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  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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

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

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    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

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

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    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

  11. 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.

  12. 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.

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

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    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

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

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    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.

  15. Designing herpes viruses as oncolytics

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    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

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

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    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.

  17. 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.

  18. Designing herpes viruses as oncolytics

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    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.

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

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    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.

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

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    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.

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

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    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.

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

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    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.

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

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    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

  4. 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

  5. Promising oncolytic agents for metastatic breast cancer treatment

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    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 

  6. 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.

  7. 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.

  8. 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

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

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    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

  10. 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

  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. 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.

  13. 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.

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

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    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

  15. 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.

  16. 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.

  17. 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

  18. 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

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

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    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

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

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

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    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.

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

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    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 

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

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    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.

  4. 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.

  5. 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.

  6. 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 ...

  7. 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

  8. 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.

  9. 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

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

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    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.

  11. 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.

  12. Oncolytic Replication of E1b-Deleted Adenoviruses

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    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.

  13. 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.

  14. 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.

  15. High-throughput screening to enhance oncolytic virus immunotherapy

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    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

  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. 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. 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.

  19. 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

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. 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...

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. 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 

  16. 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.

  17. 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...

  18. 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.)

  19. 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.)

  20. 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.

  1. 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...

  2. 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...

  3. 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.

  4. 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.

  5. 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.

  6. 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.

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

    Directory of Open Access Journals (Sweden)

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

    Directory of Open Access Journals (Sweden)

    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

  9. 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.

  10. 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.

  11. 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.

  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. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. 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

  3. 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...

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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 ...

  10. 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.

  11. 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

  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. 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

  14. 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.

  15. 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

  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. 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.

  18. 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

  19. 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

  20. 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

  1. 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.

  2. 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.

  3. 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

  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. 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.

  6. 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

  7. 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.

  8. 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.

  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. 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.

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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...

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. 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)

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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

  14. [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.

  15. 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.

  16. 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

  17. 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…

  18. 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

  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. 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.

  1. 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.

  2. 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.

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

    Directory of Open Access Journals (Sweden)

    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

  4. 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.

  5. 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)

  6. 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.

  7. 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.

  8. 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

  9. 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...

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. 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....

  17. 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 

  18. 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.

  19. 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…

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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-...

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. 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.

  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. 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.

  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. 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.

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. 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

  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. 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

  18. 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.

  19. 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.

  20. 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.

  1. 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...

  2. 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.

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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....

  10. 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…

  11. 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.

  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. 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.

  14. 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.

  15. 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.)

  16. 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.

  17. 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.

  18. 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

  19. Dual-systems and the development of reasoning: competence-procedural systems.

    Science.gov (United States)

    Overton, Willis F; Ricco, Robert B

    2011-03-01

    Dual-system, dual-process, accounts of adult cognitive processing are examined in the context of a self-organizing relational developmental systems approaches to cognitive growth. Contemporary adult dual-process accounts describe a linear architecture of mind entailing two split-off, but interacting systems; a domain general, content-free 'analytic' system (system 2) and a domain specific highly contextualized 'heuristic' system (system 1). In the developmental literature on deductive reasoning, a similar distinction has been made between a domain general competence (reflective, algorithmic) system and a domain specific procedural system. In contrast to the linear accounts offered by empiricist, nativist, and/or evolutionary explanations, the dual competence-procedural developmental perspective argues that the mature systems emerge through developmental transformations as differentiations and intercoordinations of an early relatively undifferentiated action matrix. This development, whose microscopic mechanism is action-in-the-world, is characterized as being embodied, nonlinear, and epigenetic. WIREs Cogni Sci 2011 2 231-237 DOI: 10.1002/wcs.120 For further resources related to this article, please visit the WIREs website. © 2010 John Wiley & Sons, Ltd.

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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

  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. 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.

  13. 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.

  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. Comparative proteomics as a tool for identifying specific alterations within interferon response pathways in human glioblastoma multiforme cells

    DEFF Research Database (Denmark)

    Tarasova, Irina A; Tereshkova, Alesya V; Lobas, Anna A

    2018-01-01

    An acquisition of increased sensitivity of cancer cells to viruses is a common outcome of malignant progression that justifies the development of oncolytic viruses as anticancer therapeutics. Studying molecular changes that underlie the sensitivity to viruses would help to identify cases where on...

  16. 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....

  17. 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

  18. 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

  19. 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.

  20. 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...

  1. 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.

  2. 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.

  3. Potassium-Based Dual Ion Battery with Dual-Graphite Electrode.

    Science.gov (United States)

    Fan, Ling; Liu, Qian; Chen, Suhua; Lin, Kairui; Xu, Zhi; Lu, Bingan

    2017-08-01

    A potassium ion battery has potential applications for large scale electric energy storage systems due to the abundance and low cost of potassium resources. Dual graphite batteries, with graphite as both anode and cathode, eliminate the use of transition metal compounds and greatly lower the overall cost. Herein, combining the merits of the potassium ion battery and dual graphite battery, a potassium-based dual ion battery with dual-graphite electrode is developed. It delivers a reversible capacity of 62 mA h g -1 and medium discharge voltage of ≈3.96 V. The intercalation/deintercalation mechanism of K + and PF 6 - into/from graphite is proposed and discussed in detail, with various characterizations to support. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. 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.

  5. 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.

  6. Dual vector multiplet coupled to dual N=1 supergravity in 10D

    International Nuclear Information System (INIS)

    Nishino, Hitoshi; Rajpoot, Subhash

    2005-01-01

    We couple in superspace a dual vector multiplet (C m 1 ...m 7 ,λ α ) to the dual version of N=1 supergravity (e m a ,ψ m α ,M m 1 ...m 6 ,χ α ,Φ) in ten dimensions. The 7-form field C has its 8-form field strength H dual to the 2-form field strength F of the conventional vector multiplet. To simplify the computation, we use so-called beta-function-favored superspace constraints for dual supergravity developed for β-function computations. As in a more conventional constraint set, the H-Bianchi identity must have the form N and F, where N is the 7-form field strength in dual supergravity. The potential anomaly for the dual vector multiplet can be cancelled for the particular gauge group U(1) 496 by the Green-Schwarz mechanism. As a by-product, we also give the globally supersymmetric Abelian Dirac-Born-Infeld interactions for the dual vector multiplet for the first time

  7. 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.

  8. 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.

  9. Low-dose dual-energy cone-beam CT using a total-variation minimization algorithm

    International Nuclear Information System (INIS)

    Min, Jong Hwan

    2011-02-01

    Dual-energy cone-beam CT is an important imaging modality in diagnostic applications, and may also find its use in other application such as therapeutic image guidance. Despite of its clinical values, relatively high radiation dose of dual-energy scan may pose a challenge to its wide use. In this work, we investigated a low-dose, pre-reconstruction type of dual-energy cone-beam CT (CBCT) using a total-variation minimization algorithm for image reconstruction. An empirical dual-energy calibration method was used to prepare material-specific projection data. Raw data at high and low tube voltages are converted into a set of basis functions which can be linearly combined to produce material-specific data using the coefficients obtained through the calibration process. From much fewer views than are conventionally used, material specific images are reconstructed by use of the total-variation minimization algorithm. An experimental study was performed to demonstrate the feasibility of the proposed method using a micro-CT system. We have reconstructed images of the phantoms from only 90 projections acquired at tube voltages of 40 kVp and 90 kVp each. Aluminum-only and acryl-only images were successfully decomposed. We evaluated the quality of the reconstructed images by use of contrast-to-noise ratio and detectability. A low-dose dual-energy CBCT can be realized via the proposed method by greatly reducing the number of projections

  10. 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

  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. 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.

