (HR 0.84; 95% CI 0.51-1.37) and men (HR 0.58; 95% CI 0.40-0.84; P-interaction = 0.25). The presence of MVD was associated with higher MACE rates in the short-term DAPT group in women (HR: 1.16; CI 0.60-2.23) and men (HR: 2.29; CI 1.22-4.29; P interaction = 0.25). Short-term DAPT is associated with similar rates of MACE but lower risk of bleeding when as compared with prolonged DAPT. There was no significant difference between sexes in the population studied. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  7. Dual Smarandache Curves of a Timelike Curve lying on Unit dual Lorentzian Sphere

    OpenAIRE

    Kahraman, Tanju; Hüseyin Ugurlu, Hasan

    2016-01-01

    In this paper, we give Darboux approximation for dual Smarandache curves of time like curve on unit dual Lorentzian sphere. Firstly, we define the four types of dual Smarandache curves of a timelike curve lying on dual Lorentzian sphere.

  8. Spinning self-dual particles

    International Nuclear Information System (INIS)

    Gamboa, J.; Rivelles, V.O.

    1989-02-01

    We study spinning self-dual particles in two dimensions. They are obtained from the chiral bosonic particle through the square root technique. We show that the resulting field theory can be either fermionic or bosonic and that the associated self-dual field reveals its Lorentz tensor structure which remains hidden in the usual formulations. We also calculate the spinning self-dual particle propagators using the BFV formalism. (author) [pt

  9. Adolescents and Dual Diagnosis in a Psychiatric Emergency Service.

    Science.gov (United States)

    Matali, José Luis; Andión, Oscar; Pardo, Marta; Iniesta, Raquel; Serrano, Eduard; San, Luis

    2016-03-02

    In recent years, both the prevalence of drug use and related child and adolescent psychiatric emergencies have risen sharply. There are few studies about the impact on child and adolescent emergency services. This study has a twofold aim. The first is to describe the prevalence of substance use disorders, mental disorders and dual diagnosis (substance use problems plus mental disorder) in adolescents in psychiatric emergency service. The second is to analyze clinical and healthcare differences between patients with dual diagnosis and patients with a mental disorder without substance use disorder.We retrospectively reviewed 4012 discharge forms for emergencies treated at the psychiatric emergency department during the period 2007-2009. We obtained a sample of 1795 visits. This sample was divided into two groups: the dual diagnosis group (n = 477) and the psychiatric disorder group (n = 1318).The dual diagnosis group accounted for 26.5% of psychiatric emergencies analyzed. Compared to the psychiatric disorder group,the dual diagnosis group had significantly more conduct disorders, social problems, involuntariness in the visit, less hospital admissions and less connection with the healthcare network.Adolescents with a dual diagnosis account for a high percentage of visits at child and adolescent psychiatric emergency services. This patient group requires specialized care both at emergency services and in specific units. Accordingly, these units should play a triple role when handling dual diagnosis: detection, brief treatment and referral to a specialised unit.

  10. Dual Arm Work Module Development and Appplications

    Energy Technology Data Exchange (ETDEWEB)

    Noakes, M.W.

    1999-04-25

    The dual arm work module (DAWM) was developed at Oak Ridge National Laboratory (ORNL) by the Robotics Technology Development Program (RTDP) as a development test bed to study issues related to dual arm manipulation, including platform cotilguration, controls, automation, operations, and tooling. The original platform was based on two Schilling Titan II manipulators mounted to a 5-degree-of- freedom (DOF) base fabricated by RedZone Robotics, Inc. The 5-DOF articulation provided a center torso rotation, linear actuation to change the separation between the arms, and arm base rotation joints to provide "elbows up," elbows down," or "elbows out" orientation. A series of tests were conducted on operations, tooling, and task space scene analysis (TSSA)-driven robotics for overhead transporter- mounted and crane hook-deployed scenarios. A concept was developed for DAWM deployment from a large remote work vehicle, but the project was redirected to support dismantlement of the Chicago Pile #5 (CP-5) reactor at Argonne National Laboratory in fiscal year (FY) 1997. Support of CP-5 required a change in focus of the dual arm technology from that of a development test bed to a system focussed for a specific end user. ORNL teamed with the Idaho National Environmental ,Engineering Laboratory, Sandia National Laboratory, and the Savannah River Technology Center to deliver a crane-deployed derivative of the DAWM, designated the dual arm work platform (DAWP). RTDP staff supported DAWP at CP-5 for one FY; Argonne staff continued operation through to dismantlement of the reactor internals. Lessons learned from this interaction were extensive. Beginning in FY 1999, dual arm development activities are again being pursued in the context of those lessons learned. This paper describes the progression of philosophy of the DAWM from initial test bed to lessons learned through interaction at CP-5 and to the present investigation of telerobotic assist of teleoperation and TSSA- driven robotics.

  11. Dual symmetry in gauge theories

    International Nuclear Information System (INIS)

    Koshkarov, A.L.

    1997-01-01

    Continuous dual symmetry in electrodynamics, Yang-Mills theory and gravitation is investigated. Dual invariant which leads to badly nonlinear motion equations is chosen as a Lagrangian of the pure classical dual nonlinear electrodynamics. In a natural manner some dual angle which is determined by the electromagnetic strengths at the point of the time-space appears in the model. Motion equations may well be interpreted as the equations of the standard Maxwell theory with source. Alternative interpretation is the quasi-Maxwell linear theory with magnetic charge. Analogous approach is possible in the Yang-Mills theory. In this case the dual-invariant non-Abelian theory motion equations possess the same instanton solutions as the conventional Yang-Mills equations have. An Abelian two-parameter dual group is found to exist in gravitation. Irreducible representations have been obtained: the curvature tensor was expanded into the sum of twice anti-self-dual and self-dual parts. Gravitational instantons are defined as (real )solutions to the usual duality equations. Central symmetry solutions to these equations are obtained. The twice anti-self-dual part of the curvature tensor may be used for introduction of new gravitational equations generalizing Einstein''s equations. However, the theory obtained reduces to the conformal-flat Nordstroem theory

  12. Dual-beam CRT

    International Nuclear Information System (INIS)

    1975-01-01

    A dual-beam cathode-ray tube having a pair of electron guns and associated deflection means disposed side-by-side on each side of a central axis is described. The electron guns are parallel and the deflection means includes beam centering plates and angled horizontal deflection plates to direct the electron beams toward the central axis, precluding the need for a large-diameter tube neck in which the entire gun structures are angled. Bowing control plates are disposed adjacent to the beam centering plates to minimize trace bowing, and an intergun shield is disposed between the horizontal deflection plates to control and correct display pattern geometry distortion

  13. Dual energy cardiac CT.

    Science.gov (United States)

    Carrascosa, Patricia; Deviggiano, Alejandro; Rodriguez-Granillo, Gastón

    2017-06-01

    Conventional single energy CT suffers from technical limitations related to the polychromatic nature of X-rays. Dual energy cardiac CT (DECT) shows promise to attenuate and even overcome some of these limitations, and might broaden the scope of patients eligible for cardiac CT towards the inclusion of higher risk patients. This might be achieved as a result of both safety (contrast reduction) and physiopathological (myocardial perfusion and characterization) issues. In this article, we will review the main clinical cardiac applications of DECT, that can be summarized in two core aspects: coronary artery evaluation, and myocardial evaluation.

  14. Self-dual metrics with self-dual Killing vectors

    International Nuclear Information System (INIS)

    Tod, K.P.; Ward, R.S.

    1979-01-01

    Twistor methods are used to derive a class of solutions to Einstein's vacuum equations, with anti-self dual Weyl tensor. In particular, all metrics with a Killing vector whose derivative is anti-self-dual and which admit a real positive-definite section are exhibited and shown to coincide with the metrics of Hawking. (author)

  15. Ghost free dual vector theories in 2+1 dimensions

    International Nuclear Information System (INIS)

    Dalmazi, Denis

    2006-01-01

    We explore here the issue of duality versus spectrum equivalence in dual theories generated through the master action approach. Specifically we examine a generalized self-dual (GSD) model where a Maxwell term is added to the self-dual model. A gauge embedding procedure applied to the GSD model leads to a Maxwell-Chern-Simons (MCS) theory with higher derivatives. We show here that the latter contains a ghost mode contrary to the original GSD model. By figuring out the origin of the ghost we are able to suggest a new master action which interpolates between the local GSD model and a nonlocal MCS model. Those models share the same spectrum and are ghost free. Furthermore, there is a dual map between both theories at classical level which survives quantum correlation functions up to contact terms. The remarks made here may be relevant for other applications of the master action approach

  16. Dynamical chiral-symmetry breaking in dual QCD

    International Nuclear Information System (INIS)

    Krein, G.; Williams, A.G.

    1991-01-01

    We have extended recent studies by Baker, Ball, and Zachariasen (BBZ) of dynamical chiral-symmetry breaking in dual QCD. Specifically, we have taken dual QCD to specify the nonperturbative infrared nature of the quark-quark interaction and then we have smoothly connected onto this the known leading-log perturbative QCD interaction in the ultraviolet region. In addition, we have solved for a momentum-dependent self-energy and have used the complete lowest-order dual QCD quark-quark interaction. We calculate the quark condensate left-angle bar qq right-angle and the pion decay constant f π within this model. We find that the dual QCD parameters needed to give acceptable results are reasonably consistent with those extracted from independent physical considerations by BBZ

  17. Development of Dual Power Multirotor System

    Directory of Open Access Journals (Sweden)

    Chin E. Lin

    2017-01-01

    Full Text Available Vertical take-off and landing (VTOL aircraft has good flight characteristics and system performance without runway. The multirotor system has been tried to expand into larger size for longer endurance or higher payload. But the motor power to endurance ratio has been limited. Due to the specific energy of gasoline being much higher than battery, introducing gasoline engine into multirotor system can be considered. This paper proposes a dual power multirotor system to combine a quadrotor using gasoline engines to provide major lift in shorter arm with another quadrotor using brushless DC motors to offer most controllable force with longer arm. System design, fabrication, and verification of the proposed dual power multirotor system development are presented. Preliminary flights have achieved 16 kg payload for long endurance flight. This is useful for various applications with advanced improvements.

  18. Prospective Randomized Phase 2 Trial of Intensity Modulated Radiation Therapy With or Without Oncolytic Adenovirus-Mediated Cytotoxic Gene Therapy in Intermediate-Risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Freytag, Svend O., E-mail: sfreyta1@hfhs.org [Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan (United States); Stricker, Hans [Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan (United States); Lu, Mei [Public Health Sciences, Henry Ford Health System, Detroit, Michigan (United States); Elshaikh, Mohamed; Aref, Ibrahim; Pradhan, Deepak; Levin, Kenneth; Kim, Jae Ho [Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan (United States); Peabody, James [Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan (United States); Siddiqui, Farzan; Barton, Kenneth; Pegg, Jan; Zhang, Yingshu; Cheng, Jingfang [Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan (United States); Oja-Tebbe, Nancy; Bourgeois, Renee [Public Health Sciences, Henry Ford Health System, Detroit, Michigan (United States); Gupta, Nilesh; Lane, Zhaoli [Pathology, Henry Ford Health System, Detroit, Michigan (United States); Rodriguez, Ron [Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); DeWeese, Theodore [Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); and others

    2014-06-01

    Purpose: To assess the safety and efficacy of combining oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) with intensity modulated radiation therapy (IMRT) in intermediate-risk prostate cancer. Methods and Materials: Forty-four men with intermediate-risk prostate cancer were randomly assigned to receive either OAMCGT plus IMRT (arm 1; n=21) or IMRT only (arm 2; n=23). The primary phase 2 endpoint was acute (≤90 days) toxicity. Secondary endpoints included quality of life (QOL), prostate biopsy (12-core) positivity at 2 years, freedom from biochemical/clinical failure (FFF), freedom from metastases, and survival. Results: Men in arm 1 exhibited a greater incidence of low-grade influenza-like symptoms, transaminitis, neutropenia, and thrombocytopenia than men in arm 2. There were no significant differences in gastrointestinal or genitourinary events or QOL between the 2 arms. Two-year prostate biopsies were obtained from 37 men (84%). Thirty-three percent of men in arm 1 were biopsy-positive versus 58% in arm 2, representing a 42% relative reduction in biopsy positivity in the investigational arm (P=.13). There was a 60% relative reduction in biopsy positivity in the investigational arm in men with <50% positive biopsy cores at baseline (P=.07). To date, 1 patient in each arm exhibited biochemical failure (arm 1, 4.8%; arm 2, 4.3%). No patient developed hormone-refractory or metastatic disease, and none has died from prostate cancer. Conclusions: Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer.

  19. Chimeric HCMV/HSV-1 and Δγ134.5 oncolytic herpes simplex virus elicit immune mediated antigliomal effect and antitumor memory

    Directory of Open Access Journals (Sweden)

    Mohammed G. Ghonime

    2018-02-01

    Full Text Available Malignant gliomas are the most common primary brain tumor and are characterized by rapid and highly invasive growth. Because of their poor prognosis, new therapeutic strategies are needed. Oncolytic virotherapy (OV is a promising strategy for treating cancer that incorporates both direct viral replication mediated and immune mediated mechanisms to kill tumor cells. C134 is a next generation Δγ134.5 oHSV-1 with improved intratumoral viral replication. It remains safe in the CNS environment by inducing early IFN signaling which restricts its replication in non-malignant cells. We sought to identify how C134 performed in an immunocompetent tumor model that restricts its replication advantage over first generation viruses. To achieve this we identified tumors that have intact IFN signaling responses that restrict C134 and first generation virus replication similarly. Our results show that both viruses elicit a T cell mediated anti-tumor effect and improved animal survival but that subtle difference exist between the viruses effect on median survival despite equivalent in vivo viral replication. To further investigate this we examined the anti-tumor activity in immunodeficient mice and in syngeneic models with re-challenge. These studies show that the T cell response is integral to C134 replication independent anti-tumor response and that OV therapy elicits a durable and circulating anti-tumor memory. The studies also show that repeated intratumoral administration can extend both OV anti-tumor effects and induce durable anti-tumor memory that is superior to tumor antigen exposure alone.

  20. Pediatric medulloblastoma xenografts including molecular subgroup 3 and CD133+ and CD15+ cells are sensitive to killing by oncolytic herpes simplex viruses.

    Science.gov (United States)

    Friedman, Gregory K; Moore, Blake P; Nan, Li; Kelly, Virginia M; Etminan, Tina; Langford, Catherine P; Xu, Hui; Han, Xiaosi; Markert, James M; Beierle, Elizabeth A; Gillespie, G Yancey

    2016-02-01

    Childhood medulloblastoma is associated with significant morbidity and mortality that is compounded by neurotoxicity for the developing brain caused by current therapies, including surgery, craniospinal radiation, and chemotherapy. Innate therapeutic resistance of some aggressive pediatric medulloblastoma has been attributed to a subpopulation of cells, termed cancer-initiating cells or cancer stemlike cells (CSCs), marked by the surface protein CD133 or CD15. Brain tumors characteristically contain areas of pathophysiologic hypoxia, which has been shown to drive the CSC phenotype leading to heightened invasiveness, angiogenesis, and metastasis. Novel therapies that target medulloblastoma CSCs are needed to improve outcomes and decrease toxicity. We hypothesized that oncolytic engineered herpes simplex virus (oHSV) therapy could effectively infect and kill pediatric medulloblastoma cells, including CSCs marked by CD133 or CD15. Using 4 human pediatric medulloblastoma xenografts, including 3 molecular subgroup 3 tumors, which portend worse patient outcomes, we determined the expression of CD133, CD15, and the primary HSV-1 entry molecule nectin-1 (CD111) by fluorescence activated cell sorting (FACS) analysis. Infectability and cytotoxicity of clinically relevant oHSVs (G207 and M002) were determined in vitro and in vivo by FACS, immunofluorescent staining, cytotoxicity assays, and murine survival studies. We demonstrate that hypoxia increased the CD133+ cell fraction, while having the opposite effect on CD15 expression. We established that all 4 xenografts, including the CSCs, expressed CD111 and were highly sensitive to killing by G207 or M002. Pediatric medulloblastoma, including Group 3 tumors, may be an excellent target for oHSV virotherapy, and a clinical trial in medulloblastoma is warranted. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  1. Prospective Randomized Phase 2 Trial of Intensity Modulated Radiation Therapy With or Without Oncolytic Adenovirus-Mediated Cytotoxic Gene Therapy in Intermediate-Risk Prostate Cancer

    International Nuclear Information System (INIS)

    Freytag, Svend O.; Stricker, Hans; Lu, Mei; Elshaikh, Mohamed; Aref, Ibrahim; Pradhan, Deepak; Levin, Kenneth; Kim, Jae Ho; Peabody, James; Siddiqui, Farzan; Barton, Kenneth; Pegg, Jan; Zhang, Yingshu; Cheng, Jingfang; Oja-Tebbe, Nancy; Bourgeois, Renee; Gupta, Nilesh; Lane, Zhaoli; Rodriguez, Ron; DeWeese, Theodore

    2014-01-01

    Purpose: To assess the safety and efficacy of combining oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) with intensity modulated radiation therapy (IMRT) in intermediate-risk prostate cancer. Methods and Materials: Forty-four men with intermediate-risk prostate cancer were randomly assigned to receive either OAMCGT plus IMRT (arm 1; n=21) or IMRT only (arm 2; n=23). The primary phase 2 endpoint was acute (≤90 days) toxicity. Secondary endpoints included quality of life (QOL), prostate biopsy (12-core) positivity at 2 years, freedom from biochemical/clinical failure (FFF), freedom from metastases, and survival. Results: Men in arm 1 exhibited a greater incidence of low-grade influenza-like symptoms, transaminitis, neutropenia, and thrombocytopenia than men in arm 2. There were no significant differences in gastrointestinal or genitourinary events or QOL between the 2 arms. Two-year prostate biopsies were obtained from 37 men (84%). Thirty-three percent of men in arm 1 were biopsy-positive versus 58% in arm 2, representing a 42% relative reduction in biopsy positivity in the investigational arm (P=.13). There was a 60% relative reduction in biopsy positivity in the investigational arm in men with <50% positive biopsy cores at baseline (P=.07). To date, 1 patient in each arm exhibited biochemical failure (arm 1, 4.8%; arm 2, 4.3%). No patient developed hormone-refractory or metastatic disease, and none has died from prostate cancer. Conclusions: Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer

  2. Dual Coding and Bilingual Memory.

    Science.gov (United States)

    Paivio, Allan; Lambert, Wallace

    1981-01-01

    Describes study which tested a dual coding approach to bilingual memory using tasks that permit comparison of the effects of bilingual encoding with verbal-nonverbal dual encoding items. Results provide strong support for a version of the independent or separate stories view of bilingual memory. (Author/BK)

  3. Dual Coding, Reasoning and Fallacies.

    Science.gov (United States)

    Hample, Dale

    1982-01-01

    Develops the theory that a fallacy is not a comparison of a rhetorical text to a set of definitions but a comparison of one person's cognition with another's. Reviews Paivio's dual coding theory, relates nonverbal coding to reasoning processes, and generates a limited fallacy theory based on dual coding theory. (PD)

  4. Dual-core Itanium Processor

    CERN Multimedia

    2006-01-01

    Intel’s first dual-core Itanium processor, code-named "Montecito" is a major release of Intel's Itanium 2 Processor Family, which implements the Intel Itanium architecture on a dual-core processor with two cores per die (integrated circuit). Itanium 2 is much more powerful than its predecessor. It has lower power consumption and thermal dissipation.