  13. 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...

  14. 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 ...

  15. 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.

  16. Evaluation the potential and energy efficiency of dual stage pressure retarded osmosis process

    International Nuclear Information System (INIS)

    Altaee, Ali; Zaragoza, Guillermo; Drioli, Enrico; Zhou, John

    2017-01-01

    Highlights: •Single and dual stage PRO was evaluated at different membrane configurations. •Impact of increasing module area or numbers on the power efficiency was studied. •DSPRO reduced the impact of CP & restored the osmotic potential of salinity gradient. •DSPRO outperforms single stage PRO process but depends on salinity gradient type. -- Abstract: Power generation by means of Pressure Retarded Osmosis (PRO) has been proposed for harvesting the energy of a salinity gradient. Energy recovery by the PRO process decreases along the membrane module due to depleting of the chemical potential across the membrane and concentration polarization effects. A dual stage PRO (DSPRO) design can be used to rejuvenate the chemical potential difference and reduce the concentration polarization on feed solution. Several design configurations were suggested for the membrane module arrangements in the first and second stage of the PRO process. PRO performance was evaluated for a number of salinity gradients proposed by coupling Dead Sea water or Reverse Osmosis (RO) brine with seawater or wastewater effluent. Maximum specific energy of inlet and outlet feeds was calculated using a developed computer model to identify the amount of recovered and remaining energy. Initially, specific power generation by the PRO process increased by increasing the number of modules of the first stage. Maximum specific energy is calculated along the PRO module to understand the degradation of the maximum specific energy in each module before introducing a second stage PRO process. Adding a second stage PRO process resulted in a sharp increase of the chemical potential difference and the specific energy yield of the process. Between 10% and 13% increase of the specific power generation was achieved by the DSPRO process for the Dead Sea-seawater salinity gradient depending on the dual stage design configuration. For Dead Sea-RO brine, 12–16% increase of the specific power generation was

  17. Dual Education: The Win-Win Model of Collaboration between Universities and Industry

    Directory of Open Access Journals (Sweden)

    Monika Pogatsnik

    2018-05-01

    Full Text Available The purpose of this paper is to describe the new experiences of the dual training model in engineering education in Hungary. This new model has been introduced recently in the higher education and has become a focus of interest. This is a fa-vorable program for the students to experience the real industry environment pri-or to graduation and it is a good tool to motivate them to study harder. The dual education students study in the institutional academic period together with the regular full-time students at their higher education institute, and parallel to their academic education they participate in the practical training. It gives the students an opportunity to join a specific training program at an enterprise. Being involved in specific "operational" practical tasks and project-oriented work enhances inde-pendent work, learning soft skills and experiencing the culture of work. Our ob-jectives are to analyze the benefits of the dual training for all three parties: the stu-dent, the company and university. The study confirms earlier results from prior studies which show, for example, that students who choose the dual option achieve better program outcomes.

  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. 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)

  20. 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

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. Detection of pulmonary fat embolism with dual-energy CT: an experimental study in rabbits

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Chun Xiang; Zhou, Chang Sheng; Zhao, Yan E.; Han, Zong Hong; Qi, Li; Zhang, Long Jiang; Lu, Guang Ming [Medical School of Nanjing University, Department of Medical Imaging, Jinling Hospital, Nanjing, Jiangsu (China); Schoepf, U.J. [Medical School of Nanjing University, Department of Medical Imaging, Jinling Hospital, Nanjing, Jiangsu (China); Medical University of South Carolina, Division of Cardiovascular Imaging, Department of Radiology and Radiological Science, Charleston, SC (United States); Mangold, Stefanie; Ball, B.D. [Medical University of South Carolina, Division of Cardiovascular Imaging, Department of Radiology and Radiological Science, Charleston, SC (United States)

    2017-04-15

    To evaluate the use of dual-energy CT imaging of the lung perfused blood volume (PBV) for the detection of pulmonary fat embolism (PFE). Dual-energy CT was performed in 24 rabbits before and 1 hour, 1 day, 4 days and 7 days after artificial induction of PFE via the right ear vein. CT pulmonary angiography (CTPA) and lung PBV images were evaluated by two radiologists, who recorded the presence, number, and location of PFE on a per-lobe basis. Sensitivity, specificity, and accuracy of CTPA and lung PBV for detecting PFE were calculated using histopathological evaluation as the reference standard. A total of 144 lung lobes in 24 rabbits were evaluated and 70 fat emboli were detected on histopathological analysis. The overall sensitivity, specificity and accuracy were 25.4 %, 98.6 %, and 62.5 % for CTPA, and 82.6 %, 76.0 %, and 79.2 % for lung PBV. Higher sensitivity (p < 0.001) and accuracy (p < 0.01), but lower specificity (p < 0.001), were found for lung PBV compared with CTPA. Dual-energy CT can detect PFE earlier than CTPA (all p < 0.01). Dual-energy CT provided higher sensitivity and accuracy in the detection of PFE as well as earlier detection compared with conventional CTPA in this animal model study. (orig.)

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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…

  14. 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.

  15. Using Targeted Virotherapy to Treat a Resistant Ewing Sarcoma Model: From the Bedside to the Bench and Back

    Directory of Open Access Journals (Sweden)

    Hesham Abdelbary

    2014-01-01

    Full Text Available Metastatic Ewing sarcoma (EWS is often resistant to current multimodal chemotherapeutic regimens. Oncolytic virus therapy (OV is a novel therapeutic platform whereby viruses can selectively infect as well as replicate in and kill tumor cells, while sparing normal tissues. The purpose of this study is to investigate the efficacy of the biotherapeutic oncolytic agent, vesicular stomatitis virus (VSVΔM51, to kill EWS cells that are resistant to conventional therapy. Our hypothesis is that systemic delivery of VSVΔM51 can demonstrate tumor-specific killing of resistant EWS cells, as well as a significant decrease of tumor burden in EWS bearing mice. Methods. A biopsy sample was obtained from a patient with metastatic EWS and was used to establish a novel EWS cell line. In vitro assays evaluated the oncolytic effect of vesicular stomatitis virus (VSVΔM51 on this cell line. EWS xenograft mice model bearing either lung or subcutaneous tumors was established to evaluate the antitumor specific oncolytic effect of VSVΔM51 after local and systemic delivery. Results. The established EWS cell line shared similar molecular and genetic traits to the patient’s original tumor specimen. VSVΔM51 effectively infected and killed EWS cells in vitro. In vivo, VSVΔM51 selectively infected and killed EWS and led to significant delay in tumor growth. Conclusion. This study has been designed to implement a translational link between the bedside and the bench, where a specific challenging clinical scenario guided this basic science research. This research demonstrated that a sarcoma, which is resistant to current conventional standard therapies, is still susceptible to an alternative therapeutic platform, such as OV. Adding OV to the armamentarium of sarcoma treatment can enhance the future therapeutic approach towards these cancer patients.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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...

  3. CONFLICT OF DUAL LOYALTY AND ISSUES OF LIABILITY WHEN PROVIDING HEALTH CARE

    Directory of Open Access Journals (Sweden)

    Olga Sovová

    2017-12-01

    Full Text Available The paper examines topical questions of the conflict of dual loyalty when providing health and medical care in the context of the liability of regulated medical professions. The paper specifies, describes and identifies the impact of professional particularities on the sphere of activity of the vocational holder in general and the particularities in the Czech Republic. The conflict of dual loyalty is highlighted in the relations emerging when providing the medical care, in particular in the relation patient - medical professional - provider of medical care. The article is anchored in the methods of the interpretation of law together with the interpretation from the general to the specific. The medical professionals get very often into the dual loyalty conflict, which concerns legal obligations and the ethics of the profession. The paper examines the difference between the conflicts of dual loyalty and interests. Based on the above mentioned the paper concludes that the conflict of the dual loyalty and the responsibility of medical profession have many forms, but there are legal, ethical and economic possibilities to solve in in favour of the patient.

  4. 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.

  5. Motor dual-tasking deficits predict falls in Parkinson's disease: A prospective study.

    Science.gov (United States)

    Heinzel, Sebastian; Maechtel, Mirjam; Hasmann, Sandra E; Hobert, Markus A; Heger, Tanja; Berg, Daniela; Maetzler, Walter

    2016-05-01

    Falls severely affect lives of Parkinson's disease (PD) patients. Cognitive impairment including dual-tasking deficits contribute to fall risk in PD. However, types of dual-tasking deficits preceding falls in PD are still unclear. Walking velocities during box-checking and subtracting serial 7s were assessed twice a year in 40 PD patients over 2.8 ± 1.0 years. Fourteen patients reported a fall within this period (4 excluded fallers already reported falls at baseline). Their dual-task costs (DTC; mean ± standard deviation) 4.2 ± 2.2 months before the first fall were compared with 22 patients never reporting falls. ROC analyses and logistic regressions accounting for DTC, UPDRS-III and disease duration were used for faller classification and prediction. Only walking/box-checking predicted fallers. Fallers showed higher DTC for walking while box-checking, p = 0.029, but not for box-checking while walking, p = 0.178 (combined motor DTC, p = 0.022), than non-fallers. Combined motor DTC classified fallers and non-fallers (area under curve: 0.75; 95% confidence interval, CI: 0.60-0.91) with 71.4% sensitivity (95%CI: 41.9%-91.6%) and 77.3% specificity (54.6%-92.2%), and significantly predicted future fallers (p = 0.023). Here, 20.4%-points higher combined motor DTC (i.e. the mean difference between fallers and non-fallers) was associated with a 2.6 (1.1-6.0) times higher odds to be a future faller. Motor dual-tasking is a potentially valuable predictor of falls in PD, suggesting that avoiding dual task situations as well as specific motor dual-task training might help to prevent falls in PD. These findings and their therapeutic relevance need to be further validated in PD patients without fall history, in early PD stages, and with various motor-motor dual-task challenges. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. 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.

  7. [Dual Pathology in General Population of Itagüí, Colombia].

    Science.gov (United States)

    Castaño Pérez, Guillermo A; Sierra Hincapié, Gloria Maria

    2016-01-01

    To study the prevalence of dual diagnosis (presence of a substance use disorder and an associated mental disorder) in the general population of a small town in the department of Antioquia in Colombia, through secondary analysis of survey data on Mental Health held in this city in 2011. With a sample of 415 subjects, the interview Composite International Diagnostic Interview (CIDI), WHO CAPI version, was used and statistical analysis was performed using SPSS v.21. The prevalence of dual diagnosis, considering that the presence of a diagnosis of mental disorder and a disorder snuff use of different substances was 7.2%. Substances with higher prevalence of use in life for individuals with dual diagnosis were alcohol (96.7%), marijuana (80.0%), cocaine and derivatives (33.3%), heroin (23.3%) and finally no prescription tranquilizers (13.3%), finding statistical association between drug use and dual diagnosis. Major depression (40%), oppositional defiant disorder (36.7%), posttraumatic stress (33.3%), specific phobia and attention deficit (26.7%) are the most prevalent disorders in individuals with dual diagnosis of this sample. Alcohol or drugs consumption and fulfilling diagnostic criteria for dual diagnosis have a significant statistical association for consumption of drugs like marijuana, cocaine, heroin and prescription medications (P1.00, very high when the drug is heroin consumed (RD=38.754) or non-prescription medications (RD=29.462). A family history of disease and drug use has a high statistical association with dual diagnosis, with a higher association with a history of mental illness (P<.001; RD=3.677). The study reports on the prevalence of subjects with dual diagnosis in a Colombian population. Alcohol, marijuana, cocaine and heroin are derivatives and substances mostly consumed by these patients and the most prevalent mental disorders are depression, TOD and posttraumatic stress. These findings motivate clinicians to more actively seek the presence of

  8. Dual-layer spectral detector CT: non-inferiority assessment compared to dual-source dual-energy CT in discriminating uric acid from non-uric acid renal stones ex vivo.

    Science.gov (United States)

    Ananthakrishnan, Lakshmi; Duan, Xinhui; Xi, Yin; Lewis, Matthew A; Pearle, Margaret S; Antonelli, Jodi A; Goerne, Harold; Kolitz, Elysha M; Abbara, Suhny; Lenkinski, Robert E; Fielding, Julia R; Leyendecker, John R

    2018-04-07

    To assess the non-inferiority of dual-layer spectral detector CT (SDCT) compared to dual-source dual-energy CT (dsDECT) in discriminating uric acid (UA) from non-UA stones. Fifty-seven extracted urinary calculi were placed in a cylindrical phantom in a water bath and scanned on a SDCT scanner (IQon, Philips Healthcare) and second- and third-generation dsDECT scanners (Somatom Flash and Force, Siemens Healthcare) under matched scan parameters. For SDCT data, conventional images and virtual monoenergetic reconstructions were created. A customized 3D growing region segmentation tool was used to segment each stone on a pixel-by-pixel basis for statistical analysis. Median virtual monoenergetic ratios (VMRs) of 40/200, 62/92, and 62/100 for each stone were recorded. For dsDECT data, dual-energy ratio (DER) for each stone was recorded from vendor-specific postprocessing software (Syngo Via) using the Kidney Stones Application. The clinical reference standard of X-ray diffraction analysis was used to assess non-inferiority. Area under the receiver-operating characteristic curve (AUC) was used to assess diagnostic performance of detecting UA stones. Six pure UA, 47 pure calcium-based, 1 pure cystine, and 3 mixed struvite stones were scanned. All pure UA stones were correctly separated from non-UA stones using SDCT and dsDECT (AUC = 1). For UA stones, median VMR was 0.95-0.99 and DER 1.00-1.02. For non-UA stones, median VMR was 1.4-4.1 and DER 1.39-1.69. SDCT spectral reconstructions demonstrate similar performance to those of dsDECT in discriminating UA from non-UA stones in a phantom model.