  5. Lister vaccine strain of vaccinia virus armed with the endostatin-angiostatin fusion gene: an oncolytic virus superior to dl1520 (ONYX-015) for human head and neck cancer.

    Science.gov (United States)

    Tysome, James R; Wang, Pengju; Alusi, Ghassan; Briat, Arnaud; Gangeswaran, Rathi; Wang, Jiwei; Bhakta, Vipul; Fodor, Istvan; Lemoine, Nick R; Wang, Yaohe

    2011-09-01

    Oncolytic viral therapy represents a promising strategy for the treatment of head and neck squamous cell carcinoma (HNSCC), with dl1520 (ONYX-015) the most widely used oncolytic adenovirus in clinical trials. This study aimed to determine the effectiveness of the Lister vaccine strain of vaccinia virus as well as a vaccinia virus armed with the endostatin-angiostatin fusion gene (VVhEA) as a novel therapy for HNSCC and to compare them with dl1520. The potency and replication of the Lister strain and VVhEA and the expression and function of the fusion protein were determined in human HNSCC cells in vitro and in vivo. Finally, the efficacy of VVhEA was compared with dl1520 in vivo in a human HNSCC model. The Lister vaccine strain of vaccinia virus was more effective than the adenovirus against all HNSCC cell lines tested in vitro. Although the potency of VVhEA was attenuated in vitro, the expression and function of the endostatin-angiostatin fusion protein was confirmed in HNSCC models both in vitro and in vivo. This novel vaccinia virus (VVhEA) demonstrated superior antitumor potency in vivo compared with both dl1520 and the control vaccinia virus. This study suggests that the Lister strain vaccinia virus armed with an endostatin-angiostatin fusion gene may be a potential therapeutic agent for HNSCC.

  6. Image quality optimization and evaluation of linearly mixed images in dual-source, dual-energy CT

    International Nuclear Information System (INIS)

    Yu Lifeng; Primak, Andrew N.; Liu Xin; McCollough, Cynthia H.

    2009-01-01

    In dual-source dual-energy CT, the images reconstructed from the low- and high-energy scans (typically at 80 and 140 kV, respectively) can be mixed together to provide a single set of non-material-specific images for the purpose of routine diagnostic interpretation. Different from the material-specific information that may be obtained from the dual-energy scan data, the mixed images are created with the purpose of providing the interpreting physician a single set of images that have an appearance similar to that in single-energy images acquired at the same total radiation dose. In this work, the authors used a phantom study to evaluate the image quality of linearly mixed images in comparison to single-energy CT images, assuming the same total radiation dose and taking into account the effect of patient size and the dose partitioning between the low-and high-energy scans. The authors first developed a method to optimize the quality of the linearly mixed images such that the single-energy image quality was compared to the best-case image quality of the dual-energy mixed images. Compared to 80 kV single-energy images for the same radiation dose, the iodine CNR in dual-energy mixed images was worse for smaller phantom sizes. However, similar noise and similar or improved iodine CNR relative to 120 kV images could be achieved for dual-energy mixed images using the same total radiation dose over a wide range of patient sizes (up to 45 cm lateral thorax dimension). Thus, for adult CT practices, which primarily use 120 kV scanning, the use of dual-energy CT for the purpose of material-specific imaging can also produce a set of non-material-specific images for routine diagnostic interpretation that are of similar or improved quality relative to single-energy 120 kV scans.

  7. Low-Profile, Dual-Wavelength, Dual-Polarized Antenna

    Science.gov (United States)

    Carswell, James R.

    2010-01-01

    A single-aperture, low-profile antenna design has been developed that supports dual-polarization and simultaneous operation at two wavelengths. It realizes multiple beams in the elevation plane, and supports radiometric, radar, and conical scanning applications. This antenna consists of multiple azimuth sticks, with each stick being a multilayer, hybrid design. Each stick forms the h-plane pattern of the C and Ku-band vertically and horizontally polarized antenna beams. By combining several azimuth sticks together, the elevation beam is formed. With a separate transceiver for each stick, the transmit phase and amplitude of each stick can be controlled to synthesize a beam at a specific incidence angle and to realize a particular side-lobe pattern. By changing the transmit phase distribution through the transceivers, the transmit antenna beam can be steered to different incidence angles. By controlling the amplitude distribution, different side lobe patterns and efficiencies can be realized. The receive beams are formed using digital beam synthesis techniques, resulting in very little loss in the receive path, thus enabling a very-low loss receive antenna to support passive measurements.

  8. Dual THz comb spectroscopy

    Science.gov (United States)

    Yasui, Takeshi

    2017-08-01

    Optical frequency combs are innovative tools for broadband spectroscopy because a series of comb modes can serve as frequency markers that are traceable to a microwave frequency standard. However, a mode distribution that is too discrete limits the spectral sampling interval to the mode frequency spacing even though individual mode linewidth is sufficiently narrow. Here, using a combination of a spectral interleaving and dual-comb spectroscopy in the terahertz (THz) region, we achieved a spectral sampling interval equal to the mode linewidth rather than the mode spacing. The spectrally interleaved THz comb was realized by sweeping the laser repetition frequency and interleaving additional frequency marks. In low-pressure gas spectroscopy, we achieved an improved spectral sampling density of 2.5 MHz and enhanced spectral accuracy of 8.39 × 10-7 in the THz region. The proposed method is a powerful tool for simultaneously achieving high resolution, high accuracy, and broad spectral coverage in THz spectroscopy.

  9. Dual Tank Fuel System

    Science.gov (United States)

    Wagner, Richard William; Burkhard, James Frank; Dauer, Kenneth John

    1999-11-16

    A dual tank fuel system has primary and secondary fuel tanks, with the primary tank including a filler pipe to receive fuel and a discharge line to deliver fuel to an engine, and with a balance pipe interconnecting the primary tank and the secondary tank. The balance pipe opens close to the bottom of each tank to direct fuel from the primary tank to the secondary tank as the primary tank is filled, and to direct fuel from the secondary tank to the primary tank as fuel is discharged from the primary tank through the discharge line. A vent line has branches connected to each tank to direct fuel vapor from the tanks as the tanks are filled, and to admit air to the tanks as fuel is delivered to the engine.

  10. Dual coolant blanket concept

    International Nuclear Information System (INIS)

    Malang, S.; Schleisiek, K.

    1994-11-01

    A self-cooled liquid metal breeder blanket with helium-cooled first wall ('Dual Coolant Blanket Concept') for a fusion DEMO reactor is described. This is one of the four blanket concepts under development in the frame of the European fusion technology program with the aim to select in 1995 the two most promising ones for further development. Described are the design of the blankets including the ancillary loop system and the results of the theoretical and experimental work in the fields of neutronics, magnetohydrodynamics, thermohydraulics, mechanical stresses, compatibility and purification of lead-lithium, tritium control, safety, reliability, and electrically insulating coatings. The remaining open questions and the required R and D programme are identified. (orig.) [de

  11. Baryons and dual unitarization

    International Nuclear Information System (INIS)

    Konishi, K.-I.

    1977-05-01

    Processes involving baryons are discussed in the scheme of dual unitarization. In particular, the topological expansion is generalized to any hadronic S-matrix elements involving baryons and/or mesons. The expansion is based on a model for the baryon propagator, which is a set of three planar Feynman diagrams joined at a junction line. The resulting expansion is a double expansion in 1/N (N = the number of quark flavours) and in the number of baryon loops. Based on this, several new observations are made in phenomenological problems, and a unifying point of view in stressed. The scheme is evidently crossing invariant, and unitarity constraints are imposed order by order in 1/N and in the baryon loop number. (author)

  12. Motor-cognitive dual-task deficits in individuals with early-mid stage Huntington disease.

    Science.gov (United States)

    Fritz, Nora E; Hamana, Katy; Kelson, Mark; Rosser, Anne; Busse, Monica; Quinn, Lori

    2016-09-01

    Huntington disease (HD) results in a range of cognitive and motor impairments that progress throughout the disease stages; however, little research has evaluated specific dual-task abilities in this population, and the degree to which they may be related to functional ability. The purpose of this study was to a) examine simple and complex motor-cognitive dual-task performance in individuals with HD, b) determine relationships between dual-task walking ability and disease-specific measures of motor, cognitive and functional ability, and c) examine the relationship of dual-task measures to falls in individuals with HD. Thirty-two individuals with HD were evaluated for simple and complex dual-task ability using the Walking While Talking Test. Demographics and disease-specific measures of motor, cognitive and functional ability were also obtained. Individuals with HD had impairments in simple and complex dual-task ability. Simple dual-task walking was correlated to disease-specific motor scores as well as cognitive performance, but complex dual-task walking was correlated with total functional capacity, as well as a range of cognitive measures. Number of prospective falls was moderately-strongly correlated to dual-task measures. Our results suggest that individuals with HD have impairments in cognitive-motor dual-task ability that are related to disease progression and specifically functional ability. Dual-task measures appear to evaluate a unique construct in individuals with early to mid-stage HD, and may have value in improving the prediction of falls risk in this population. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. The Power of Integrators, Financiers, and Insurers to Reduce Proliferation Risks: Nuclear Dual-Use Goods

    Energy Technology Data Exchange (ETDEWEB)

    Weise, Rachel A. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Hund, Gretchen [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2015-05-01

    Globalization of manufacturing supply chains has changed the nature of nuclear proliferation. Before 1991, nonproliferation efforts focused almost exclusively on limiting the spread of materials and equipment specifically designed for nuclear use -- reactors, centrifuges, and fissile material. Dual-use items, those items with both nuclear and non-nuclear applications, were not closely scrutinized or controlled. However, in 1991 the international community discovered that Iraq had developed a fairly sophisticated nuclear weapons program by importing dual-use items; this discovery spurred the international community to increase controls on dual-use technologies. Despite these international efforts, dual-use items are still a challenge for those seeking to limit proliferation.

  14. The Power of Integrators, Financiers, and Insurers to Reduce Proliferation Risks: Nuclear Dual-Use Goods

    International Nuclear Information System (INIS)

    Weise, Rachel A.; Hund, Gretchen

    2015-01-01

    Globalization of manufacturing supply chains has changed the nature of nuclear proliferation. Before 1991, nonproliferation efforts focused almost exclusively on limiting the spread of materials and equipment specifically designed for nuclear use -- reactors, centrifuges, and fissile material. Dual-use items, those items with both nuclear and non-nuclear applications, were not closely scrutinized or controlled. However, in 1991 the international community discovered that Iraq had developed a fairly sophisticated nuclear weapons program by importing dual-use items; this discovery spurred the international community to increase controls on dual-use technologies. Despite these international efforts, dual-use items are still a challenge for those seeking to limit proliferation.

  15. Dual-band dual-polarized array for WLAN applications

    CSIR Research Space (South Africa)

    Steyn, JM

    2009-01-01

    Full Text Available dual-band dual-polarized (DBDP) antenna design for WLAN applications. The antenna is in the form of an array consisting of four double-dipole radiators. The basic radiating element consists of a rhombus shaped dipole above a planar ground plane... the ground planes and the respective feedlines. Substrate cuts and difierent heights for the horizontal feedlines were necessary to achieve the latter. The 2nd conflguration (for vertical polarization) has a slightly difierent feeding network layout...

  16. Dual Credit Enrollment and GPA by Ethnicity and Gender at Texas 2-Year Colleges

    Science.gov (United States)

    Young, Robert D., Jr.

    2013-01-01

    Purpose: The purpose of this investigation was to determine the extent to which differences were present in dual credit course enrollment. Specifically examined were whether differences were present in the first semester GPA and at the end of the first two semesters for students who enrolled in dual credit courses while in high school from…

  17. Lp-dual affine surface area

    Science.gov (United States)

    Wei, Wang; Binwu, He

    2008-12-01

    According to the notion of Lp-affine surface area by Lutwak, in this paper, we introduce the concept of Lp-dual affine surface area. Further, we establish the affine isoperimetric inequality and the Blaschke-Santaló inequality for Lp-dual affine surface area. Besides, the dual Brunn-Minkowski inequality for Lp-dual affine surface area is presented.

  18. Dual of QCD with One Adjoint Fermion

    DEFF Research Database (Denmark)

    Mojaza, Matin; Nardecchia, Marco; Pica, Claudio

    2011-01-01

    We construct the magnetic dual of QCD with one adjoint Weyl fermion. The dual is a consistent solution of the 't Hooft anomaly matching conditions, allows for flavor decoupling and remarkably constitutes the first nonsupersymmetric dual valid for any number of colors. The dual allows to bound...

  19. Self-dual monopoles and toda molecules

    Science.gov (United States)

    Ganoulis, N.; Goddard, P.; Olive, D.

    1982-07-01

    Stable static solutions to a gauge field theory with a Higgs field in the adjoint representation and with vanishing self-coupling are self-dual in the sense of Bogomolny. Leznov and Saveliev showed that a specific form of spherical symmetry reduces these equations to a modified form of the Toda molecule equations associated with the overall gauge symmetry G. Values of the constants of integration are found in terms of the distant Higgs field, guaranteeing regularity of the solution at the origin. The expressions hold for any simple Lie group G, depending on G via its root system.

  20. The HDAC Inhibitors Scriptaid and LBH589 Combined with the Oncolytic Virus Delta24-RGD Exert Enhanced Anti-Tumor Efficacy in Patient-Derived Glioblastoma Cells.

    Directory of Open Access Journals (Sweden)

    Lotte M E Berghauser Pont

    Full Text Available A phase I/II trial for glioblastoma with the oncolytic adenovirus Delta24-RGD was recently completed. Delta24-RGD conditionally replicates in cells with a disrupted retinoblastoma-pathway and enters cells via αvβ3/5 integrins. Glioblastomas are differentially sensitive to Delta24-RGD. HDAC inhibitors (HDACi affect integrins and share common cell death pathways with Delta24-RGD. We studied the combination treatment effects of HDACi and Delta24-RGD in patient-derived glioblastoma stem-like cells (GSC, and we determined the most effective HDACi.SAHA, Valproic Acid, Scriptaid, MS275 and LBH589 were combined with Delta24-RGD in fourteen distinct GSCs. Synergy was determined by Chou Talalay method. Viral infection and replication were assessed using luciferase and GFP encoding vectors and hexon-titration assays. Coxsackie adenovirus receptor and αvβ3 integrin levels were determined by flow cytometry. Oncolysis and mechanisms of cell death were studied by viability, caspase-3/7, LDH and LC3B/p62, phospho-p70S6K. Toxicity was studied on normal human astrocytes. MGMT promotor methylation status, TCGA classification, Rb-pathway and integrin gene expression levels were assessed as markers of responsiveness.Scriptaid and LBH589 acted synergistically with Delta24-RGD in approximately 50% of the GSCs. Both drugs moderately increased αvβ3 integrin levels and viral infection in responding but not in non-responding GSCs. LBH589 moderately increased late viral gene expression, however, virus titration revealed diminished viral progeny production by both HDACi, Scriptaid augmented caspase-3/7 activity, LC3B conversion, p62 and phospho-p70S6K consumption, as well as LDH levels. LBH589 increased LDH and phospho-p70S6K consumption. Responsiveness correlated with expression of various Rb-pathway genes and integrins. Combination treatments induced limited toxicity to human astrocytes.LBH589 and Scriptaid combined with Delta24-RGD revealed synergistic anti

  1. Symmetries of the dual metrics

    International Nuclear Information System (INIS)

    Baleanu, D.