  9. Demonstration and evaluation of dual-fuel technology; Demonstration och utvaerdering av dual-fuel-tekniken

    Energy Technology Data Exchange (ETDEWEB)

    Staalhammar, Per; Erlandsson, Lennart; Willner, Kristina (AVL MTC Motortestcenter AB (Sweden)); Johannesson, Staffan (Ecoplan AB (Sweden))

    2011-06-15

    There is an increased interest for Dual Fuel (methane-Diesel) applications in Sweden since this technology is seen as one of the more interesting options for a fast and cost effective introduction of biomethane as fuel for HD engines. The Dual Fuel technology has been used for many years, mainly for stationary purpose (generators, pumps and ships) while the Spark Ignited (SI) 'Otto' technology has been used for trucks and busses. One obstacle for introducing Dual Fuel technology for busses and trucks is the EU legislation that don't allow for HD on road certification of Dual Fuel applications. Challenges with the Dual Fuel technology is to develop cost effective applications that is capable of reaching low emissions (especially CH{sub 4} and NO{sub x}) in combination with high Diesel replacement in the test cycles used for on road applications. AVL MTC Motortestcenter AB (hereinafter called AVL) has on commission by SGC (Swedish Gas technical Centre) carried out this project with the objectives to analyze the Dual Fuel (Diesel-methane) technology with focus on emissions, fuel consumption and technical challenges. One important part of this project was to carry out emission tests on selected Dual Fuel applications in Sweden and to compile experiences from existing Dual Fuel technology. This report also summarizes other commonly used technologies for methane engines and compares the Dual Fuel with conventional Diesel and Otto technologies. The major challenges with Dual Fuel applications for on road vehicles will be to develop robust and cost effective solutions that meet the emission legislations (with aged catalysts) and to increase the Diesel replacement to achieve reasonable reduction of green house gases (GHG). This is especially important when biomethane is available as fuel but not Bio-Diesel. It will probably be possible to reach EURO V emission limits with advanced Dual Fuel systems but none of the tested systems reached EURO V emission levels

  10. 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...

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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...

  17. 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.

  18. 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...

  19. 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

  20. Dual-isotope technique for determination of in vivo ketone body kinetics

    International Nuclear Information System (INIS)

    Miles, J.M.; Schwenk, W.F.; McClean, K.L.; Haymond, M.W.

    1986-01-01

    Total ketone body specific activity has been widely used in studies of ketone body metabolism to circumvent so-called isotope disequilibrium between the two major ketone body pools, acetoacetate and beta-hydroxybutyrate. Recently, this approach has been criticized on theoretical grounds. In the present studies, [13C]acetoacetate and beta-[14C]hydroxybutyrate were simultaneously infused in nine mongrel dogs before and during an infusion of either unlabeled sodium acetoacetate or unlabeled sodium beta-hydroxybutyrate. Ketone body turnover was determined using total ketone body specific activity, total ketone body moles % enrichment, and an open two-pool model, both before and during the exogenous infusion of unlabeled ketone bodies. Basal ketone body turnover rates were significantly higher using [13C]acetoacetate than with either beta-[14C]hydroxybutyrate alone or the dual-isotope model (3.6 +/- 0.5 vs. 2.2 +/- 0.2 and 2.7 +/- 0.2 mumol X kg-1 X min-1, respectively, P less than 0.05). During exogenous infusion of unlabeled sodium acetoacetate, the dual-isotope model provided the best estimate of ketone body inflow, whereas 14C specific activity underestimated the known rate of acetoacetate infusion by 55% (P less than 0.02). During sodium beta-hydroxybutyrate infusion, [13C]-acetoacetate overestimated ketone body inflow by 55% (P = NS), while better results were obtained with 14C beta-hydroxybutyrate alone and the two-pool model. Ketone body interconversion as estimated by the dual-isotope technique increased markedly during exogenous ketone body infusion. In conclusion, significant errors in estimation of ketone body inflow were made using single-isotope techniques, whereas a dual-isotope model provided reasonably accurate estimates of ketone body inflow during infusion of exogenous acetoacetate and beta-hydroxybutyrate

  1. p16/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women.

    Science.gov (United States)

    Wentzensen, Nicolas; Fetterman, Barbara; Castle, Philip E; Schiffman, Mark; Wood, Shannon N; Stiemerling, Eric; Tokugawa, Diane; Bodelon, Clara; Poitras, Nancy; Lorey, Thomas; Kinney, Walter

    2015-12-01

    Human papillomavirus (HPV)-based cervical cancer screening requires triage markers to decide who should be referred to colposcopy. p16/Ki-67 dual stain cytology has been proposed as a biomarker for cervical precancers. We evaluated the dual stain in a large population of HPV-positive women. One thousand five hundred and nine HPV-positive women screened with HPV/cytology cotesting at Kaiser Permanente California were enrolled into a prospective observational study in 2012. Dual stain cytology was performed on residual Surepath material, and slides were evaluated for dual stain-positive cells. Disease endpoints were ascertained from the clinical database at KPNC. We evaluated the clinical performance of the assay among all HPV-positive women and among HPV-positive, cytology-negative women. We used internal benchmarks for clinical management to evaluate the clinical relevance of the dual stain assay. We evaluated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the dual stain compared with Pap cytology. All statistical tests were two-sided. The dual stain had lower positivity (45.9%) compared with cytology at an ASC-US threshold (53.4%). For detection of CIN2+, the dual stain had similar sensitivity (83.4% vs 76.6%, P = .1), and statistically higher specificity (58.9% vs 49.6%, P < .001), PPV (21.0% vs 16.6%, P < .001), and NPV (96.4% vs 94.2%, P = .01) compared with cytology. Similar patterns were observed for CIN3+. Women with a positive test had high enough risk for referral to colposcopy, while the risk for women with negative tests was below a one-year return threshold based on current US management guidelines. Dual stain cytology showed good risk stratification for all HPV-positive women and for HPV-positive women with normal cytology. Additional follow-up is needed to determine how long dual stain negative women remain at low risk of precancer. Published by Oxford University Press 2015. This work is written by (a

  2. 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…

  3. 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.

  4. 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

  5. Theory and Metatheory in the Study of Dual Processing: Reply to Comments.

    Science.gov (United States)

    Evans, Jonathan St B T; Stanovich, Keith E

    2013-05-01

    In this article, we respond to the four comments on our target article. Some of the commentators suggest that we have formulated our proposals in a way that renders our account of dual-process theory untestable and less interesting than the broad theory that has been critiqued in recent literature. Our response is that there is a confusion of levels. Falsifiable predictions occur not at the level of paradigm or metatheory-where this debate is taking place-but rather in the instantiation of such a broad framework in task level models. Our proposal that many dual-processing characteristics are only correlated features does not weaken the testability of task-level dual-processing accounts. We also respond to arguments that types of processing are not qualitatively distinct and discuss specific evidence disputed by the commentators. Finally, we welcome the constructive comments of one commentator who provides strong arguments for the reality of the dual-process distinction. © The Author(s) 2013.

  6. 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.

  7. 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.