    1998-01-01

    The geometric duality between the metric g μν and a Killing tensor K μν is studied. The conditions were found when the symmetries of the metric g μν and the dual metric K μν are the same. Dual spinning space was constructed without introduction of torsion. The general results are applied to the case of Kerr-Newmann metric

  2. Homogeneous M2 duals

    International Nuclear Information System (INIS)

    Figueroa-O’Farrill, José; Ungureanu, Mara

    2016-01-01

    Motivated by the search for new gravity duals to M2 branes with N>4 supersymmetry — equivalently, M-theory backgrounds with Killing superalgebra osp(N|4) for N>4 — we classify (except for a small gap) homogeneous M-theory backgrounds with symmetry Lie algebra so(n)⊕so(3,2) for n=5,6,7. We find that there are no new backgrounds with n=6,7 but we do find a number of new (to us) backgrounds with n=5. All backgrounds are metrically products of the form AdS 4 ×P 7 , with P riemannian and homogeneous under the action of SO(5), or S 4 ×Q 7 with Q lorentzian and homogeneous under the action of SO(3,2). At least one of the new backgrounds is supersymmetric (albeit with only N=2) and we show that it can be constructed from a supersymmetric Freund-Rubin background via a Wick rotation. Two of the new backgrounds have only been approximated numerically.

  3. Dual temperature concentration system

    International Nuclear Information System (INIS)

    Spevack, J.S.

    1975-01-01

    In a dual temperature isotope exchange system--exemplified by exchange of deuterium and protium between water and hydrogen sulfide gas in hot and cold towers, in which the feed stream (water) containing the desired isotope is passed through a pair of towers maintained at different temperatures wherein it effects isotope exchange with countercurrently circulated auxiliary fluid (H 2 S) and is impoverished in said isotope and then disposed of, e.g. discharged to waste,--the flow of isotope enriched auxiliary fluid between said towers (hot H 2 S saturated with water vapor) is divided and a part thereof is adjusted in its temperature (to cold tower conditions) and then passed to the auxiliary fluid impoverishing (cold) tower, while the remainder of the divided flow of such enriched auxiliary fluid is passed through a subsequent isotope concentration treatment to produce a product more highly enriched in the desired isotope and wherein it is also adjusted in its temperature and is impoverished in said isotope during said subsequent treatment before it is delivered to the said auxiliary fluid impoverishing (cold) tower. Certain provisions are made for returning to the hot tower liquid carried as vapor by the remainder of the divided flow to the subsequent isotope concentration treatment, for recovering sensible and latent heat, and for reducing passage of auxiliary fluid to waste

  4. Homogeneous M2 duals

    Energy Technology Data Exchange (ETDEWEB)

    Figueroa-O’Farrill, José [School of Mathematics and Maxwell Institute for Mathematical Sciences,The University of Edinburgh,James Clerk Maxwell Building, The King’s Buildings, Peter Guthrie Tait Road,Edinburgh EH9 3FD, Scotland (United Kingdom); Ungureanu, Mara [Humboldt-Universität zu Berlin, Institut für Mathematik,Unter den Linden 6, 10099 Berlin (Germany)

    2016-01-25

    Motivated by the search for new gravity duals to M2 branes with N>4 supersymmetry — equivalently, M-theory backgrounds with Killing superalgebra osp(N|4) for N>4 — we classify (except for a small gap) homogeneous M-theory backgrounds with symmetry Lie algebra so(n)⊕so(3,2) for n=5,6,7. We find that there are no new backgrounds with n=6,7 but we do find a number of new (to us) backgrounds with n=5. All backgrounds are metrically products of the form AdS{sub 4}×P{sup 7}, with P riemannian and homogeneous under the action of SO(5), or S{sup 4}×Q{sup 7} with Q lorentzian and homogeneous under the action of SO(3,2). At least one of the new backgrounds is supersymmetric (albeit with only N=2) and we show that it can be constructed from a supersymmetric Freund-Rubin background via a Wick rotation. Two of the new backgrounds have only been approximated numerically.

  5. Reasoning on the Autism Spectrum: A Dual Process Theory Account

    Science.gov (United States)

    Brosnan, Mark; Lewton, Marcus; Ashwin, Chris

    2016-01-01

    Dual process theory proposes two distinct reasoning processes in humans, an intuitive style that is rapid and automatic and a deliberative style that is more effortful. However, no study to date has specifically examined these reasoning styles in relation to the autism spectrum. The present studies investigated deliberative and intuitive reasoning…

  6. anti ee annihilation into hadrons from dual unitarisation

    International Nuclear Information System (INIS)

    Hong-mo, C.

    1976-09-01

    By grafting to the dual unitarisation scheme for hadron reactions a quark-current coupling suggested by the parton model, a model is obtained for anti ee annihilations in which the conversion of quarks into final hadrons is specific. As a first application, the correction to the value of R given by the parton model is estimated. (author)

  7. "Compromises That We Make": Whiteness in the Dual Language Context

    Science.gov (United States)

    Burns, Meg

    2017-01-01

    This case study of a two-way dual language school explores the role of whiteness in a bilingual space, specifically with regards to parent involvement. I ask how whiteness operates in this setting and how the school's response to parent involvement reflects and/or challenges white supremacy. Using the concept of "interest convergence"…

  8. The three dimensional dual of 4D chirality

    International Nuclear Information System (INIS)

    Porrati, M.; Girardello, L.

    2009-01-01

    Chiral gauge theories can be defined in four-dimensional Anti de Sitter space, but AdS boundary conditions explicitly break the chiral symmetry in a specific, well defined manner, which in turns results in an anomalous Ward identity. When the 4D theory admits a dual description in terms of a 3D CFT, the 3D dual of the broken chiral symmetry is a certain double-trace deformation of the CFT, which produces the same anomalous chiral Ward identities that obtains in the 4D bulk theory.

  9. Testing the Limits of Optimizing Dual-Task Performance in Younger and Older Adults

    Science.gov (United States)

    Strobach, Tilo; Frensch, Peter; Müller, Herrmann Josef; Schubert, Torsten

    2012-01-01

    Impaired dual-task performance in younger and older adults can be improved with practice. Optimal conditions even allow for a (near) elimination of this impairment in younger adults. However, it is unknown whether such (near) elimination is the limit of performance improvements in older adults. The present study tests this limit in older adults under conditions of (a) a high amount of dual-task training and (b) training with simplified component tasks in dual-task situations. The data showed that a high amount of dual-task training in older adults provided no evidence for an improvement of dual-task performance to the optimal dual-task performance level achieved by younger adults. However, training with simplified component tasks in dual-task situations exclusively in older adults provided a similar level of optimal dual-task performance in both age groups. Therefore through applying a testing the limits approach, we demonstrated that older adults improved dual-task performance to the same level as younger adults at the end of training under very specific conditions. PMID:22408613

  10. Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scFv against programmed cell death -1 (PD-1) allows their intratumoral delivery and an improved tumor-growth inhibition.

    Science.gov (United States)

    Kleinpeter, Patricia; Fend, Laetitia; Thioudellet, Christine; Geist, Michel; Sfrontato, Nathalie; Koerper, Véronique; Fahrner, Catherine; Schmitt, Doris; Gantzer, Murielle; Remy-Ziller, Christelle; Brandely, Renée; Villeval, Dominique; Rittner, Karola; Silvestre, Nathalie; Erbs, Philippe; Zitvogel, Laurence; Quéméneur, Eric; Préville, Xavier; Marchand, Jean-Baptiste

    2016-01-01

    We report here the successful vectorization of a hamster monoclonal IgG (namely J43) recognizing the murine Programmed cell death-1 (mPD-1) in Western Reserve (WR) oncolytic vaccinia virus. Three forms of mPD-1 binders have been inserted into the virus: whole antibody (mAb), Fragment antigen-binding (Fab) or single-chain variable fragment (scFv). MAb, Fab and scFv were produced and assembled with the expected patterns in supernatants of cells infected by the recombinant viruses. The three purified mPD-1 binders were able to block the binding of mPD-1 ligand to mPD-1 in vitro . Moreover, mAb was detected in tumor and in serum of C57BL/6 mice when the recombinant WR-mAb was injected intratumorally (IT) in B16F10 and MCA 205 tumors. The concentration of circulating mAb detected after IT injection was up to 1,900-fold higher than the level obtained after a subcutaneous (SC) injection (i.e., without tumor) confirming the virus tropism for tumoral cells and/or microenvironment. Moreover, the overall tumoral accumulation of the mAb was higher and lasted longer after IT injection of WR-mAb1, than after IT administration of 10 µg of J43. The IT injection of viruses induced a massive infiltration of immune cells including activated lymphocytes (CD8 + and CD4 + ). Interestingly, in the MCA 205 tumor model, WR-mAb1 and WR-scFv induced a therapeutic control of tumor growth similar to unarmed WR combined to systemically administered J43 and superior to that obtained with an unarmed WR. These results pave the way for next generation of oncolytic vaccinia armed with immunomodulatory therapeutic proteins such as mAbs.

  11. Switched diversity strategies for dual-hop amplify-and-forward relaying systems

    KAUST Repository

    Gaaloul, Fakhreddine; Radaydeh, Redha Mahmoud Mesleh; Alouini, Mohamed-Slim

    2012-01-01

    This study investigates different receive single-branch switch-based diversity schemes for dual-hop amplify-and-forward relaying networks. Specifically, three receive processing algorithms are adopted, in which the receive branch is selected using

  12. The First World War as Collapse Catalyst of Dual Monarchy Regime in Russia

    Directory of Open Access Journals (Sweden)

    Fomenkov А. А.

    2014-01-01

    Full Text Available The article is devoted to the specific features of the form of government in Russia in the years 1906–1917. The causes of the Dual Monarchy regime collapse in February 1917 have been revealed

  13. Measuring treatment effects on dual-task performance: a framework for research and clinical practice

    Directory of Open Access Journals (Sweden)

    Prudence ePlummer

    2015-04-01

    Full Text Available The relevance of dual-task walking to everyday ambulation is widely acknowledged, and numerous studies have demonstrated that dual-task interference can significantly impact recovery of functional walking in people with neurological disorders. The magnitude and direction of dual-task interference is influenced by the interaction between the two tasks, including how individuals spontaneously prioritize their attention. Therefore, to accurately interpret and characterize dual-task interference and identify changes over time, it is imperative to evaluate single and dual-task performance in both tasks, as well as the tasks relative to each other. Yet, reciprocal dual-task effects are frequently ignored. The purpose of this perspective paper is to present a framework for measuring treatment effects on dual-task interference, specifically taking into account the interactions between the two tasks and how this can provide information on whether overall dual-task capacity has improved or a different attentional strategy has been adopted. In discussing the clinical implications of using this framework, we provide specific examples of using this method and provide some explicit recommendations for research and clinical practice.

  14. Accuracy of Combined Computed Tomography Colonography and Dual Energy Iiodine Map Imaging for Detecting Colorectal masses using High-pitch Dual-source CT.

    Science.gov (United States)

    Sun, Kai; Han, Ruijuan; Han, Yang; Shi, Xuesen; Hu, Jiang; Lu, Bin

    2018-02-28

    To evaluate the diagnostic accuracy of combined computed tomography colonography (CTC) and dual-energy iodine map imaging for detecting colorectal masses using high-pitch dual-source CT, compared with optical colonography (OC) and histopathologic findings. Twenty-eight consecutive patients were prospectively enrolled in this study. All patients were underwent contrast-enhanced CTC acquisition using dual-energy mode and OC and pathologic examination. The size of the space-occupied mass, the CT value after contrast enhancement, and the iodine value were measured and statistically compared. The sensitivity, specificity, accuracy rate, and positive predictive and negative predictive values of dual-energy contrast-enhanced CTC were calculated and compared between conventional CTC and dual-energy iodine images. The iodine value of stool was significantly lower than the colonic neoplasia (P dual-energy iodine maps imaging was 95.6% (95% CI = 77.9%-99.2%). The specificity of the two methods was 42.8% (95% CI = 15.4%-93.5%) and 100% (95% CI = 47.9%-100%; P = 0.02), respectively. Compared with optical colonography and histopathology, combined CTC and dual-energy iodine maps imaging can distinguish stool and colonic neoplasia, distinguish between benign and malignant tumors initially and improve the diagnostic accuracy of CTC for colorectal cancer screening.

  15. Dual recycling for GEO 600

    International Nuclear Information System (INIS)

    Grote, H; Freise, A; Malec, M; Heinzel, G; Willke, B; Lueck, H; Strain, K A; Hough, J; Danzmann, K

    2004-01-01

    Dual recycling is the combination of signal recycling and power recycling; both optical techniques improve the shot-noise-limited sensitivity of interferometric gravitational-wave detectors. In addition, signal recycling can reduce the loss of light power due to imperfect interference and allows us, in principle, to beat the standard quantum limit. The interferometric gravitational-wave detector GEO 600 is the first of the kilometre-scale detectors to use signal recycling. We have recently equipped the detector with a signal-recycling mirror with a transmittance of 1%. In this paper, we present details of the detector commissioning and the first locks of the dual-recycled interferometer

  16. Pairs of dual periodic frames

    DEFF Research Database (Denmark)

    Christensen, Ole; Goh, Say Song

    2012-01-01

    The time–frequency analysis of a signal is often performed via a series expansion arising from well-localized building blocks. Typically, the building blocks are based on frames having either Gabor or wavelet structure. In order to calculate the coefficients in the series expansion, a dual frame...... is needed. The purpose of the present paper is to provide constructions of dual pairs of frames in the setting of the Hilbert space of periodic functions L2(0,2π). The frames constructed are given explicitly as trigonometric polynomials, which allows for an efficient calculation of the coefficients...

  17. UWB dual burst transmit driver

    Science.gov (United States)

    Dallum, Gregory E [Livermore, CA; Pratt, Garth C [Discovery Bay, CA; Haugen, Peter C [Livermore, CA; Zumstein, James M [Livermore, CA; Vigars, Mark L [Livermore, CA; Romero, Carlos E [Livermore, CA

    2012-04-17

    A dual burst transmitter for ultra-wideband (UWB) communication systems generates a pair of precisely spaced RF bursts from a single trigger event. An input trigger pulse produces two oscillator trigger pulses, an initial pulse and a delayed pulse, in a dual trigger generator. The two oscillator trigger pulses drive a gated RF burst (power output) oscillator. A bias driver circuit gates the RF output oscillator on and off and sets the RF burst packet width. The bias driver also level shifts the drive signal to the level that is required for the RF output device.

  18. Towards a big crunch dual

    Energy Technology Data Exchange (ETDEWEB)

    Hertog, Thomas E-mail: hertog@vulcan2.physics.ucsb.edu; Horowitz, Gary T

    2004-07-01

    We show there exist smooth asymptotically anti-de Sitter initial data which evolve to a big crunch singularity in a low energy supergravity limit of string theory. This opens up the possibility of using the dual conformal field theory to obtain a fully quantum description of the cosmological singularity. A preliminary study of this dual theory suggests that the big crunch is an endpoint of evolution even in the full string theory. We also show that any theory with scalar solitons must have negative energy solutions. The results presented here clarify our earlier work on cosmic censorship violation in N=8 supergravity. (author)

  19. The dual description of long-distance QCD (Dual QCD)

    International Nuclear Information System (INIS)

    Baker, M.

    1990-01-01

    We construct and solve a local field theory which describes in terms of dual variables a system having an A μ propagator behaving like M 2 /q 4 in the infrared and discuss how this theory can be used as a starting point for describing long-distance QCD. 3 refs

  20. CARDIOVASCULAR ENDOCRINOLOGY Dual RAAS blockade has dual effects on outcome

    NARCIS (Netherlands)

    Heerspink, Hiddo J. Lambers; de Zeeuw, Dick

    Makani and colleagues report that dual blockade of the renin-angiotensin-aldosterone system is associated with harm despite previous studies showing that this approach decreases blood pressure and albuminuria. Do these results imply that we should abandon surrogate markers? Or should we become more

  1. Dual modality densitometry

    International Nuclear Information System (INIS)

    Tjugum, Stein-Arild

    2003-01-01

    Different measurement principles and design issues for gamma-ray densitometry for pipe flow are investigated. The dual modality densitometry (DMD) principle for salinity measurement and flow regime identification by multibeam densitometry are tested and verified. The measurement principles are implemented in a compact instrument design with low energy source and compact detectors. The DMD principle is experimentally verified for 3 inch and 2 inch pipes. These measurements are done on homogenous brine/gas mixtures. Both salinity independent GVF measurements and salinity measurements are obtained. The standard deviation of the salinity measurements are about 2 percent. This measurement inaccuracy is mainly caused by inhomogeneity in the liquid/gas distribution, and measurements are thus sensitive to changes in the flow regime. Models for the generation of scattered radiation are developed, and these have been used in the data-analysis and for producing special sensitivity maps for the generation of scattered radiation. The models are a useful tool for further development of the DMD principle. The work on multibeam gamma-ray densitometry has shown that flow regimes can be identified with as few as two detectors. This is verified in the flow-loop tests. Unambiguous flow regime identification will often require that the multibeam measurements are combined with other flow measurements. With a higher number of detectors more detailed information is found, and from the 9-beam measurements with the University of Bergen (UoB) gamma-ray tomography different flow regimes could clearly be identified from time series plots of the data. A laboratory prototype compact gamma-ray densitometer, the MiniGamma, has been built up and tested. Both the DMD measurement principle and the multibeam arrangement for flow regime identification are implemented in the instrument, and are successfully tested. The detector-types tested are CdZnTe semiconductor detectors, a miniature scintillation

  2. Some dual relations in twistor theory

    International Nuclear Information System (INIS)

    Tarski, J.

    1983-08-01

    The option of employing twistors or dual twistors in integral representations, etc., is considered. In particular, dual-space analyses are presented which relate to the problem of background electromagnetic fields, and to the inverse transformation. (author)

  3. Dual-Doppler Feasibility Study

    Science.gov (United States)

    Huddleston, Lisa L.

    2012-01-01

    When two or more Doppler weather radar systems are monitoring the same region, the Doppler velocities can be combined to form a three-dimensional (3-D) wind vector field thus providing for a more intuitive analysis of the wind field. A real-time display of the 3-D winds can assist forecasters in predicting the onset of convection and severe weather. The data can also be used to initialize local numerical weather prediction models. Two operational Doppler Radar systems are in the vicinity of Kennedy Space Center (KSC) and Cape Canaveral Air Force Station (CCAFS); these systems are operated by the 45th Space Wing (45 SW) and the National Weather Service Melbourne, Fla. (NWS MLB). Dual-Doppler applications were considered by the 45 SW in choosing the site for the new radar. Accordingly, the 45th Weather Squadron (45 WS), NWS MLB and the National Aeronautics and Space Administration tasked the Applied Meteorology Unit (AMU) to investigate the feasibility of establishing dual-Doppler capability using the two existing systems. This study investigated technical, hardware, and software requirements necessary to enable the establishment of a dual-Doppler capability. Review of the available literature pertaining to the dual-Doppler technique and consultation with experts revealed that the physical locations and resulting beam crossing angles of the 45 SW and NWS MLB radars make them ideally suited for a dual-Doppler capability. The dual-Doppler equations were derived to facilitate complete understanding of dual-Doppler synthesis; to determine the technical information requirements; and to determine the components of wind velocity from the equation of continuity and radial velocity data collected by the two Doppler radars. Analysis confirmed the suitability of the existing systems to provide the desired capability. In addition, it is possible that both 45 SW radar data and Terminal Doppler Weather Radar data from Orlando International Airport could be used to alleviate any

  4. Dual-comb spectroscopy of water vapor with a free-running semiconductor disk laser.

    Science.gov (United States)

    Link, S M; Maas, D J H C; Waldburger, D; Keller, U

    2017-06-16

    Dual-comb spectroscopy offers the potential for high accuracy combined with fast data acquisition. Applications are often limited, however, by the complexity of optical comb systems. Here we present dual-comb spectroscopy of water vapor using a substantially simplified single-laser system. Very good spectroscopy measurements with fast sampling rates are achieved with a free-running dual-comb mode-locked semiconductor disk laser. The absolute stability of the optical comb modes is characterized both for free-running operation and with simple microwave stabilization. This approach drastically reduces the complexity for dual-comb spectroscopy. Band-gap engineering to tune the center wavelength from the ultraviolet to the mid-infrared could optimize frequency combs for specific gas targets, further enabling dual-comb spectroscopy for a wider range of industrial applications. Copyright © 2017, American Association for the Advancement of Science.

  5. Dual Identity and Prejudice: The Moderating Role of Group Boundary Permeability

    Science.gov (United States)

    Shi, Yuanyuan; Dang, Jianning; Zheng, Wenwen; Liu, Li

    2017-01-01

    Past work suggested that dual identity was effective to reduce prejudice. This study extended research on dual identity and prejudice by identifying a boundary condition in this relationship, that is, group permeability. In Study 1, we replicated previous studies with Chinese individuals and found that inducing dual identity (emphasizing subgroup differences and a common nation identity), compared to the control condition, decreased the urban residents’ prejudice against rural-to-urban migrants. In Study 2, we manipulated the group boundary permeability using the Hukou system reform, and found that when the group boundary was permeable, dual identity was effective in reducing prejudice against rural-to-urban migrants. However, this effect vanished in the condition where the group boundary was impermeable. These results point to the importance of inducing dual identity under specific conditions for research on decreasing prejudice. Some practical implications of the findings for urbanization and immigration are discussed. PMID:28261130

  6. Working Memory Training Improves Dual-Task Performance on Motor Tasks.

    Science.gov (United States)

    Kimura, Takehide; Kaneko, Fuminari; Nagahata, Keita; Shibata, Eriko; Aoki, Nobuhiro

    2017-01-01

    The authors investigated whether working memory training improves motor-motor dual-task performance consisted of upper and lower limb tasks. The upper limb task was a simple reaction task and the lower limb task was an isometric knee extension task. 45 participants (age = 21.8 ± 1.6 years) were classified into a working memory training group (WM-TRG), dual-task training group, or control group. The training duration was 2 weeks (15 min, 4 times/week). Our results indicated that working memory capacity increased significantly only in the WM-TRG. Dual-task performance improved in the WM-TRG and dual-task training group. Our study provides the novel insight that working memory training improves dual-task performance without specific training on the target motor task.

  7. Dual-energy mammography: simulation studies

    International Nuclear Information System (INIS)

    Bliznakova, K; Kolitsi, Z; Pallikarakis, N

    2006-01-01

    This paper presents a mammography simulator and demonstrates its applicability in feasibility studies in dual-energy (DE) subtraction mammography. This mammography simulator is an evolution of a previously presented x-ray imaging simulation system, which has been extended with new functionalities that are specific for DE simulations. The new features include incident exposure and dose calculations, the implementation of a DE subtraction algorithm as well as amendments to the detector and source modelling. The system was then verified by simulating experiments and comparing their results against published data. The simulator was used to carry out a feasibility study of the applicability of DE techniques in mammography, and more precisely to examine whether this modality could result in better visualization and detection of microcalcifications. Investigations were carried out using a 3D breast software phantom of average thickness, monoenergetic and polyenergetic beam spectra and various detector configurations. Dual-shot techniques were simulated. Results showed the advantage of using monoenergetic in comparison with polyenergetic beams. Optimization studies with monochromatic sources were carried out to obtain the optimal low and high incident energies, based on the assessment of the figure of merit of the simulated microcalcifications in the subtracted images. The results of the simulation study with the optimal energies demonstrated that the use of the DE technique can improve visualization and increase detectability, allowing identification of microcalcifications of sizes as small as 200 μm. The quantitative results are also verified by means of a visual inspection of the synthetic images

  8. Peptides with Dual Antimicrobial and Anticancer Activities

    Science.gov (United States)

    Felício, Mário R.; Silva, Osmar N.; Gonçalves, Sônia; Santos, Nuno C.; Franco, Octávio L.

    2017-02-01

    In recent years, the number of people suffering from cancer and multi-resistant infections has increased, such that both diseases are already seen as current and future major causes of death. Moreover, chronic infections are one of the main causes of cancer, due to the instability in the immune system that allows cancer cells to proliferate. Likewise, the physical debility associated with cancer or with anticancer therapy itself often paves the way for opportunistic infections. It is urgent to develop new therapeutic methods, with higher efficiency and lower side effects. Antimicrobial peptides (AMPs) are found in the innate immune system of a wide range of organisms. Identified as the most promising alternative to conventional molecules used nowadays against infections, some of them have been shown to have dual activity, both as antimicrobial and anticancer peptides (ACPs). Highly cationic and amphipathic, they have demonstrated efficacy against both conditions, with the number of nature-driven or synthetically designed peptides increasing year by year. With similar properties, AMPs that can also act as ACPs are viewed as future chemotherapeutic drugs, with the advantage of low propensity to resistance, which started this paradigm in the pharmaceutical market. These peptides have already been described as molecules presenting killing mechanisms at the membrane level, but also acting towards intracellular targets, which increases their success comparatively to specific one-target drugs. This review will approach the desirable characteristics of small peptides that demonstrated dual activity against microbial infections and cancer, as well as the peptides engaged in clinical trials.

  9. Sparsity and spectral properties of dual frames

    DEFF Research Database (Denmark)

    Krahmer, Felix; Kutyniok, Gitta; Lemvig, Jakob

    2013-01-01

    We study sparsity and spectral properties of dual frames of a given finite frame. We show that any finite frame has a dual with no more than $n^2$ non-vanishing entries, where $n$ denotes the ambient dimension, and that for most frames no sparser dual is possible. Moreover, we derive an expressio...

  10. Dual Enrollment for High School Students

    Science.gov (United States)

    Edwards, Linsey; Hughes, Katherine

    2011-01-01

    Dual enrollment programs allow high school students to enroll in college courses and potentially earn college credit. The term concurrent enrollment is sometimes used interchangeably with dual enrollment, and sometimes to refer to a particular model of dual enrollment. In some programs, students earn high school and college credit simultaneously;…

  11. Dual Processing and Diagnostic Errors

    Science.gov (United States)

    Norman, Geoff

    2009-01-01

    In this paper, I review evidence from two theories in psychology relevant to diagnosis and diagnostic errors. "Dual Process" theories of thinking, frequently mentioned with respect to diagnostic error, propose that categorization decisions can be made with either a fast, unconscious, contextual process called System 1 or a slow, analytical,…

  12. Dual temperature isotope exchange system

    International Nuclear Information System (INIS)

    Spevack, J.S.

    1976-01-01

    Improvements in the method for isotope concentration by dual temperature exchange between feed and auxiliary fluids in a multistage system are described. In a preferred embodiment the first is a vaporizable liquid and the auxiliary fluid a gas, comprising steps for improving the heating and/or cooling and/or humidifying and/or dehumidifying operations

  13. Physical Health and Dual Diagnosis

    OpenAIRE

    Robson, Debbie; Keen, Sarah; Mauro, Pia

    2008-01-01

    The physical health of people with mental illness may be neglected for a variety of reasons. This paper looks at the common physical health problems experienced by people with a dual diagnosis of substance misuse and serious mental illness, and suggests ways of assessing and managing them.

  14. Dual model for parton densities

    International Nuclear Information System (INIS)

    El Hassouni, A.; Napoly, O.

    1981-01-01

    We derive power-counting rules for quark densities near x=1 and x=0 from parton interpretations of one-particle inclusive dual amplitudes. Using these rules, we give explicit expressions for quark distributions (including charm) inside hadrons. We can then show the compatibility between fragmentation and recombination descriptions of low-p/sub perpendicular/ processes

  15. Dual fields and E11

    International Nuclear Information System (INIS)

    Riccioni, Fabio; West, Peter

    2007-01-01

    We show that the adjoint representation of E 11 contains generators corresponding to the infinite possible dual descriptions of the bosonic on-shell degrees of freedom of eleven-dimensional supergravity. We also give an interpretation for the fields corresponding to many of the other generators in the adjoint representation

  16. Dual approaches for defects condensation

    Energy Technology Data Exchange (ETDEWEB)

    Rougemont, Romulo; Grigorio, Leonardo de Souza; Wotzasek, Clovis [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil); Guimaraes, Marcelo Santos [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil)

    2009-07-01

    Full text. Due to the fact that the QCD running coupling constant becomes larger as we go into the low energy (or large distance) limit of the theory, a perturbative treatment of its infrared (IR) region is impossible. In particular, a formal mathematical demonstration of color confinement and a complete physical understanding of the exact mechanism that confines quarks and gluons are two missing points in our current knowledge of the IR-QCD. It was known that due to the Meissner effect of expulsion of magnetic fields in a electric condensate that usual superconductors should confine magnetic monopoles. That point led to the conjecture that the QCD vacuum could be a condensate of chromomagnetic monopoles, a dual superconductor (DSC). Such a chromomagnetic condensate should be responsible for the dual Meissner effect which is expected to lead to the confinement of color charges immersed in this medium. In dual superconductor models of color confinement, magnetic monopoles appear as topological defects in points of the space where the abelian projection becomes singular. Also, condensation of other kinds of defects such as vortices in superfluids and line-like defects in solids are responsible for a great variety of phase transitions, which once more proves the relevance of the subject. In the present work we review two methods that allow us to approach the condensation of defects: the Kleinert Mechanism (KM) and the Julia-Toulouse Mechanism (JTM). We show that in the limit where the vortex gauge field goes to zero, which we identify as the signature of the condensation of defects in the dual picture, these are two equivalent dual prescriptions for obtaining an effective theory for a phase where defects are condensed, starting from the fundamental theory defined in the normal phase where defects are diluted. (author)

  17. The Dual Orlicz-Brunn-Minkowski Theory

    OpenAIRE

    Gardner, Richard J.; Hug, Daniel; Weil, Wolfgang; Ye, Deping

    2014-01-01

    This paper introduces the dual Orlicz-Brunn-Minkowski theory for star sets. A radial Orlicz addition of two or more star sets is proposed and a corresponding dual Orlicz-Brunn-Minkowski inequality is established. Based on a radial Orlicz linear combination of two star sets, a formula for the dual Orlicz mixed volume is derived and a corresponding dual Orlicz-Minkowski inequality proved. The inequalities proved yield as special cases the precise duals of the conjectured log-Brunn-Minkowski and...

  18. Dual deflectable beam strip engine development.

    Science.gov (United States)

    Dulgeroff, C. R.; Zuccaro, D. E.; Kami, S.; Schnelker, D. E.; Ward, J. W.

    1972-01-01

    This paper describes a dual beam thruster that has been designed, constructed, and tested. The system is suitable for two-axes attitude control and is comprised of two orthogonal strips, each capable of producing 0.30 mlb thrust and beam deflections of more than plus or minus 20 deg. The nominal specific impulse for the thruster is 5000 sec, and the thrust level from each strip can be varied from 0 to 100%. Neutralizer filaments that were developed and life tested over 2000 hours producing more than 40 mA of electron emission per watt of input power are also discussed. The system power required for clean ionizers is approximately 200 W.

  19. Theoretical Model of Professional Competence Development in Dual-Specialty Students (On the Example of the "History, Religious Studies" Specialty)

    Science.gov (United States)

    Karimova, A. E.; Amanova, A. S.; Sadykova, A. M.; Kuzembaev, N. E.; Makisheva, A. T.; Kurmangazina, G. Zh.; Sakenov, Janat

    2016-01-01

    The article explores the significant problem of developing a theoretical model of professional competence development in dual-specialty students (on the example of the "History, Religious studies" specialty). In order to validate the specifics of the professional competence development in dual-specialty students (on the example of the…

  20. QCD as a dual superconductor

    International Nuclear Information System (INIS)

    Zachariasen, F.

    1986-01-01

    The author describes the construction of an effective action describing long-range Yang-Mills theory. This action is motivated by a study of the system of Dyson equations and Ward identities, but cannot (yet) be derived from the underlying quantum theory. The effective action turns out to describe a medium very much like a dual relativistic superconductor; that is, with electric and magnetic fields interchanged. There is a dual Meissner effect, which serves to compress color electric fields into flux tubes, containing quantized units of color electric flux. This produces electric confinement. There is a magnetic condensate, resulting from a spontaneous symmetry breaking analogous to that in the relativistic superconductor, as in the Abelian Higgs model. He gives the motivation leading to the effective action, and describes the quantized electric flux tube solutions. Finally, he mentions briefly some other applications

  1. Vacuum transitions in dual models

    International Nuclear Information System (INIS)

    Pashnev, A.I.; Volkov, D.V.; Zheltukhin, A.A.

    1976-01-01

    The investigation is continued of the spontaneous vacuum transition problem in the Neview-Schwartz dual model (NSDM). It is shown that vacuum transitions allow disclosing of supplementary degeneration in the resonance state spectrum. The dual amplitudes possess an internal structure corresponding to the presence of an infinite number of quarks with increasing masses and retained charges. The Adler principle holds. Analytic continuation on the constant of induced vacuum transitions makes it possible to establish the existence of spontaneous vacuum transitions in the NSDM. The consequence of this fact is the exact SU(2) symmetry of π, rho meson trajectories and the Higgs mechanism in the model. In this case the ratios of masses of particles leading trajectories are analogous to those obtained in the current algebra. It is shown that in the NSDM there arises chiral SU(2) x SU(2) x U(1) x U(1) x ... symmetry resulting from spontaneous vacuum transitions

  2. Wavelet frames and their duals

    DEFF Research Database (Denmark)

    Lemvig, Jakob

    2008-01-01

    frames with good time localization and other attractive properties. Furthermore, the dual wavelet frames are constructed in such a way that we are guaranteed that both frames will have the same desirable features. The construction procedure works for any real, expansive dilation. A quasi-affine system....... The signals are then represented by linear combinations of the building blocks with coefficients found by an associated frame, called a dual frame. A wavelet frame is a frame where the building blocks are stretched (dilated) and translated versions of a single function; such a frame is said to have wavelet...... structure. The dilation of the wavelet building blocks in higher dimension is done via a square matrix which is usually taken to be integer valued. In this thesis we step away from the "usual" integer, expansive dilation and consider more general, expansive dilations. In most applications of wavelet frames...

  3. Dual topological unitarization -- phenomenological aspect

    International Nuclear Information System (INIS)

    Tan, C.I.

    1978-01-01

    An assessment is provided on the viability of dual topological unitarization as a practical scheme for organizing and interpreting hadronic phenomena at current machine energies. Previous detailed reviews are complemented, with emphasis on phenomenological aspects and more recent developments. Diffraction scattering, a test of P--f identity hypothesis, the flavor model, the P--f identity versus the Veneziano two-jet picture, and an illustration of the new phenomenology are included. 24 references

  4. Dual arm master controller concept

    International Nuclear Information System (INIS)

    Kuban, D.P.; Perkins, G.S.