  8. Insulated hsp70B' promoter: stringent heat-inducible activity in replication-deficient, but not replication-competent adenoviruses.

    Science.gov (United States)

    Rohmer, Stanimira; Mainka, Astrid; Knippertz, Ilka; Hesse, Andrea; Nettelbeck, Dirk M

    2008-04-01

    Key to the realization of gene therapy is the development of efficient and targeted gene transfer vectors. Therapeutic gene transfer by replication-deficient or more recently by conditionally replication-competent/oncolytic adenoviruses has shown much promise. For specific applications, however, it will be advantageous to provide vectors that allow for external control of gene expression. The efficient cellular heat shock system in combination with available technology for focused and controlled hyperthermia suggests heat-regulated transcription control as a promising tool for this purpose. We investigated the feasibility of a short fragment of the human hsp70B' promoter, with and without upstream insulator elements, for the regulation of transgene expression by replication-deficient or oncolytic adenoviruses. Two novel adenoviral vectors with an insulated hsp70B' promoter were developed and showed stringent heat-inducible gene expression with induction ratios up to 8000-fold. In contrast, regulation of gene expression from the hsp70B' promoter without insulation was suboptimal. In replication-competent/oncolytic adenoviruses regulation of the hsp70B' promoter was lost specifically during late replication in permissive cells and could not be restored by the insulators. We developed novel adenovirus gene transfer vectors that feature improved and stringent regulation of transgene expression from the hsp70B' promoter using promoter insulation. These vectors have potential for gene therapy applications that benefit from external modulation of therapeutic gene expression or for combination therapy with hyperthermia. Furthermore, our study reveals that vector replication can deregulate inserted cellular promoters, an observation which is of relevance for the development of replication-competent/oncolytic gene transfer vectors. (c) 2008 John Wiley & Sons, Ltd.

  9. 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)

  10. Towards dual recycling with the aid of time and frequency domain simulations

    International Nuclear Information System (INIS)

    Malec, M; Grote, H; Freise, A; Heinzel, G; Strain, K A; Hough, J; Danzmann, K

    2004-01-01

    Dual recycling, the combination of the interferometric techniques of power and signal recycling, allows the improvement of the shot noise limited sensitivity of interferometric gravitational wave detectors. GEO 600 is the first km-scale gravitational wave detector using dual recycling. The hardware installation is completed and dual recycling has become a great challenge in terms of commissioning of GEO 600. Simulations show that lock acquisition of the optical system can only be achieved in certain detector states. Thus as we need to start with a locked detector in such a specific state, an appropriate strategy is needed to change the state of detector operation without losing lock. The basic concepts and first results based on time and frequency domain simulations will be presented in this paper

  11. Understanding Counterfactuality: A Review of Experimental Evidence for the Dual Meaning of Counterfactuals

    Science.gov (United States)

    Nieuwland, Mante S.

    2016-01-01

    Abstract Cognitive and linguistic theories of counterfactual language comprehension assume that counterfactuals convey a dual meaning. Subjunctive‐counterfactual conditionals (e.g., ‘If Tom had studied hard, he would have passed the test’) express a supposition while implying the factual state of affairs (Tom has not studied hard and failed). The question of how counterfactual dual meaning plays out during language processing is currently gaining interest in psycholinguistics. Whereas numerous studies using offline measures of language processing consistently support counterfactual dual meaning, evidence coming from online studies is less conclusive. Here, we review the available studies that examine online counterfactual language comprehension through behavioural measurement (self‐paced reading times, eye‐tracking) and neuroimaging (electroencephalography, functional magnetic resonance imaging). While we argue that these studies do not offer direct evidence for the online computation of counterfactual dual meaning, they provide valuable information about the way counterfactual meaning unfolds in time and influences successive information processing. Further advances in research on counterfactual comprehension require more specific predictions about how counterfactual dual meaning impacts incremental sentence processing. PMID:27512408

  12. Impact of the role of senior dual disability coordinator on the perceived self-efficacy and job satisfaction of mental health clinicians.

    Science.gov (United States)

    Hendren, Amanda Jayne; Kendall, Melissa Bianca

    2015-01-01

    This study aimed to evaluate a new service role in mental health services, namely, the senior dual disability coordinator role (SDDC) for its impact on the perceived self-efficacy of mental health clinicians in managing clients with dual disability (mental illness and acquired brain injury and/or intellectual disability) and their job satisfaction. Mental health clinicians from a health service district in Queensland, Australia who contacted the SDDC for clinical consultation and liaison between July 2011 and July 2013 were asked to complete a questionnaire assessing perceived self-efficacy in working with clients with dual disability as well as their job satisfaction, prior to (T1) and following (T2) their contact with the SDDC. Twenty-five clinicians completed and returned pre- and post-measure questionnaires. Self-reported knowledge of dual disability, clinical skills in dual disability, service knowledge in dual disability as well as perceived self-efficacy, and job satisfaction increased significantly from T1 to T2. There were no significant differences across professional discipline or years of service. The delivery of a clinical consultation liaison service as part of the role of SDDC may assist mental health clinicians with self-efficacy and job satisfaction, regardless of the number of years they have worked in the service or their professional discipline. Mental health clinicians with improved self-efficacy for working with clients with dual disability may be more likely to consider the client suitable for services through mental health and follow-up with treatment and linking the client with other identified suitable services. Implications for Rehabilitation Dual disability (mental illness and acquired brain injury and/or intellectual disability) presents specific challenges for mental health services Specific strategies are needed to build capacity among mental health practitioners in order to meet the needs of people with dual disability and provide

  13. 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)

  14. 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.

  15. 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...

  16. 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.

  17. 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

  18. Persistency and flexibility of complex brain networks underlie dual-task interference.

    Science.gov (United States)

    Alavash, Mohsen; Hilgetag, Claus C; Thiel, Christiane M; Gießing, Carsten

    2015-09-01

    Previous studies on multitasking suggest that performance decline during concurrent task processing arises from interfering brain modules. Here, we used graph-theoretical network analysis to define functional brain modules and relate the modular organization of complex brain networks to behavioral dual-task costs. Based on resting-state and task fMRI we explored two organizational aspects potentially associated with behavioral interference when human subjects performed a visuospatial and speech task simultaneously: the topological overlap between persistent single-task modules, and the flexibility of single-task modules in adaptation to the dual-task condition. Participants showed a significant decline in visuospatial accuracy in the dual-task compared with single visuospatial task. Global analysis of topological similarity between modules revealed that the overlap between single-task modules significantly correlated with the decline in visuospatial accuracy. Subjects with larger overlap between single-task modules showed higher behavioral interference. Furthermore, lower flexible reconfiguration of single-task modules in adaptation to the dual-task condition significantly correlated with larger decline in visuospatial accuracy. Subjects with lower modular flexibility showed higher behavioral interference. At the regional level, higher overlap between single-task modules and less modular flexibility in the somatomotor cortex positively correlated with the decline in visuospatial accuracy. Additionally, higher modular flexibility in cingulate and frontal control areas and lower flexibility in right-lateralized nodes comprising the middle occipital and superior temporal gyri supported dual-tasking. Our results suggest that persistency and flexibility of brain modules are important determinants of dual-task costs. We conclude that efficient dual-tasking benefits from a specific balance between flexibility and rigidity of functional brain modules. © 2015 Wiley