    1984-01-01

    The Advanced Servomanipulator (ASM) slave was designed with an anthropomorphic stance, gear/torque tube power drives, and modular construction. These features resulted in increased inertia, friction, and backlash relative to tape-driven manipulators. Studies were performed which addressed the human factors design and performance trade-offs associated with the corresponding master controller best suited for the ASM. The results of these studies, as well as the conceptual design of the dual arm master controller, are presented. 6 references, 3 figures

  5. Dual arm master controller development

    Science.gov (United States)

    Kuban, D. P.; Perkins, G. S.

    1985-01-01

    The advanced servomanipulator (ASM) slave was designed with an anthropomorphic stance gear/torque tube power drives, and modular construction. These features resulted in increased inertia, friction, and backlash relative to tape driven manipulators. Studies were performed which addressed to human factor design and performance tradeoffs associated with the corresponding master controller best suited for the ASM. The results of these studies, as well as the conceptual design of the dual arm master controller, are presented.

  6. Lexicons, contexts, events, and images: commentary on Elman (2009) from the perspective of dual coding theory.

    Science.gov (United States)

    Paivio, Allan; Sadoski, Mark

    2011-01-01

    Elman (2009) proposed that the traditional role of the mental lexicon in language processing can largely be replaced by a theoretical model of schematic event knowledge founded on dynamic context-dependent variables. We evaluate Elman's approach and propose an alternative view, based on dual coding theory and evidence that modality-specific cognitive representations contribute strongly to word meaning and language performance across diverse contexts which also have effects predictable from dual coding theory. Copyright © 2010 Cognitive Science Society, Inc.

  7. Dual leadership in a hospital practice

    DEFF Research Database (Denmark)

    Thude, Bettina Ravnborg; Thomsen, Svend Erik; Stenager, Egon

    2017-01-01

    , this study aims to analyse three different dual leadership pairs at a Danish hospital. Furthermore, this study develops a tool to characterize dual leadership teams from each other. Design/methodology/approach This is a qualitative study using semi-structured interviews. Six leaders were interviewed...... to clarify how dual leadership works in a hospital context. All interviews were transcribed and coded. During coding, focus was on the nine principles found in the literature and another principle was found by looking at the themes that were generic for all six interviews. Findings Results indicate......Purpose Despite the practice of dual leadership in many organizations, there is relatively little research on the topic. Dual leadership means two leaders share the leadership task and are held jointly accountable for the results of the unit. To better understand how dual leadership works...

  8. Time to and predictors of dual incontinence in older nursing home admissions.

    Science.gov (United States)

    Bliss, Donna Z; Gurvich, Olga V; Eberly, Lynn E; Harms, Susan

    2018-01-01

    There are few studies of nursing home residents that have investigated the development of dual incontinence, perhaps the most severe type of incontinence as both urinary and fecal incontinence occur. To determine the time to and predictors of dual incontinence in older nursing home residents. Using a cohort design, records of older nursing home admissions who were continent or had only urinary or only fecal incontinence (n = 39,181) were followed forward for report of dual incontinence. Four national US datasets containing potential predictors at multiple levels describing characteristics of nursing home residents, nursing homes (n = 445), and socioeconomic and sociodemographic status of the community surrounding nursing homes were analyzed. A Cox proportional hazard regression with nursing home-specific random effect was used. At 6 months after admission, 28% of nursing home residents developed dual incontinence, at 1 year 42% did so, and at 2 years, 61% had dual incontinence. Significant predictors for time to developing dual incontinence were having urinary incontinence, greater functional or cognitive deficits, more comorbidities, older age, and lesser quality of nursing home care. The development of dual incontinence is a major problem among nursing home residents. Predictors in this study offer guidance in developing interventions to prevent and reduce the time to developing this problem which may improve the quality of life of nursing residents. © 2017 Wiley Periodicals, Inc.

  9. Dual computations of non-Abelian Yang-Mills theories on the lattice

    International Nuclear Information System (INIS)

    Cherrington, J. Wade; Khavkine, Igor; Christensen, J. Daniel

    2007-01-01

    In the past several decades there have been a number of proposals for computing with dual forms of non-Abelian Yang-Mills theories on the lattice. Motivated by the gauge-invariant, geometric picture offered by dual models and successful applications of duality in the U(1) case, we revisit the question of whether it is practical to perform numerical computation using non-Abelian dual models. Specifically, we consider three-dimensional SU(2) pure Yang-Mills as an accessible yet nontrivial case in which the gauge group is non-Abelian. Using methods developed recently in the context of spin foam quantum gravity, we derive an algorithm for efficiently computing the dual amplitude and describe Metropolis moves for sampling the dual ensemble. We relate our algorithms to prior work in non-Abelian dual computations of Hari Dass and his collaborators, addressing several problems that have been left open. We report results of spin expectation value computations over a range of lattice sizes and couplings that are in agreement with our conventional lattice computations. We conclude with an outlook on further development of dual methods and their application to problems of current interest

  10. Effect of dual modification with hydroxypropylation and cross-linking on physicochemical properties of taro starch.

    Science.gov (United States)

    Hazarika, Bidyut Jyoti; Sit, Nandan

    2016-04-20

    Dual modification of taro starch by hydroxypropylation and cross-linking was carried out and the properties of the modified starches were investigated. Two different levels of hydroxypropylation (5 and 10%) and cross-linking (0.05 and 0.10%) were used in different sequences. The amylose contents of the starch decreased due to single and dual modification. For the dual-modified starches, the swelling, solubility and clarity was found to increase with level of hydroxypropylation and decrease with level of cross-linking. The freeze-thaw stability of the dual-modified starches was also affected by the sequence of modification. The viscosities of the cross-linked and dual-modified starches were more than native and hydroxypropylated starches. The firmness of the dual-modified starches was also higher than native and single modified starches. The dual-modified starches have benefits of both type of modifications and could be used for specific purposes e.g. food products requiring high viscosity as well as freeze-thaw stability. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Behavioral Assessment of Listening Effort Using a Dual-Task Paradigm

    Directory of Open Access Journals (Sweden)

    Jean-Pierre Gagné

    2017-01-01

    Full Text Available Published investigations (n = 29 in which a dual-task experimental paradigm was employed to measure listening effort during speech understanding in younger and older adults were reviewed. A summary of the main findings reported in the articles is provided with respect to the participants’ age-group and hearing status. Effects of different signal characteristics, such as the test modality, on dual-task outcomes are evaluated, and associations with cognitive abilities and self-report measures of listening effort are described. Then, several procedural issues associated with the use of dual-task experiment paradigms are discussed. Finally, some issues that warrant future research are addressed. The review revealed large variability in the dual-task experimental paradigms that have been used to measure the listening effort expended during speech understanding. The differences in experimental procedures used across studies make it difficult to draw firm conclusions concerning the optimal choice of dual-task paradigm or the sensitivity of specific paradigms to different types of experimental manipulations. In general, the analysis confirmed that dual-task paradigms have been used successfully to measure differences in effort under different experimental conditions, in both younger and older adults. Several research questions that warrant further investigation in order to better understand and characterize the intricacies of dual-task paradigms were identified.

  12. A Hodge dual for soldered bundles

    International Nuclear Information System (INIS)

    Lucas, Tiago Gribl; Pereira, J G

    2009-01-01

    In order to account for all possible contractions allowed by the presence of the solder form, a generalized Hodge dual is defined for the case of soldered bundles. Although for curvature the generalized dual coincides with the usual one, for torsion it gives a completely new dual definition. Starting from the standard form of a gauge Lagrangian for the translation group, the generalized Hodge dual yields precisely the Lagrangian of the teleparallel equivalent of general relativity, and consequently also the Einstein-Hilbert Lagrangian of general relativity

  13. Nonword Reading: Comparing Dual-Route Cascaded and Connectionist Dual-Process Models with Human Data

    Science.gov (United States)

    Pritchard, Stephen C.; Coltheart, Max; Palethorpe, Sallyanne; Castles, Anne

    2012-01-01

    Two prominent dual-route computational models of reading aloud are the dual-route cascaded (DRC) model, and the connectionist dual-process plus (CDP+) model. While sharing similarly designed lexical routes, the two models differ greatly in their respective nonlexical route architecture, such that they often differ on nonword pronunciation. Neither…

  14. Egalité filles-garçons : un objectif à l’épreuve du double usage des dispositifs d’accompagnement à la scolarité Girl-boy equality: an objective against specific help project’s dual-use

    Directory of Open Access Journals (Sweden)

    Cyrille Morin

    2011-10-01

    Full Text Available Cet article propose un regard sur l’égalité scolaire filles-garçons par le biais des dispositifs d’accompagnement à la scolarité en collectif, c'est-à-dire en équipements de quartier. Basé sur une recherche ethnographique, il s’interroge plus précisément sur la manière dont les enfants s’approprient les dispositifs d’accompagnement proposés. Les premiers résultats montrent qu’ils en ont un « double usage » de soutien scolaire et d’aide aux devoirs, mais aussi de socialisation et d’apprentissages des rôles parentaux, notamment par les filles. Les enfants sont « libres » de fréquenter l’un ou l’autre des dispositifs du quartier. Cette « liberté » s’exerce dans une logique d’appropriation sexuée du quartier comme territoire de jeux et de socialisation qui entre en correspondance avec les spécialisations de l’offre d’accompagnement scolaire locale. Cette correspondance n’est pas sans rappeler les rapports socio-sexués au savoir, qui sont construits au sein de l’école. Ainsi, on constate d’une part que l’appropriation est genrée et d’autre part qu’elle reflète les scolarités proposées aux filles et aux garçons. En ne tenant pas compte de la socialisation sexuée et des rapports socio-sexués au savoir, les dispositifs vont dans le sens des inégalités de genre en construction chez les jeunes.This article looks at gender inequality in specific help projects for students. In French city suburbs, children are offered to get some extra homework help. These projects are implemented by associations in order to help students who need to be explained how to learn and do their homework. Based on an ethnographic approach, this research tried to determine how children appropriate themselves this help. First results indicate that children have a “dual use” of homework help projects. The first use is about homework, but there is another use for girls who have to learn parental

  15. Dual arm master controller development

    International Nuclear Information System (INIS)

    Kuban, D.P.; Perkins, G.S.

    1985-01-01

    The advanced servomanipulator (ASM) slave was designed with an anthropomorphic stance, gear/torque tube power drives, and modular construction. These features resulted in increased inertia, friction, and backlash relative to tape-driven manipulators. Studies were performed which addressed the human factors design and performance trade-offs associated with the corresponding master controller best suited for the ASM. The results of these studies, as well as the conceptual design of the dual arm master controller, are presented. This work was performed as part of the Consolidated Fuel Reprocessing Program at the Oak Ridge National Laboratory. 5 refs., 7 figs., 1 tab

  16. A primal-dual exterior point algorithm for linear programming problems

    Directory of Open Access Journals (Sweden)

    Samaras Nikolaos

    2009-01-01

    Full Text Available The aim of this paper is to present a new simplex type algorithm for the Linear Programming Problem. The Primal - Dual method is a Simplex - type pivoting algorithm that generates two paths in order to converge to the optimal solution. The first path is primal feasible while the second one is dual feasible for the original problem. Specifically, we use a three-phase-implementation. The first two phases construct the required primal and dual feasible solutions, using the Primal Simplex algorithm. Finally, in the third phase the Primal - Dual algorithm is applied. Moreover, a computational study has been carried out, using randomly generated sparse optimal linear problems, to compare its computational efficiency with the Primal Simplex algorithm and also with MATLAB's Interior Point Method implementation. The algorithm appears to be very promising since it clearly shows its superiority to the Primal Simplex algorithm as well as its robustness over the IPM algorithm.

  17. Dual ectopic thyroid: A case report with review of literature

    International Nuclear Information System (INIS)

    Sood, A.; Seam, R. K.; Gupta, M.; Raj Sharma, D.; Bhardwaj, P.

    2011-01-01

    The ectopic thyroid gland is a rare entity which is mostly found along the line of descent of the thyroid gland. Most of the patients present with midline swelling and usually seek medical attention. Dual ectopic thyroid gland is even rarer. The clinical examination and different imaging modalities establish its diagnosis. Radionuclide studies are highly sensitive and specific in demonstrating the functional tissues in patients with ectopic thyroid, thereby guiding further management. The authors reported a case of ectopic thyroid gland in a girl with midline neck swelling initially, subsequently lost to follow-up. She again presented with enlarged swelling after a period of three years with dual ectopic thyroid in the neck region on thyroid scan. Thyroid scintigraphy demonstrated that progression in the size of ectopic glands was due to neglect in treatment.

  18. Dual energy MDCT assessment of renal lesions: an overview

    International Nuclear Information System (INIS)

    Mileto, Achille; Marin, Daniele; Nelson, Rendon C.; Boll, Daniel T.; Ascenti, Giorgio

    2014-01-01

    With the expansion of cross-sectional imaging, the number of renal lesions that are incidentally discovered has increased. Multidetector CT (MDCT) is the investigation of choice for characterising and staging renal lesions. Although a definitive diagnosis can be confidently posed for most of them, a number of renal lesions remain indeterminate following MDCT. Further imaging tests are therefore needed, with subsequent increase of healthcare costs, radiation exposure, and patient anxiety. By addressing most of the issues with conventional MDCT imaging, dual-energy MDCT can improve the diagnosis of renal lesions and, potentially, may represent a paradigm shift from a merely attenuation-based to a material-specific spectral imaging investigation. The purpose of this review is to provide an overview of current clinical applications of dual-energy CT in the evaluation of renal lesions. Key Points. (orig.)

  19. A dual system model of preferences under risk.

    Science.gov (United States)

    Mukherjee, Kanchan

    2010-01-01

    This article presents a dual system model (DSM) of decision making under risk and uncertainty according to which the value of a gamble is a combination of the values assigned to it independently by the affective and deliberative systems. On the basis of research on dual process theories and empirical research in Hsee and Rottenstreich (2004) and Rottenstreich and Hsee (2001) among others, the DSM incorporates (a) individual differences in disposition to rational versus emotional decision making, (b) the affective nature of outcomes, and (c) different task construals within its framework. The model has good descriptive validity and accounts for (a) violation of nontransparent stochastic dominance, (b) fourfold pattern of risk attitudes, (c) ambiguity aversion, (d) common consequence effect, (e) common ratio effect, (f) isolation effect, and (g) coalescing and event-splitting effects. The DSM is also used to make several novel predictions of conditions under which specific behavior patterns may or may not occur.

  20. Implication of dual-purpose nuclear desalination plants

    International Nuclear Information System (INIS)

    Kutbi, I.I.

    1983-01-01

    Available dual purpose nuclear desalination schemes are reviewed. Three specific issues namely, impact of availability and reliability of the desalination stage of the plant, integration of the desalination and power production stages and new safety concerns of dual system, relating to desalination schemes are discussed. Results of operational and reliability studies of nuclear power stations, reverse osmosis and multistage flash distillation desalination plants are considered. Operational aspects of nuclear-multistage flash distillation, nuclear-reverse osmosis and nuclear-multistage flash distillation-reverse osmosis are compared. Concludes that the combined nuclear-multistage flash distillation-reverse osmosis plant arrangement permits very large production capacity, high availability, improvement of plant reliability and proovision of savings on the cost of water and power produced. 23 Ref

  1. Dual energy MDCT assessment of renal lesions: an overview

    Energy Technology Data Exchange (ETDEWEB)

    Mileto, Achille [Duke University Medical Center, Department of Radiology, Durham, NC (United States); University of Messina, Department of Biomedical Sciences and Morphologic and Functional Imaging, Policlinico ' ' G. Martino' ' , Messina (Italy); Marin, Daniele; Nelson, Rendon C.; Boll, Daniel T. [Duke University Medical Center, Department of Radiology, Durham, NC (United States); Ascenti, Giorgio [University of Messina, Department of Biomedical Sciences and Morphologic and Functional Imaging, Policlinico ' ' G. Martino' ' , Messina (Italy)

    2014-02-15

    With the expansion of cross-sectional imaging, the number of renal lesions that are incidentally discovered has increased. Multidetector CT (MDCT) is the investigation of choice for characterising and staging renal lesions. Although a definitive diagnosis can be confidently posed for most of them, a number of renal lesions remain indeterminate following MDCT. Further imaging tests are therefore needed, with subsequent increase of healthcare costs, radiation exposure, and patient anxiety. By addressing most of the issues with conventional MDCT imaging, dual-energy MDCT can improve the diagnosis of renal lesions and, potentially, may represent a paradigm shift from a merely attenuation-based to a material-specific spectral imaging investigation. The purpose of this review is to provide an overview of current clinical applications of dual-energy CT in the evaluation of renal lesions. Key Points. (orig.)

  2. Robot Kinematics, using Dual Quaternions

    Directory of Open Access Journals (Sweden)

    Mahmoud Gouasmi

    2012-03-01

    Full Text Available From the point of view of classical mechanics, deriving the equations of motion for systems of coupled rigid bodies is regarded as a straightforward procedure: once a suitable set of generalized coordinates and reference frames have been chosen, what remains is to either apply Lagrange’s equations or Newton and Euler’s equations to obtain the differential equations of motion. As the complexity of multibody system increases, the need for more elegant formulation of the equation of motion becomes an issue of paramount importance. Our primary focus is on the kinematic analysis of rigid bodies and serial manipulators (robotic systems  using simultaneously, both homogeneous transformations (4x4 matrices and Dual Quaternions, for the sake of results comparisons (cost,complexity,storage capacity etc. . This paper has been done mainly for educational and peadagogical purposes, hoping that the scientific community will finally adopt and use Dual Quaternions at least when dealing with multibody systems and specially robotics.

  3. Behavioral interventions for dual-diagnosis patients.

    Science.gov (United States)

    Goldsmith, R Jeffrey; Garlapati, Vamsi

    2004-12-01

    Dual diagnosis patients come to treatment with a variety of deficits,talents, and motivations. A biopsychosocial treatment plan involves multiple interventions, including medications, medical treatment, psychotherapy, family therapy, housing, and vocational rehabilitation. Treatment must be individualized and integrated, and this requires collaboration among a variety of health caregivers. There is empirical evidence that dual-diagnosis patients can be helped to stabilize, to remain in the community,and even to enter the workforce. Behavioral interventions are key ingredients to integrated and comprehensive treatment planning. There is no single model for dual disorders that explains why substance use and psychiatric illness co-occur so frequently. Mueser et al described four theoretical models accounting for the increased rates of comorbidity between psychiatric disorders and substance use disorders. They suggested that there could be a common factor that accounts for both, primary psychiatric disorder causing secondary substance abuse, primary substance abuse causing secondary psychiatric disorder, or a bidirectional problem, where each contributes to the other. There is evidence for each, although some are more compelling than others, and none is so compelling that it stands alone. Although family studies and genetic research could explain the common factor, no common gene has appeared. Antisocial personality disorder has been associated with very high rates of substance use disorders and mental illness; however, its prevalence is too low to explain most of the co-occurring phenomena. Common neurobiology, specifically the dopamine-releasing neurons in the mesolimbic system, also may be involved in mental illness, but this is not compelling at the moment. The Self-medication model is very appealing to mental health professionals, as an explanation for the secondary substance abuse model. Mueser et al suggest that three lines of evidence would be present to

  4. Diagnostic performance of dual-staining cytology for cervical cancer screening: A systematic literature review.

    Science.gov (United States)

    Tjalma, Wiebren A A

    2017-03-01

    Cervical cancer screening saves lives. Secondary prevention in cervical cancer screening relies on the results of primary cytology and/or HPV testing. However, primary screening with cytology has a low sensitivity, and HPV screening has a low specificity. This means that either cancers are missed, or women are over-treated. To improve performance outcomes, the concept of dual-stain cytology (CINtec ® PLUS Cytology test) has been introduced. In this approach, additional staining with p16/Ki-67 is performed in cases where cytology results are abnormal (LSIL or ASCUS) and/or HPV-positive. Another way to describe this approach might be "diagnostic" cytology. In order to assess the value of this "diagnostic cytology", a systematic literature review was conducted of dual-stain cytology performance across multiple studies until May 2016. In a Belgian screening population (women age 25-65 years), dual-stain cytology was significantly more sensitive (66%) and slightly less specific (-1.0%) than cytology. In the population referred to colposcopy or with abnormal cytology (ASCUS, LSIL), dual-staining showed a significantly higher increase in specificity, and a slightly lower sensitivity than HPV testing. Specificity gains resulted in fewer false positives and an increase in the number of correct referrals to colposcopy. Dual-staining with p16/Ki-67 cytology is an attractive biomarker approach for triage in cervical cancer screening. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. L p -Dual geominimal surface area

    Directory of Open Access Journals (Sweden)

    Weidong Wang

    2011-01-01

    Full Text Available Abstract Lutwak proposed the notion of Lp -geominimal surface area according to the Lp -mixed volume. In this article, associated with the Lp -dual mixed volume, we introduce the Lp -dual geominimal surface area and prove some inequalities for this notion. 2000 Mathematics Subject Classification: 52A20 52A40.

  6. Dual EC : a standardized back door

    NARCIS (Netherlands)

    Bernstein, D.J.; Lange, T.; Niederhagen, R.F.

    2015-01-01

    Dual EC is an algorithm to compute pseudorandom numbers starting from some random input. Dual EC was standardized by NIST, ANSI, and ISO among other algorithms to generate pseudorandom numbers. For a long time this algorithm was considered suspicious -- the entity designing the algorithm could have

  7. Dual-Career Couples: Keeping Them Together.

    Science.gov (United States)

    Wolf-Wendel, Lisa E.; Twombly, Susan; Rice, Suzanne

    2000-01-01

    Reports results of a survey of 360 chief academic officers at member institutions of the American Association of Colleges and Universities regarding their policies and practices for assisting dual-career couples. Examines the motivations, barriers, consequences, and policy implications of institutional responses to dual-career couples. (DB)

  8. A Dual Processing Approach to Stereotype Change.

    Science.gov (United States)

    Johnston, Lucy; Coolen, Petra

    1995-01-01

    Considered stereotype change within a framework of dual process models. Using three experiments, manipulated task involvement, source credibility, and message quality. Findings proved dual process as appropriate when considering the processing of stereotype-disconfirming information and processing's impact on existing stereotypes. Different…

  9. 7 CFR 7.17 - Dual office.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Dual office. 7.17 Section 7.17 Agriculture Office of... STATE, COUNTY AND COMMUNITY COMMITTEES § 7.17 Dual office. (a) County committee membership. A member of... any other county office employee. (b) Community committee membership. A member of the community...

  10. Dual wound dc brush motor gearhead

    Science.gov (United States)

    Henson, Barrie W.

    1986-01-01

    The design requirements, the design, development tests and problems, the qualification and life test and the findings of the strip examination of a dual wound DC brushed motor gearhead are described. It is the only space qualified dual wound dc brushed motor gearhead in Europe.

  11. Dual chiral density wave in quark matter

    International Nuclear Information System (INIS)

    Tatsumi, Toshitaka

    2002-01-01

    We prove that quark matter is unstable for forming a dual chiral density wave above a critical density, within the Nambu-Jona-Lasinio model. Presence of a dual chiral density wave leads to a uniform ferromagnetism in quark matter. A similarity with the spin density wave theory in electron gas and the pion condensation theory is also pointed out. (author)

  12. Symmetries of Taub-NUT dual metrics

    International Nuclear Information System (INIS)

    Baleanu, D.; Codoban, S.

    1998-01-01

    Recently geometric duality was analyzed for a metric which admits Killing tensors. An interesting example arises when the manifold has Killing-Yano tensors. The symmetries of the dual metrics in the case of Taub-NUT metric are investigated. Generic and non-generic symmetries of dual Taub-NUT metric are analyzed

  13. Quotient functions of dual quermassintegrals | Zhao | Quaestiones ...

    African Journals Online (AJOL)

    Motivated by the notion of volume difference functions, we introduce quotient functions of dual quermassintegrals and establish Brunn-Minkowski type inequalities for them, which have several recent results as special cases. Keywords: Volume difference function, dual quermassintegrals, quotient function, radial Blaschke ...

  14. Limitations in dual-task performance

    NARCIS (Netherlands)

    Pannebakker, Merel Mathilde

    2009-01-01

    In this thesis, the effect of information-processing overload on working-memory dependent information processing was examined using dual-task paradigms. The experiments described strengthen the importance of a functional explanation for dual-task limitations. First, it showed evidence for a unified

  15. The effect of single-task and dual-task balance exercise programs on balance performance in adults with osteoporosis: a randomized controlled preliminary trial.

    Science.gov (United States)

    Konak, H E; Kibar, S; Ergin, E S

    2016-11-01

    Osteoporosis is a serious disease characterized by muscle weakness in the lower extremities, shortened length of trunk, and increased dorsal kyphosis leading to poor balance performance. Although balance impairment increases in adults with osteoporosis, falls and fall-related injuries have been shown to occur mainly during the dual-task performance. Several studies have shown that dual-task performance was improved with specific repetitive dual-task exercises. The aims of this study were to compare the effect of single- and dual-task balance exercise programs on static balance, dynamic balance, and activity-specific balance confidence in adults with osteoporosis and to assess the effectiveness of dual-task balance training on gait speed under dual-task conditions. Older adults (N = 42) (age range, 45-88 years) with osteoporosis were randomly assigned into two groups. Single-task balance training group was given single-task balance exercises for 4 weeks, whereas dual-task balance training group received dual-task balance exercises. Participants received 45-min individualized training session, three times a week. Static balance was evaluated by one-leg stance (OLS) and a kinesthetic ability trainer (KAT) device. Dynamic balance was measured by the Berg Balance Scale (BBS), Time Up and Go (TUG) test, and gait speed. Self-confidence was assessed with the Activities-specific Balance Confidence (ABC-6) scale. Assessments were performed at baseline and after the 4-week program. At the end of the treatment periods, KAT score, BBS score, time in OLS and TUG, gait speeds under single- and dual-task conditions, and ABC-6 scale scores improved significantly in all patients (p gait speeds under single- and dual-task conditions showed significantly greater improvement in the dual-task balance training group than in the single-task balance training group (p gait speeds showed greater improvement following the application of a specific type of dual-task exercise programs

  16. Performance Enhancements Under Dual-task Conditions

    Science.gov (United States)

    Kramer, A. F.; Wickens, C. D.; Donchin, E.

    1984-01-01

    Research on dual-task performance has been concerned with delineating the antecedent conditions which lead to dual-task decrements. Capacity models of attention, which propose that a hypothetical resource structure underlies performance, have been employed as predictive devices. These models predict that tasks which require different processing resources can be more successfully time shared than tasks which require common resources. The conditions under which such dual-task integrality can be fostered were assessed in a study in which three factors likely to influence the integrality between tasks were manipulated: inter-task redundancy, the physical proximity of tasks and the task relevant objects. Twelve subjects participated in three experimental sessions in which they performed both single and dual-tasks. The primary task was a pursuit step tracking task. The secondary tasks required the discrimination between different intensities or different spatial positions of a stimulus. The results are discussed in terms of a model of dual-task integrality.

  17. El anillo de los números duales

    OpenAIRE

    Jiménez, Haydee; Luque, Carlos Julio

    2007-01-01

    Se inicia con una presentación de la estructura de * - Álgebra de los números duales; se muestran diferentes representaciones que permiten la definición de potencias racionales de números duales, lo que exige una extensión de su estructura a un anillo de números duales con coeficientes complejos. Seguidamente se estudian la función exponencial dual y la función logaritmo dual que permiten la definición de potencias duales de un número dual; luego se estudian ecuaciones en los números duales h...

  18. Quantum dynamics in dual spaces

    International Nuclear Information System (INIS)

    Sudarshan, E.C.G.

    1993-01-01

    Quantum mechanics gives us information about spectra of dynamical variables and transition rates including scattering cross sections. They can be exhibited as spectral information in analytically continued spaces and their duals. Quantum mechanics formulated in these generalized spaces is used to study scattering and time evolution. It is shown that the usual asymptotic condition is inadequate to deal with scattering of composite or unstable particles. Scattering theory needs amendment when the interacting system is not isospectral with the free Hamiltonian, and the amendment is formulated. Perturbation theory in generalized spaces is developed and used to study the deletion and augmentation of the spectrum of the Hamiltonian. A complete set of algebraically independent constants for an interacting system is obtained. The question of the breaking of time symmetry is discussed

  19. The yang mills gravity dual

    International Nuclear Information System (INIS)

    Crooks, David E.; Evans, Nick

    2003-01-01

    We describe a ten dimensional supergravity geometry which is dual to a gauge theory that is non-supersymmetric Yang Mills in the infra-red but reverts to N=4 super Yang Mills in the ultra-violet. A brane probe of the geometry shows that the scalar potential of the gauge theory is stable. We discuss the infra-red behaviour of the solution. The geometry describes a Schroedinger equation potential that determines the glueball spectrum of the theory; there is a mass gap and a discrete spectrum. The glueball mass predictions match previous AdS/CFT Correspondence computations in the non-supersymmetric Yang Mills theory, and lattice data, at the 10% level. (author)

  20. Dual-band infrared camera

    Science.gov (United States)

    Vogel, H.; Schlemmer, H.

    2005-10-01

    Every year, numerous accidents happen on European roads due to bad visibility (fog, night, heavy rain). Similarly, the dramatic aviation accidents of year 2001 in Milan and Zurich have reminded us that aviation safety is equally affected by reduced visibility. A dual-band thermal imager was developed in order to raise human situation awareness under conditions of reduced visibility especially in the automotive and aeronautical context but also for all transportation or surveillance tasks. The chosen wavelength bands are the Short Wave Infrared SWIR and the Long Wave Infrared LWIR band which are less obscured by reduced visibility conditions than the visible band. Furthermore, our field tests clearly show that the two different spectral bands very often contain complementary information. Pyramidal fusion is used to integrate complementary and redundant features of the multi-spectral images into a fused image which can be displayed on a monitor to provide more and better information for the driver or pilot.

  1. Dual-ROI radionuclide ventriculography

    International Nuclear Information System (INIS)

    Standke, R.; Hoer, G.; Kanemoto, N.; Maul, F.D.

    1981-01-01

    Accurate determination of the left ventricular activity function is the precondition for a quantitative analysis of the ventricular volume function. During the volume reduction period, extra-myocardial tissue penetrates into the ROI of the late diastole. This curve-distorting activity cannot be eliminated by a single-ROI technique. Of the multiple-ROI techniques, the dual-ROI method is the least complex and tedions and involves the least methodological error. At the time of maximum volume change rates, the curve may be distorted if the late diastolic ROI is inaccurately defined. A method is described which uses only the counting rate over the late diastolic ROI and corrects it only on the basis of the counting rate of the late systolic ROI. The time parameters remain uninfluenced by this correction method while the volumetric parameters are corrected. (orig./APR) [de

  2. Dual manifold heat pipe evaporator

    Science.gov (United States)

    Adkins, D.R.; Rawlinson, K.S.

    1994-01-04

    An improved evaporator section is described for a dual manifold heat pipe. Both the upper and lower manifolds can have surfaces exposed to the heat source which evaporate the working fluid. The tubes in the tube bank between the manifolds have openings in their lower extensions into the lower manifold to provide for the transport of evaporated working fluid from the lower manifold into the tubes and from there on into the upper manifold and on to the condenser portion of the heat pipe. A wick structure lining the inner walls of the evaporator tubes extends into both the upper and lower manifolds. At least some of the tubes also have overflow tubes contained within them to carry condensed working fluid from the upper manifold to pass to the lower without spilling down the inside walls of the tubes. 1 figure.

  3. Saturation in dual radiation action

    International Nuclear Information System (INIS)

    Rossi, H.H.; Zaider, M.

    1988-01-01

    The theory of dual radiation action (TDRA) was developed with the aim of applying microdosimetry to radiobiology. It therefore can deal only with the first phases in a long chain of events that results in patent effects. It is, however, clear that the initial spatial and temporal pattern of energy deposition has a profound influence on the ultimate outcome. As often happens, the early formulation of the theory contained a number of simplifying assumptions. Although most of these were explicitly stated when the first version of the TDRA was published experimental data obtained when the limitations are important were cited as contrary evidence causing considerable confusion. A more advanced version eliminated some of the restrictions but there remain others, one of which relates to certain aspects of saturation which are addressed here

  4. Dual processing and diagnostic errors.

    Science.gov (United States)

    Norman, Geoff

    2009-09-01

    In this paper, I review evidence from two theories in psychology relevant to diagnosis and diagnostic errors. "Dual Process" theories of thinking, frequently mentioned with respect to diagnostic error, propose that categorization decisions can be made with either a fast, unconscious, contextual process called System 1 or a slow, analytical, conscious, and conceptual process, called System 2. Exemplar theories of categorization propose that many category decisions in everyday life are made by unconscious matching to a particular example in memory, and these remain available and retrievable individually. I then review studies of clinical reasoning based on these theories, and show that the two processes are equally effective; System 1, despite its reliance in idiosyncratic, individual experience, is no more prone to cognitive bias or diagnostic error than System 2. Further, I review evidence that instructions directed at encouraging the clinician to explicitly use both strategies can lead to consistent reduction in error rates.

  5. [Design of Dual-Beam Spectrometer in Spectrophotometer for Colorimetry].

    Science.gov (United States)

    Liu, Yi-xuan; Yan, Chang-xiang

    2015-07-01

    Spectrophotometers for colorimetry are usually composed of two independent and identical spectrometers. In order to reduce the volume of spectrophotometer for colorimetry, a design method of double-beam spectrometer is put forward. A traditional spectrometer is modified so that a new spectrometer can realize the function of double spectrometers, which is especially suitable for portable instruments. One slit is replaced by the double-slit, than two beams of spectrum can be detected. The working principle and design requirement of double-beam spectrometer are described. A spectrometer of portable spectrophotometer is designed by this method. A toroidal imaging mirror is used for the Czerny-Turner double-beam spectrometer in this paper, which can better correct astigmatism, and prevent the dual-beam spectral crosstalk. The results demonstrate that the double-beam spectrometer designed by this method meets the design specifications, with the spectral resolution less than 10 nm, the spectral length of 9.12 mm, and the volume of 57 mm x 54 mm x 23 mm, and without the dual-beam spectral overlap in the detector either. Comparing with a traditional spectrophotometer, the modified spectrophotometer uses a set of double-beam spectrometer instead of two sets of spectrometers, which can greatly reduce the volume. This design method can be specially applied in portable spectrophotometers, also can be widely applied in other double-beam spectrophotometers, which offers a new idea for the design of dual-beam spectrophotometers.