  19. Mass thickness measurement of dual-sample by dual-energy X-rays

    International Nuclear Information System (INIS)

    Chen Mincong; Li Hongmei; Chen Ziyu; Shen Ji

    2008-01-01

    X-ray equivalent energy can be used to measure mass thicknesses of materials. Based on this, a method of mass thickness measurement of dual-sample was discussed. It was found that in the range of sample mass thickness under investigation, the equivalent mass attenuation coefficient of a component could be used to compute mass thicknesses of a dual-sample, with relative errors of less than 5%. Mass thickness measurement of a fish sample was performed, and the fish bone and flesh could be displayed separately and clearly by their own mass thicknesses. This indicates that the method is effective in mass thickness measurement of dual-sample of suitable thicknesses. (authors)

  20. Hierarchical porous TiO{sub 2} thin films by soft and dual templating

    Energy Technology Data Exchange (ETDEWEB)

    Henrist, Catherine, E-mail: catherine.henrist@ulg.ac.be [University of Liege, Department of Chemistry, GREENMAT-LCIS, B6 Sart Tilman, Liege 4000 (Belgium); University of Liege, Center for Applied Technology in Microscopy (CATmu), B6 Sart Tilman, Liege 4000 (Belgium); Dewalque, Jennifer [University of Liege, Department of Chemistry, GREENMAT-LCIS, B6 Sart Tilman, Liege 4000 (Belgium); Cloots, Rudi [University of Liege, Department of Chemistry, GREENMAT-LCIS, B6 Sart Tilman, Liege 4000 (Belgium); University of Liege, Center for Applied Technology in Microscopy (CATmu), B6 Sart Tilman, Liege 4000 (Belgium); Vertruyen, Bénédicte; Jonlet, Jonathan; Colson, Pierre [University of Liege, Department of Chemistry, GREENMAT-LCIS, B6 Sart Tilman, Liege 4000 (Belgium)

    2013-07-31

    Hierarchical porous structures, with different pore sizes, including pores larger than 10 nm, constitute an important field of research for many applications such as selective molecule detection, catalysis, dye-sensitized solar cells, nanobiotechnology and nanomedecine. However, increasing the pore size logically results in the decrease of specific surface. There is a need to quantify and predict the resulting porosity and specific surface. We have prepared hierarchical porous TiO{sub 2} thin films either by surfactant templating (soft) or dual surfactant/nanospheres templating (soft/hard). They all show narrow, bimodal distribution of pores. Soft templating route uses a modified sol–gel procedure by adding a swelling agent (polypropylene glycol) to a precursor solution containing Ti alkoxide and block-copolymer surfactant. This scheme leads to very thin films showing high specific surface and bimodal porosity with diameters of 10 nm and 54 nm. Dual templating route combines a precursor solution made of Ti alkoxide and block-copolymer surfactant with polystyrene (PS) nanospheres (diam. 250 nm) in a one-pot simple process. This gives thicker films with a bimodal distribution of pores (8 nm and 165-200 nm). The introduction of PS nanospheres in the surfactant–Ti system does not interfere with the soft templating process and results in a macroporosity with a pore diameter 20–30% smaller than the original beads diameter. The dye loading of hierarchical films is compared to pure surfactant-templated TiO{sub 2} films and shows a relative decrease of 29% for soft templating and 43% for dual templating. The microstructure of bimodal porous films is characterized by several techniques such as transmission and scanning electron microscopy, X-ray diffraction, profilometry and ellipsometry. Finally, a geometrical model is proposed and validated for each system, based on the agreement between calculated specific surfaces and experimental dye loading with N719 dye

  1. 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…

  2. Dual-fuel HCCI operation with DME/LPG/gasoline/hydrogen

    International Nuclear Information System (INIS)

    Bae, C.

    2009-01-01

    The advantages of homogeneous charge compression ignition (HCCI) engines include usage of the different type of fuels, ultra low nitrogen oxide and particulate matter emissions and improved fuel economy. Disadvantages include an excessive combustion rate, engine noise, and hydrocarbon and carbon emissions. An experiment on dual-fuel HCCI operation with dimethyl ether (DME)/liquefied petroleum gas (LPG)/gasoline/hydrogen was presented. The advantages and disadvantages were first presented and the dual-fuel HCCI combustion engine was illustrated through an experimental apparatus. The experimental conditions were also presented in terms of engine speed, DME injection quantity, LPC injection quantity, and LPC composition. Experimental results were discussed for output performance and indicated mean effective pressure (IMEP). It was concluded that the effect of LPG composition in a DME-LPG dual-fueled HCCI engine at various injection quantity and injective timing were observed. Specifically, it was found that propane was a more effective way to increase IMEP in this study, and that in a DME HCCI engine, higher load limit was extended by using LPG as an ignition inhibitor. tabs., figs.

  3. The effect of cognitive aging on implicit sequence learning and dual tasking

    Directory of Open Access Journals (Sweden)

    Jochen eVandenbossche

    2014-02-01

    Full Text Available We investigated the influence of attentional demands on sequence-specific learning by means of the serial reaction time (SRT task (Nissen & Bullemer, 1987 in young (age 18-25 and aged (age 55-75 adults. Participants had to respond as fast as possible to a stimulus presented in one of four horizontal locations by pressing a key corresponding to the spatial position of the stimulus. During the training phase sequential blocks were accompanied by (1 no secondary task (single, (2 a secondary tone counting task (dual tone, or (3 a secondary shape counting task (dual shape. Both secondary tasks were administered to investigate whether low and high interference tasks interact with implicit learning and age. The testing phase, under baseline single condition, was implemented to assess differences in sequence-specific learning between young and aged adults. Results indicate that (1 aged subjects show less sequence learning compared to young adults, (2 young participants show similar implicit learning effects under both single and dual task conditions when we account for explicit awareness, and (3 aged adults demonstrate reduced learning when the primary task is accompanied with a secondary task, even when explicit awareness is included as a covariate in the analysis. These findings point to implicit learning deficits under dual task conditions that can be related to cognitive aging, demonstrating the need for sufficient cognitive resources while performing a sequence learning task.

  4. A dual-task paradigm for behavioral and neurobiological studies in nonhuman primates.

    Science.gov (United States)

    Watanabe, Kei; Funahashi, Shintaro

    2015-05-15

    The dual-task paradigm is a procedure in which subjects are asked to perform two behavioral tasks concurrently, each of which involves a distinct goal with a unique stimulus-response association. Due to the heavy demand on subject's cognitive abilities, human studies using this paradigm have provided detailed insights regarding how the components of cognitive systems are functionally organized and implemented. Although dual-task paradigms are widely used in human studies, they are seldom used in nonhuman animal studies. We propose a novel dual-task paradigm for monkeys that requires the simultaneous performance of two cognitively demanding component tasks, each of which uses an independent effector for behavioral responses (hand and eyes). We provide a detailed description of an optimal training protocol for this paradigm, which has been lacking in the existing literature. An analysis of behavioral performance showed that the proposed dual-task paradigm (1) was quickly learned by monkeys (less than 40 sessions) with step-by-step training protocols, (2) produced specific behavioral effects, known as dual-task interference in human studies, and (3) achieved rigid and independent control of the effectors for behavioral responses throughout the trial. The proposed dual-task paradigm has a scalable task structure, in that each of the two component tasks can be easily replaced by other tasks, while preserving the overall structure of the paradigm. This paradigm should be useful for investigating executive control that underlies dual-task performance at both the behavioral and neuronal levels. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. 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.)