  6. Optimized batteries for cars with dual electrical architecture

    Science.gov (United States)

    Douady, J. P.; Pascon, C.; Dugast, A.; Fossati, G.

    During recent years, the increase in car electrical equipment has led to many problems with traditional starter batteries (such as cranking failure due to flat batteries, battery cycling etc.). The main causes of these problems are the double function of the automotive battery (starter and service functions) and the difficulties in designing batteries well adapted to these two functions. In order to solve these problems a new concept — the dual-concept — has been developed with two separate batteries: one battery is dedicated to the starter function and the other is dedicated to the service function. Only one alternator charges the two batteries with a separation device between the two electrical circuits. The starter battery is located in the engine compartment while the service battery is located at the rear of the car. From the analysis of new requirements, battery designs have been optimized regarding the two types of functions: (i) a small battery with high specific power for the starting function; for this function a flooded battery with lead-calcium alloy grids and thin plates is proposed; (ii) for the service function, modified sealed gas-recombinant batteries with cycling and deep-discharge ability have been developed. The various advantages of the dual-concept are studied in terms of starting reliability, battery weight, and voltage supply. The operating conditions of the system and several dual electrical architectures have also been studied in the laboratory and the car. The feasibility of the concept is proved.

  7. Protection of Lithium (Li) Anodes Using Dual Phase Electrolytes

    Energy Technology Data Exchange (ETDEWEB)

    Mikhaylik, Yuriy [Sion Power Corporation, Tucson, AZ (United States)

    2014-09-30

    Sion Power focused on metallic lithium anode protection, employing the Dual-Phase Electrolyte approach. The objective of this project was to develop a unique electrolyte providing two liquid phases having good Li+ conductivity, self-partitioning and immiscibility, serving separately the cathode and anode electrodes. This Dual-Phase Electrolyte was combined with thin film multi-layer, physical barrier membranes developed partially under a separate ARPA-E funded project. All these protective structures were stabilized by externally applied pressure. This strategy was used for Li-S cells. The development directly addressed cell safety, particularly higher thermal stability, while also allowing higher energies and cycle life. Safety tests showed that 100% of cells with Dual-Phase Electrolyte were intact and did not exhibit thermal runaway up to 178 °C and thus met the project objective of increasing the runaway temperature to >165°C. Cells also passed cycling at USABC Dynamic Stress Test conditions developed for Electric Vehicle applications and generated specific energy > 300 Wh/kg.

  8. Dual antiretroviral therapy for HIV infection.

    Science.gov (United States)

    Soriano, Vicente; Fernandez-Montero, Jose Vicente; Benitez-Gutierrez, Laura; Mendoza, Carmen de; Arias, Ana; Barreiro, Pablo; Peña, José M; Labarga, Pablo

    2017-08-01

    For two decades, triple combinations of antiretrovirals have been the standard treatment for HIV infection. The challenges of such lifelong therapy include long-term side effects, high costs and reduced drug adherence. The recent advent of more potent and safer antiretrovirals has renewed the interest for simpler HIV regimens. Areas covered: We discuss the pros and cons of dual antiretroviral therapies in both drug-naïve and in treatment-experienced patients with viral suppression (switch strategy). Expert opinion: Some dual antiretroviral regimens are safe and efficacious, particularly as maintenance therapy. At this time, combinations of dolutegravir plus rilpivirine represent the best dual regimen. Longer follow-up and larger study populations are needed before supporting dolutegravir plus lamivudine. In contrast, dual therapy based on maraviroc is less effective. Although dual regimens with boosted protease inhibitors plus either lamivudine or raltegravir may be effective, they are penalized by metabolic side effects and risk for drug interactions. The newest dual regimens could save money, reduce toxicity and spare drug options for the future. For the first time in HIV therapeutics, less can be more. Dual therapy switching has set up a new paradigm in HIV treatment that uses induction-maintenance.

  9. Novel CFT duals for extreme black holes

    International Nuclear Information System (INIS)

    Chen Bin; Zhang Jiaju

    2012-01-01

    In this paper, we study the CFT duals for extreme black holes in the stretched horizon formalism. We consider the extremal RN, Kerr-Newman-AdS-dS, as well as the higher dimensional Kerr-AdS-dS black holes. In all these cases, we reproduce the well-established CFT duals. Actually we show that for stationary extreme black holes, the stretched horizon formalism always gives rise to the same dual CFT pictures as the ones suggested by ASG of corresponding near horizon geometries. Furthermore, we propose new CFT duals for 4D Kerr-Newman-AdS-dS and higher dimensional Kerr-AdS-dS black holes. We find that every dual CFT is defined with respect to a rotation in certain angular direction, along which the translation defines a U(1) Killing symmetry. In the presence of two sets of U(1) symmetry, the novel CFT duals are generated by the modular group SL(2,Z), and for n sets of U(1) symmetry there are general CFT duals generated by T-duality group SL(n,Z).

  10. Dual voltage power supply with 48 volt

    Energy Technology Data Exchange (ETDEWEB)

    Froeschl, Joachim; Proebstle, Hartmut; Sirch, Ottmar [BMW Group, Muenchen (Germany)

    2012-11-01

    Automotive electrics/electronics have just reached a period of tremendous change. High voltage systems for Hybrid, Plug-In Hybrid or Battery Electric Vehicles with high power electric motors, high energy accumulators and electric climate compressors will be introduced in order to achieve the challenging targets for CO{sub 2} emissions and energy efficiency and to anticipate the mobility of the future. Additionally, innovations and the continuous increase of functionality for comfort, safety, driver assistance and infotainment systems require more and more electrical power of the vehicle power supply at all. On the one hand side electrified vehicles will certainly achieve a significant market share, on the other hand side they will increase the pressure to conventional vehicles with combustion engines for fuel consumption and CO{sub 2} emissions. These vehicles will be enabled to keep their competitiveness by new functions and the optimization of their electric systems. A dual voltage power supply with 48 Volt and 12 Volt will be one of the key technologies to realize these requirements. The power capability of the existing 12 Volt power supply has reached its limits. Further potentials can only be admitted by the introduction of 48 Volt. For this reason the car manufacturers Audi, BMW, Daimler, Porsche and Volkswagen started very early on this item and developed a common specification of the new voltage range. Now, it is necessary to identify the probable systems at this voltage range and to start the developments. (orig.)

  11. Studies on biogas-fuelled compression ignition engine under dual fuel mode.

    Science.gov (United States)

    Mahla, Sunil Kumar; Singla, Varun; Sandhu, Sarbjot Singh; Dhir, Amit

    2018-04-01

    Experimental investigation has been carried out to utilize biogas as an alternative source of energy in compression ignition (CI) engine under dual fuel operational mode. Biogas was inducted into the inlet manifold at different flow rates along with fresh air through inlet manifold and diesel was injected as a pilot fuel to initiate combustion under dual fuel mode. The engine performance and emission characteristics of dual fuel operational mode were analyzed at different biogas flow rates and compared with baseline conventional diesel fuel. Based upon the improved performance and lower emission characteristics under the dual fuel operation, the optimum flow rate of biogas was observed to be 2.2 kg/h. The lower brake thermal efficiency (BTE) and higher brake-specific energy consumption (BSEC) were noticed with biogas-diesel fuel under dual fuel mode when compared with neat diesel operation. Test results showed reduced NO x emissions and smoke opacity level in the exhaust tailpipe emissions. However, higher hydrocarbon (HC) and carbon monoxide (CO) emissions were noticed under dual fuel mode at entire engine loads when compared with baseline fossil petro-diesel. Hence, the use of low-cost gaseous fuel such as biogas would be an economically viable proposition to address the current and future problems of energy scarcity and associated environmental concerns.

  12. Effects of dual pathology on cognitive outcome following left anterior temporal lobectomy for treatment of epilepsy.

    Science.gov (United States)

    Prayson, B E; Prayson, R A; Kubu, C S; Bingaman, W; Najm, I M; Busch, R M

    2013-09-01

    The objective of this retrospective study was to determine if dual pathology [DUAL - focal cortical dysplasia (FCD) and mesial temporal sclerosis (MTS)] in patients with left temporal lobe epilepsy is associated with greater risk for cognitive decline following temporal lobectomy than single pathology (MTS only). Sixty-three adults (Mage=36.5years, female: 52.4%) who underwent left anterior temporal lobectomy for treatment of epilepsy (MTS=28; DUAL=35) completed preoperative and postoperative neuropsychological evaluations. The base rate of dual pathology was 55.5%. Repeated measures ANOVAs yielded significant 2-way interactions (group×time) on most measures of language and memory with generally moderate effect sizes. Specifically, patients with MTS only demonstrated postoperative declines, while those with dual pathology remained unchanged or improved. Results suggest that dual pathology may be associated with better cognitive outcome following epilepsy surgery than MTS alone, possibly reflecting limited functionality of the resected tissue or intrahemispheric reorganization of function in the context of a developmental lesion. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Feasibility of a dual regime gyrotron

    International Nuclear Information System (INIS)

    Sawant, Ashwini; Jain, Prerit; Kartikeyan, M.V.

    2012-01-01

    The design concept of a 42/84 GHz, 500 kW, CW, dual-regime gyrotron for ECRH of plasma in an experimental Tokamak will be presented in this paper. Operation at 42 GHz is fundamental where as that in 84 GHz will be second harmonic so that a similar guidance system will be retained for dual regime operation. In this paper, the mode competition and mode selection procedures are presented for such a dual regime operation. Cold cavity design and self-consistent calculations will be carried out for power and efficiencies. (author)

  14. Dual of big bang and big crunch

    International Nuclear Information System (INIS)

    Bak, Dongsu

    2007-01-01

    Starting from the Janus solution and its gauge theory dual, we obtain the dual gauge theory description of the cosmological solution by the procedure of double analytic continuation. The coupling is driven either to zero or to infinity at the big-bang and big-crunch singularities, which are shown to be related by the S-duality symmetry. In the dual Yang-Mills theory description, these are nonsingular as the coupling goes to zero in the N=4 super Yang-Mills theory. The cosmological singularities simply signal the failure of the supergravity description of the full type IIB superstring theory

  15. Deep white matter hyperintensities, microstructural integrity and dual task walking in older people.

    Science.gov (United States)

    Ghanavati, Tabassom; Smitt, Myriam Sillevis; Lord, Stephen R; Sachdev, Perminder; Wen, Wei; Kochan, Nicole A; Brodaty, Henry; Delbaere, Kim

    2018-01-03

    To examine neural, physiological and cognitive influences on gait speed under single and dual-task conditions. Sixty-two community-dwelling older people (aged 80.0 ± 4.2 years) participated in our study. Gait speed was assessed with a timed 20-meter walk under single and dual-task (reciting alternate letters of the alphabet) conditions. Participants also underwent tests to estimate physiological fall risk based on five measures of sensorimotor function, cognitive function across five domains, brain white matter (WM) hyperintensities and WM microstructural integrity by measuring fractional anisotropy (FA). Univariate linear regression analyses showed that global physiological and cognitive measures were associated with single (β = 0.594 and β=-0.297, respectively) and dual-task gait speed (β = 0.306 and β=-0.362, respectively). Deep WMHs were associated with dual-task gait speed only (β = 0.257). Multivariate mediational analyses showed that global and executive cognition reduced the strength of the association between deep WMHs and dual-task gait speed by 27% (β = 0.188) and 44% (β = 0.145) respectively. There was a significant linear association between single-task gait speed and mean FA values of the genu (β=-0.295) and splenium (β=-0.326) of the corpus callosum, and between dual-task gait speed and mean FA values of Superior Cerebellar Peduncle (β=-0.284), splenium of the Corpus Callosum (β=-0.286) and Cingulum (β=-0.351). Greater deep WMH volumes are associated with slower walking speed under dual-task conditions, and this relationship is mediated in part by global cognition and executive abilities specifically. Furthermore, both cerebellum and cingulum are related to dual-task walking due to their role in motor skill performance and attention, respectively.

  16. Pattern and predictors of dual antiplatelet use after coronary artery bypass graft surgery.

    Science.gov (United States)

    Mori, Makoto; Shioda, Kayoko; Yun, James J; Mangi, Abeel A; Darr, Umer; Geirsson, Arnar

    2018-02-01

    Resumption of dual antiplatelet therapy after coronary artery bypass grafting in patients presenting with acute coronary syndrome is recommended, but the current practice pattern in the United States remains unknown. We aimed to investigate the current pattern of dual antiplatelet therapy use after coronary artery bypass grafting at the Yale-New Haven Hospital. We conducted a single-center retrospective review of patients who presented with acute coronary syndrome and underwent coronary artery bypass grafting between 2014 and 2016. The primary outcome was hospital discharge with dual antiplatelet therapy. Mixed-effect multivariate logistic regression was used to evaluate predictors of dual antiplatelet therapy use or nonuse, accounting for surgeon-specific preference. The discriminatory ability of the model was evaluated with receiver operating characteristics analysis. Of 572 patients included, only 29% were discharged with dual antiplatelet therapy. In the mixed-effect multivariate model isolating surgeon preferences, increase in age (odds ratio, 0.95; 95% confidence interval, 0.92-0.98; P dual antiplatelet therapy use. Off-pump coronary artery bypass grafting compared with on-pump coronary artery bypass grafting was associated with increased odds of dual antiplatelet therapy use (odds ratio, 31.5; 95% confidence interval, 12.8-77.2; P dual antiplatelet therapy use in patients with acute coronary syndrome who underwent coronary artery bypass grafting was low and variable among surgeons. The use or nonuse was guided by previously established risk factors of recurrent ischemia and bleeding, along with surgeon preference. Published by Elsevier Inc.

  17. Adapting Nielsen's Design Heuristics to Dual Processing for Clinical Decision Support.

    Science.gov (United States)

    Taft, Teresa; Staes, Catherine; Slager, Stacey; Weir, Charlene

    2016-01-01

    The study objective was to improve the applicability of Nielson's standard design heuristics for evaluating electronic health record (EHR) alerts and linked ordering support by integrating them with Dual Process theory. Through initial heuristic evaluation and a user study of 7 physicians, usability problems were identified. Through independent mapping of specific usability criteria to support for each of the Dual Cognitive processes (S1 and S2) and deliberation, agreement was reached on mapping criteria. Finally, usability errors from the heuristic and user study were mapped to S1 and S2. Adding a dual process perspective to specific heuristic analysis increases the applicability and relevance of computerized health information design evaluations. This mapping enables designers to measure that their systems are tailored to support attention allocation. System 1 will be supported by improving pattern recognition and saliency, and system 2 through efficiency and control of information access.

  18. Adapting Nielsen’s Design Heuristics to Dual Processing for Clinical Decision Support

    Science.gov (United States)

    Taft, Teresa; Staes, Catherine; Slager, Stacey; Weir, Charlene

    2016-01-01

    The study objective was to improve the applicability of Nielson’s standard design heuristics for evaluating electronic health record (EHR) alerts and linked ordering support by integrating them with Dual Process theory. Through initial heuristic evaluation and a user study of 7 physicians, usability problems were identified. Through independent mapping of specific usability criteria to support for each of the Dual Cognitive processes (S1 and S2) and deliberation, agreement was reached on mapping criteria. Finally, usability errors from the heuristic and user study were mapped to S1 and S2. Adding a dual process perspective to specific heuristic analysis increases the applicability and relevance of computerized health information design evaluations. This mapping enables designers to measure that their systems are tailored to support attention allocation. System 1 will be supported by improving pattern recognition and saliency, and system 2 through efficiency and control of information access. PMID:28269915

  19. On R-duals and the duality principle

    DEFF Research Database (Denmark)

    Christensen, Ole; Stoeva, Diana

    2015-01-01

    . In this paper we discuss the relationship between the R-duals and a variant, called R-duals of type III, introduced in 2014. In contrast to the original R-duals, it is known that the R-duals of type III generalize the duality principle for all Gabor frames, but we believe that a smaller and more convenient...

  20. Properties of dual codes defined by nondegenerate forms

    Directory of Open Access Journals (Sweden)

    Steve Szabo

    2017-01-01

    Full Text Available Dual codes are defined with respect to non-degenerate sesquilinear or bilinear forms over a finite Frobenius ring. These dual codes have the properties one expects from a dual code: they satisfy a double-dual property, they have cardinality complementary to that of the primal code, and they satisfy the MacWilliams identities for the Hamming weight.

  1. Specifying Specification.

    Science.gov (United States)

    Paulo, Norbert

    2016-03-01

    This paper tackles the accusation that applied ethics is no serious academic enterprise because it lacks theoretical bracing. It does so in two steps. In the first step I introduce and discuss a highly acclaimed method to guarantee stability in ethical theories: Henry Richardson's specification. The discussion shows how seriously ethicists take the stability of the connection between the foundational parts of their theories and their further development as well as their "application" to particular problems or cases. A detailed scrutiny of specification leads to the second step, where I use insights from legal theory to inform the debate around stability from that point of view. This view reveals some of specification's limitations. I suggest that, once specification is sufficiently specified, it appears astonishingly similar to deduction as used in legal theory. Legal theory also provides valuable insight into the functional range of deduction and its relation to other forms of reasoning. This leads to a richer understanding of stability in normative theories and to a smart division of labor between deduction and other forms of reasoning. The comparison to legal theory thereby provides a framework for how different methods such as specification, deduction, balancing, and analogy relate to one another.

  2. Dual diagnosis resource needs in Spain: a national survey of professionals.

    Science.gov (United States)

    Szerman, Nestor; Vega, Pablo; Grau-López, Lara; Barral, Carmen; Basurte-Villamor, Ignacio; Mesías, Beatriz; Rodríguez-Cintas, Laia; Martínez-Raga, José; Casas, Miguel; Roncero, Carlos

    2014-01-01

    Since provision of integrated services for patients with dual pathology or dual disorders (coexistence of an addictive disorder and another mental health disorder) is an important challenge in mental health, this study assessed health care professionals' perceptions and knowledge of the current state of specific resources for patients with dual pathology in Spain. We conducted a national survey of health care professionals seeing patients with dual pathology in treatment facilities throughout Spain. Participants completed a specific online questionnaire about the needs of and available resources for patients with dual pathology. A total of 659 professionals, mostly psychologists (n = 286, 43.4%) or psychiatrists (n = 217, 32.9%), participated in the study. Nearly all participants who responded to these items reported that specific resources for dual pathology were needed (n = 592/635, 93.2%); 76.7% (n = 487) identified intermediate resources, 68.8% (n = 437) acute detoxification units, and 64.6% (n = 410) medium-stay rehabilitation units as particularly necessary. In the opinion of 54.0% of respondents (n = 343), integrated mental health and addiction treatment services were available. Of the participants who answered these items, only a small proportion (n = 162/605, 26.8%) reported that there were appropriate outpatient programs for dual pathology, 30.4% (n = 184/605) specific hospitalization units, 16.9% (n = 99/587) subacute inpatient units, 34.2% (n = 201/587) outpatient intermediate resources, 15.5% (n = 91/587) day hospitals, and 21.5% (n = 126/587) day centers. Conversely, 62.5% (n = 378/587) of participants reported a greater presence of specific detoxification/withdrawal units, 47.3% (n = 286/587) psychiatric acute admission units, and 41.9% (n = 246/587) therapeutic communities. In the professionals' opinion, the presence of specialty programs was low; 11.6% of respondents (n = 68/587) reported that vocational programs and 16.7% (n = 98/587) reported

  3. A Dual Process Approach to Understand Tourists’ Destination Choice Processes

    DEFF Research Database (Denmark)

    Kock, Florian; Josiassen, Alexander; Assaf, Albert

    2017-01-01

    Most studies that investigate tourists' choices of destinations apply the concept of mental destination representations, also referred to as destination image. The present study investigates tourists’ destination choice processes by conceptualizing how different components of destination image...... are mentally processed in tourists' minds. Specifically, the seminal dual processing approach is applied to the destination image literature. By doing this, we argue that some components of mental destination representations are processed systematically while others serve as inputs for heuristics...... that individuals apply to inform their decision making. Understanding how individuals make use of their mental destination representations and how they color their decision-making is essential in order to better explain tourist behavior....

  4. Dual Headquarters Involvement in Multibusiness Firms

    DEFF Research Database (Denmark)

    Nell, Phillip Christopher; Kappen, Philip; Dellestrand, Henrik

    The strategy literature has shown that headquarters involve themselves into subsidiary operations to add value. Yet, little is known about the extent to which multiple headquarters do so. Therefore, we investigate antecedents of corporate and divisional headquarters’ involvement in innovation...... development projects of subsidiaries. Analyses of 85 innovation development projects reveal that dual innovation importance (innovation that is important for the division and the rest of the firm), and dual dual embeddedness (innovating subsidiary is embedded both within the division and in the rest...... of the firm) lead to greater dual headquarters involvement, especially when the innovation development network is large. The results contribute to the literature on complex parenting and theory of selective headquarters involvement....

  5. Dual Component Removable Partial Denture shows improved ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-02-18

    Feb 18, 2009 ... 2Faculty of Dentistry, the University of Hong Kong, Hong Kong. 3Department of ... an example of poor oral condition caused mainly by periodontitis, and ... working model of the Dual Component Removable Partial Denture.

  6. Searching for dual active galactic nuclei

    Indian Academy of Sciences (India)

    K. Rubinur

    2018-02-09

    Feb 9, 2018 ... Abstract. Binary or dual active galactic nuclei (DAGN) are expected from galaxy formation theories. How- ... cuss results from the multi-frequency Expanded Very .... mid-IR color using WISE observations where they have.

  7. Dual Enrollment Participation from the Student Perspective

    Science.gov (United States)

    Kanny, M. Allison

    2015-01-01

    This chapter examines the experiences of five high school students previously enrolled in dual enrollment courses, and discusses the perceived benefits and disadvantages of these experiences from the student perspective.

  8. Dual Eligibles and Potentially Avoidable Hospitalizations

    Data.gov (United States)

    U.S. Department of Health & Human Services — About 25 percent of the hospitalizations for dual eligible beneficiaries in 2005 were potentially avoidable. Medicare and Medicaid spending for those potentially...

  9. Dual Career Marriages: Elements for Potential Success.

    Science.gov (United States)

    Maples, Mary F.

    1981-01-01

    Examines the family and work relationships of dual career couples and discusses the advantages and disadvantages of these relationships. Various ingredients including personality traits that contribute to the success of the two-career partnership are listed. (RC)

  10. Truncated Dual-Cap Nucleation Site Development

    Science.gov (United States)

    Matson, Douglas M.; Sander, Paul J.

    2012-01-01

    During heterogeneous nucleation within a metastable mushy-zone, several geometries for nucleation site development must be considered. Traditional spherical dual cap and crevice models are compared to a truncated dual cap to determine the activation energy and critical cluster growth kinetics in ternary Fe-Cr-Ni steel alloys. Results of activation energy results indicate that nucleation is more probable at grain boundaries within the solid than at the solid-liquid interface.

  11. Limitations in dual-task performance

    OpenAIRE

    Pannebakker, Merel Mathilde

    2009-01-01

    In this thesis, the effect of information-processing overload on working-memory dependent information processing was examined using dual-task paradigms. The experiments described strengthen the importance of a functional explanation for dual-task limitations. First, it showed evidence for a unified coding medium (as put forward in the theory of event coding; Hommel, Müsseler, Aschersleben, & Prinz, 2001) in which features, operations and responses are available and can influence each other. A...

  12. Probe specificity

    International Nuclear Information System (INIS)

    Laget, J.M.

    1986-11-01

    Specificity and complementarity of hadron and electron probes must be systematically developed to answer three questions currently asked in intermediate energy nuclear physics: what is nucleus structure at short distances, what is nature of short range correlations, what is three body force nature [fr

  13. Dual-energy CT for detection of endoleaks after endovascular abdominal aneurysm repair: usefulness of colored iodine overlay.

    Science.gov (United States)

    Ascenti, Giorgio; Mazziotti, Silvio; Lamberto, Salvatore; Bottari, Antonio; Caloggero, Simona; Racchiusa, Sergio; Mileto, Achille; Scribano, Emanuele

    2011-06-01

    The purpose of our study was to evaluate the value of dual-source dual-energy CT with colored iodine overlay for detection of endoleaks after endovascular abdominal aortic aneurysm repair. We also calculated the potential dose reduction by using a dual-energy CT single-phase protocol. From November 2007 to November 2009, 74 patients underwent CT angiography 2-7 days after endovascular repair during single-energy unenhanced and dual-energy venous phases. By using dual-energy software, the iodine overlay was superimposed on venous phase images with different percentages ranging between 0 (virtual unenhanced images) and 50-75% to show the iodine in an orange color. Two blinded readers evaluated the data for diagnosis of endoleaks during standard unenhanced and venous phase images (session 1, standard of reference) and virtual unenhanced and venous phase images with colored iodine overlay images (session 2). We compared the effective dose radiation of a single-energy biphasic protocol with that of a single-phase dual-energy protocol. The diagnostic accuracy of session 2 was calculated. The mean dual-energy effective dose was 7.27 mSv. By using a dual-energy single-phase protocol, we obtained a mean dose reduction of 28% with respect to a single-energy biphasic protocol. The diagnostic accuracy of session 2 was: 100% sensitivity, 100% specificity, 100% negative predictive value, and 100% positive predictive value. Statistically significant differences in the level of confidence for endoleak detection between the two sessions were found by reviewers for scores 3-5. Dual-energy CT with colored iodine overlay is a useful diagnostic tool in endoleak detection. The use of a dual-energy single-phase study protocol will lower radiation exposure to patients.

  14. Dynamic dual-tracer PET reconstruction.

    Science.gov (United States)

    Gao, Fei; Liu, Huafeng; Jian, Yiqiang; Shi, Pengcheng

    2009-01-01

    Although of important medical implications, simultaneous dual-tracer positron emission tomography reconstruction remains a challenging problem, primarily because the photon measurements from dual tracers are overlapped. In this paper, we propose a simultaneous dynamic dual-tracer reconstruction of tissue activity maps based on guidance from tracer kinetics. The dual-tracer reconstruction problem is formulated in a state-space representation, where parallel compartment models serve as continuous-time system equation describing the tracer kinetic processes of dual tracers, and the imaging data is expressed as discrete sampling of the system states in measurement equation. The image reconstruction problem has therefore become a state estimation problem in a continuous-discrete hybrid paradigm, and H infinity filtering is adopted as the estimation strategy. As H infinity filtering makes no assumptions on the system and measurement statistics, robust reconstruction results can be obtained for the dual-tracer PET imaging system where the statistical properties of measurement data and system uncertainty are not available a priori, even when there are disturbances in the kinetic parameters. Experimental results on digital phantoms, Monte Carlo simulations and physical phantoms have demonstrated the superior performance.

  15. Improving Sustainability through a Dual Audit System

    Directory of Open Access Journals (Sweden)

    Shun-Ji Jin

    2018-01-01

    Full Text Available As a consequence of a large-scale accounting fraud, China implemented a dual audit system for listed companies issuing foreign stocks (B shares and H shares from 2001 to 2006, before adopting Chinese-IFRS in 2007. At the end of 2010, the EU proposed that listed corporations over a certain size should be required to implement a joint audit system. However, only a few countries have implemented this system, and thus, data and references are extremely limited. The dual audit system is called the “twin” of the joint audit system. We analyze whether the dual system improves a company’s earnings quality. Earnings quality is studied by means of real earnings management, and the variable of loss aversion. We find that real earnings management of dual audited enterprises is lower than that of single audited (A-share enterprises, and the inclination toward loss aversion of enterprises in the foreign share market has not increased significantly relative to the A-share enterprises after the abolition of the dual audit system. The results indicate that a dual audit system improves earnings quality. We expect that the conclusions of this research will resolve the issues and concerns about the joint audit system.

  16. Myocardial perfusion imaging with dual energy CT

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Kwang Nam [Division of Cardiovascular Imaging, Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC (United States); Department of Radiology, SMG-SNU Boramae Medical Center, Seoul (Korea, Republic of); De Cecco, Carlo N. [Division of Cardiovascular Imaging, Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC (United States); Caruso, Damiano [Division of Cardiovascular Imaging, Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC (United States); Department of Radiological Sciences, Oncology and Pathology, University of Rome “Sapienza”, Rome (Italy); Tesche, Christian [Division of Cardiovascular Imaging, Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC (United States); Department of Cardiology and Intensive Care Medicine, Heart Center Munich-Bogenhausen, Munich (Germany); Spandorfer, Adam; Varga-Szemes, Akos [Division of Cardiovascular Imaging, Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC (United States); Schoepf, U. Joseph, E-mail: schoepf@musc.edu [Division of Cardiovascular Imaging, Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC (United States); Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, SC (United States)

    2016-10-15

    Highlights: • Stress dual-energy sCTMPI offers the possibility to directly detect the presence of myocardial perfusion defects. • Stress dual-energy sCTMPI allows differentiating between reversible and fixed myocardial perfusion defects. • The combination of coronary CT angiography and dual-energy sCTMPI can improve the ability of CT to detect hemodynamically relevant coronary artery disease. - Abstract: Dual-energy CT (DECT) enables simultaneous use of two different tube voltages, thus different x-ray absorption characteristics are acquired in the same anatomic location with two different X-ray spectra. The various DECT techniques allow material decomposition and mapping of the iodine distribution within the myocardium. Static dual-energy myocardial perfusion imaging (sCTMPI) using pharmacological stress agents demonstrate myocardial ischemia by single snapshot images of myocardial iodine distribution. sCTMPI gives incremental values to coronary artery stenosis detected on coronary CT angiography (CCTA) by showing consequent reversible or fixed myocardial perfusion defects. The comprehensive acquisition of CCTA and sCTMPI offers extensive morphological and functional evaluation of coronary artery disease. Recent studies have revealed that dual-energy sCTMPI shows promising diagnostic accuracy for the detection of hemodynamically significant coronary artery disease compared to single-photon emission computed tomography, invasive coronary angiography, and cardiac MRI. The aim of this review is to present currently available DECT techniques for static myocardial perfusion imaging and recent clinical applications and ongoing investigations.

  17. Combined Cytolytic Effects of a Vaccinia Virus Encoding a Single Chain Trimer of MHC-I with a Tax-Epitope and Tax-Specific CTLs on HTLV-I-Infected Cells in a Rat Model

    Directory of Open Access Journals (Sweden)

    Takashi Ohashi

    2014-01-01

    Full Text Available Adult T cell leukemia (ATL is a malignant lymphoproliferative disease caused by human T cell leukemia virus type I (HTLV-I. To develop an effective therapy against the disease, we have examined the oncolytic ability of an attenuated vaccinia virus (VV, LC16m8Δ (m8Δ, and an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL line, 4O1/C8, against an HTLV-I-infected rat T cell line, FPM1. Our results demonstrated that m8Δ was able to replicate in and lyse tumorigenic FPM1 cells but was incompetent to injure 4O1/C8 cells, suggesting the preferential cytolytic activity toward tumor cells. To further enhance the cytolysis of HTLV-I-infected cells, we modified m8Δ and obtained m8Δ/RT1AlSCTax180L, which can express a single chain trimer (SCT of rat major histocompatibility complex class I with a Tax-epitope. Combined treatment with m8Δ/RT1AlSCTax180L and 4O1/C8 increased the cytolysis of FPM1V.EFGFP/8R cells, a CTL-resistant subclone of FPM1, compared with that using 4O1/C8 and m8Δ presenting an unrelated peptide, suggesting that the activation of 4O1/C8 by m8Δ/RT1AlSCTax180L further enhanced the killing of the tumorigenic HTLV-I-infected cells. Our results indicate that combined therapy of oncolytic VVs with SCTs and HTLV-I-specific CTLs may be effective for eradication of HTLV-I-infected cells, which evade from CTL lysis and potentially develop ATL.

  18. Anatomical decomposition in dual energy chest digital tomosynthesis

    Science.gov (United States)

    Lee, Donghoon; Kim, Ye-seul; Choi, Sunghoon; Lee, Haenghwa; Choi, Seungyeon; Kim, Hee-Joung

    2016-03-01

    Lung cancer is the leading cause of cancer death worldwide and the early diagnosis of lung cancer has recently become more important. For early screening lung cancer, computed tomography (CT) has been used as a gold standard for early diagnosis of lung cancer [1]. The major advantage of CT is that it is not susceptible to the problem of misdiagnosis caused by anatomical overlapping while CT has extremely high radiation dose and cost compared to chest radiography. Chest digital tomosynthesis (CDT) is a recently introduced new modality for lung cancer screening with relatively low radiation dose compared to CT [2] and also showing high sensitivity and specificity to prevent anatomical overlapping occurred in chest radiography. Dual energy material decomposition method has been proposed for better detection of pulmonary nodules as means of reducing the anatomical noise [3]. In this study, possibility of material decomposition in CDT was tested by simulation study and actual experiment using prototype CDT. Furthermore organ absorbed dose and effective dose were compared with single energy CDT. The Gate v6 (Geant4 application for tomographic emission), and TASMIP (Tungsten anode spectral model using the interpolating polynomial) code were used for simulation study and simulated cylinder shape phantom consisted of 4 inner beads which were filled with spine, rib, muscle and lung equivalent materials. The patient dose was estimated by PCXMC 1.5 Monte Carlo simulation tool [4]. The tomosynthesis scan was performed with a linear movement and 21 projection images were obtained over 30 degree of angular range with 1.5° degree of angular interval. The proto type CDT system has same geometry with simulation study and composed of E7869X (Toshiba, Japan) x-ray tube and FDX3543RPW (Toshiba, Japan) detector. The result images showed that reconstructed with dual energy clearly visualize lung filed by removing unnecessary bony structure. Furthermore, dual energy CDT could enhance

  19. Dual Treatments as Starting Point for Integrative Perceptions in Teaching Mathematics

    Science.gov (United States)

    Kërënxhi, Svjetllana; Gjoci, Pranvera

    2015-01-01

    In this paper, we recommend mathematical teaching through dual treatments. The dual treatments notion, classified in dual interpretations, dual analyses, dual solutions, and dual formulations, is explained through concrete examples taken from mathematical textbooks of elementary education. Dual treatments provide opportunities for creating…

  20. Emotion-Work Performance among Dual-Earner Couples: Testing Four Theoretical Perspectives

    Science.gov (United States)

    Minnotte, Krista Lynn; Stevens, Daphne Pedersen; Minnotte, Michael C.; Kiger, Gary

    2007-01-01

    This study compares four theories of domestic labor in their ability to predict relative emotion-work performance among dual-earner couples. Specifically, the authors investigate the effects of gender ideology, time availability, relative resources, and crossover factors on the dependent variable of relative emotion-work performance using…