  6. 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.

  7. In vitro differentiation of renal stone composition using dual-source, dual-energy CT

    International Nuclear Information System (INIS)

    Zhou Changsheng; Zhang Longjiang; Xu Feng; Qi Li; Zhao Yan'e; Zheng Ling; Huang Wei; Liu Youhuang; Lu Guangming

    2012-01-01

    Objective: To evaluate the ability of dual-source. dual-energy CT in differentiating uric acid stones from non-uric acid stones with infrared spectroscopy as reference standard. Materials and Methods: Urinary calculus from 308 patients were scanned in first generation dual-source CT with dual-energy mode between July 2011 and June 2012. Renal Stone application was used to analyze their composition. The uric acid stones color were coded red and non-uric acid stones were blue. CT values were measured in 60 selective urinary calculus including 30 uric acid stones and 30 non-uric acid stones. The accuracy of dual energy CT to differentiate uric acid and no-uric acid stones was calculated. Results: Of 308 patients, 60 patients had uric acid stones and 248 non-uric acid stones. No difference was found for uric acid stone at 80 kV and 140 kV (375.8±69.2 HU vs. 374.1±69.4 HU; t=-0.217, P=0.830), while CT values of non-uric acid stones were higher at 80 kV than those at 140 kV (1455.1±312.4 HU vs. 1039.6±194.4 HU; t=-12.16. P<0.001). CT values of non-uric acid stones at 80 kV, 140 kV, and average weighted images (1455.1±312.4 HU, 1 039.6±194.4 HU, and 882.0±176.4 HU, respectively) were higher than those of uric acid stones (375.8±69.2 HU, 374.1±69.4 HU, and 366.3±80.1 HU, respectively; P<0.001). With infrared spectrum findings as reference standard, the accuracy of dual energy CT in differentiating uric acid stones from non-uric acid stones was 100%. Conclusions: Dual-source, dual-energy CT can accurately differentiate uric acid stones from non-uric acid stones, and plays an important role in treatment planning of renal stones. (authors)

  8. 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.

  9. 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.

  10. Dual-Task Assessment Protocols in Concussion Assessment: A Systematic Literature Review.

    Science.gov (United States)

    Kleiner, Michelle; Wong, Lynne; Dubé, Alexandra; Wnuk, Katie; Hunter, Susan W; Graham, Laura J

    2018-02-01

    Study Design Systematic review. Background When assessed in isolation, balance and neurocognitive testing may not be sufficiently responsive to capture changes that occur with concussion. Normal daily activities require simultaneous cognitive and physical demands. Therefore, a dual-task assessment paradigm should be considered to identify performance deficits. Objectives To evaluate the literature and to identify dual-task testing protocols associated with changes in gait after concussion. Methods A systematic review of articles of individuals with concussion who underwent dual-task testing with a combination of motor and cognitive tasks was conducted. The AMED, CINAHL, Embase, PsycINFO, PubMed, Scopus, SPORTDiscus, and Web of Science databases and gray literature were searched from inception to January 29, 2017. Title and abstract, full-text, and quality review and data abstraction were performed by 2 independent reviewers. Results Twenty-four articles met the inclusion criteria. Eleven articles reported decreased gait velocity and increased medial-lateral displacement for individuals with concussion during dual-task conditions. Overall, included articles were of poor to moderate methodological quality. Fifteen articles used the same participants and data sets, creating a threat to validity and limiting the ability to make conclusions. Conclusion A deterioration in gait performance during dual-task testing is present among people with concussion. Specific recommendations for the use of a dual-task protocol to assess individuals with suspected concussion injury in a clinical setting have yet to be determined. J Orthop Sports Phys Ther 2018;48(2):87-103. Epub 7 Nov 2017. doi:10.2519/jospt.2018.7432.

  11. A decision-directed network for dual-polarization crosstalk cancellation

    Science.gov (United States)

    Weber, W. J., III

    1979-01-01

    Frequency reuse in the specific form of dual-polarized microwave communication systems has grown in importance in recent years as a practical means of radio spectrum conservation. Ideally the capacity of a given frequency allocation can be doubled through dual-polarization. However, hardware imperfections and propagation effects, particularly rain depolarization, prevent the achievement of this doubling without severe system performance degradation. A decision-directed cross-polarization correction network is presented whose operation depends on only simple base-band signal processing. No pilot tones or frequency offsets are required. The loop can work with any two-dimensional signal set for digital data transmission. The loop has been experimentally verified and provides a means of doubling the data capacity with little performance degradation.

  12. WORK-FAMILY CONFLICT AND SOURCES OF SUPPORT AMONGST MALAYSIAN DUAL-CAREER EMPLOYEES

    Directory of Open Access Journals (Sweden)

    Meera Komarraju

    2006-01-01

    Full Text Available As the number of dual-career employees entering the workplace increases, it is important to understand how the integration of work and family responsibilities influences work outcomes. The current study examined occupational role salience, work-family conflict, basic understandings, spousal support, and organizational support as predictors of work satisfaction. One hundred and sixteen dual-career faculty and staff from three Malaysian universities completed a survey questionnaire. Results from stepwise regression analyses showed that across all employees, work-family conflict was the most significant predictor of work satisfaction. More specifically, for male employees, spousal support was the most important predictor of work satisfaction followed by work-family conflict. Interestingly, for female employees, work-family conflict was the most significant predictor followed by organizational support. These results suggest that dual-career employees who find family responsibilities intruding into their work activities are likely to experience lesser work satisfaction. Dual-career employees receiving support and encouragement from a spouse or from the employing organization are more likely to experience increased work satisfaction.

  13. IMPLICIT DUAL CONTROL BASED ON PARTICLE FILTERING AND FORWARD DYNAMIC PROGRAMMING.

    Science.gov (United States)

    Bayard, David S; Schumitzky, Alan

    2010-03-01

    This paper develops a sampling-based approach to implicit dual control. Implicit dual control methods synthesize stochastic control policies by systematically approximating the stochastic dynamic programming equations of Bellman, in contrast to explicit dual control methods that artificially induce probing into the control law by modifying the cost function to include a term that rewards learning. The proposed implicit dual control approach is novel in that it combines a particle filter with a policy-iteration method for forward dynamic programming. The integration of the two methods provides a complete sampling-based approach to the problem. Implementation of the approach is simplified by making use of a specific architecture denoted as an H-block. Practical suggestions are given for reducing computational loads within the H-block for real-time applications. As an example, the method is applied to the control of a stochastic pendulum model having unknown mass, length, initial position and velocity, and unknown sign of its dc gain. Simulation results indicate that active controllers based on the described method can systematically improve closed-loop performance with respect to other more common stochastic control approaches.

  14. 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.

  15. Separation of hepatic iron and fat by dual-source dual-energy computed tomography based on material decomposition: an animal study.

    Science.gov (United States)

    Ma, Jing; Song, Zhi-Qiang; Yan, Fu-Hua

    2014-01-01

    To explore the feasibility of dual-source dual-energy computed tomography (DSDECT) for hepatic iron and fat separation in vivo. All of the procedures in this study were approved by the Research Animal Resource Center of Shanghai Ruijin Hospital. Sixty rats that underwent DECT scanning were divided into the normal group, fatty liver group, liver iron group, and coexisting liver iron and fat group, according to Prussian blue and HE staining. The data for each group were reconstructed and post-processed by an iron-specific, three-material decomposition algorithm. The iron enhancement value and the virtual non-iron contrast value, which indicated overloaded liver iron and residual liver tissue, respectively, were measured. Spearman's correlation and one-way analysis of variance (ANOVA) were performed, respectively, to analyze statistically the correlations with the histopathological results and differences among groups. The iron enhancement values were positively correlated with the iron pathology grading (r = 0.729, pVNC) values were negatively correlated with the fat pathology grading (r = -0.642,pVNC values (F = 25.308,pVNC values were only observed between the fat-present and fat-absent groups. Separation of hepatic iron and fat by dual energy material decomposition in vivo was feasible, even when they coexisted.

  16. 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.

  17. 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.

  18. 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...

  19. 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.

  20. 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...

  1. 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.

  2. Interobserver reproducibility and accuracy of p16/Ki-67 dual-stain cytology in cervical cancer screening.

    Science.gov (United States)

    Wentzensen, Nicolas; Fetterman, Barbara; Tokugawa, Diane; Schiffman, Mark; Castle, Philip E; Wood, Shannon N; Stiemerling, Eric; Poitras, Nancy; Lorey, Thomas; Kinney, Walter

    2014-12-01

    Dual-stain cytology for p16 and Ki-67 has been proposed as a biomarker in cervical cancer screening. The authors evaluated the reproducibility and accuracy of dual-stain cytology among 10 newly trained evaluators. In total, 480 p16/Ki-67-stained slides from human papillomavirus-positive women were evaluated in masked fashion by 10 evaluators. None of the evaluators had previous experience with p16 or p16/Ki-67 cytology. All participants underwent p16/Ki-67 training and subsequent proficiency testing. Reproducibility of dual-stain cytology was measured using the percentage agreement, individual and aggregate κ values, as well as McNemar statistics. Clinical performance for the detection of cervical intraepithelial neoplasia grade 2 or greater (CIN2+) was evaluated for each individual evaluator and for all evaluators combined compared with the reference evaluation by a cytotechnologist who had extensive experience with dual-stain cytology. The percentage agreement of individual evaluators with the reference evaluation ranged from 83% to 91%, and the κ values ranged from 0.65 to 0.81. The combined κ value was 0.71 for all evaluators and 0.73 for cytotechnologists. The average sensitivity and specificity for the detection of CIN2+ among novice evaluators was 82% and 64%, respectively; whereas the reference evaluation had 84% sensitivity and 63% specificity, respectively. Agreement on dual-stain positivity increased with greater numbers of p16/Ki-67-positive cells on the slides. Good to excellent reproducibility of p16/Ki-67 dual-stain cytology was observed with almost identical clinical performance of novice evaluators compared with reference evaluations. The current findings suggest that p16/Ki-67 dual-stain evaluation can be implemented in routine cytology practice with limited training. © 2014 American Cancer Society.

  3. Cognitive and motor dual task gait training improve dual task gait performance after stroke - A randomized controlled pilot trial.

    Science.gov (United States)

    Liu, Yan-Ci; Yang, Yea-Ru; Tsai, Yun-An; Wang, Ray-Yau

    2017-06-22

    This study investigated effects of cognitive and motor dual task gait training on dual task gait performance in stroke. Participants (n = 28) were randomly assigned to cognitive dual task gait training (CDTT), motor dual task gait training (MDTT), or conventional physical therapy (CPT) group. Participants in CDTT or MDTT group practiced the cognitive or motor tasks respectively during walking. Participants in CPT group received strengthening, balance, and gait training. The intervention was 30 min/session, 3 sessions/week for 4 weeks. Three test conditions to evaluate the training effects were single walking, walking while performing cognitive task (serial subtraction), and walking while performing motor task (tray-carrying). Parameters included gait speed, dual task cost of gait speed (DTC-speed), cadence, stride time, and stride length. After CDTT, cognitive-motor dual task gait performance (stride length and DTC-speed) was improved (p = 0.021; p = 0.015). After MDTT, motor dual task gait performance (gait speed, stride length, and DTC-speed) was improved (p = 0.008; p = 0.008; p = 0.008 respectively). It seems that CDTT improved cognitive dual task gait performance and MDTT improved motor dual task gait performance although such improvements did not reach significant group difference. Therefore, different types of dual task gait training can be adopted to enhance different dual task gait performance in stroke.

  4. Accuracy of iodine quantification using dual energy CT in latest generation dual source and dual layer CT.

    Science.gov (United States)

    Pelgrim, Gert Jan; van Hamersvelt, Robbert W; Willemink, Martin J; Schmidt, Bernhard T; Flohr, Thomas; Schilham, Arnold; Milles, Julien; Oudkerk, Matthijs; Leiner, Tim; Vliegenthart, Rozemarijn

    2017-09-01

    To determine the accuracy of iodine quantification with dual energy computed tomography (DECT) in two high-end CT systems with different spectral imaging techniques. Five tubes with different iodine concentrations (0, 5, 10, 15, 20 mg/ml) were analysed in an anthropomorphic thoracic phantom. Adding two phantom rings simulated increased patient size. For third-generation dual source CT (DSCT), tube voltage combinations of 150Sn and 70, 80, 90, 100 kVp were analysed. For dual layer CT (DLCT), 120 and 140 kVp were used. Scans were repeated three times. Median normalized values and interquartile ranges (IQRs) were calculated for all kVp settings and phantom sizes. Correlation between measured and known iodine concentrations was excellent for both systems (R = 0.999-1.000, p < 0.0001). For DSCT, median measurement errors ranged from -0.5% (IQR -2.0, 2.0%) at 150Sn/70 kVp and -2.3% (IQR -4.0, -0.1%) at 150Sn/80 kVp to -4.0% (IQR -6.0, -2.8%) at 150Sn/90 kVp. For DLCT, median measurement errors ranged from -3.3% (IQR -4.9, -1.5%) at 140 kVp to -4.6% (IQR -6.0, -3.6%) at 120 kVp. Larger phantom sizes increased variability of iodine measurements (p < 0.05). Iodine concentration can be accurately quantified with state-of-the-art DECT systems from two vendors. The lowest absolute errors were found for DSCT using the 150Sn/70 kVp or 150Sn/80 kVp combinations, which was slightly more accurate than 140 kVp in DLCT. • High-end CT scanners allow accurate iodine quantification using different DECT techniques. • Lowest measurement error was found in scans with largest photon energy separation. • Dual-source CT quantified iodine slightly more accurately than dual layer CT.

  5. 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...

  6. Technical Note: Insertion of digital lesions in the projection domain for dual-source, dual-energy CT.

    Science.gov (United States)

    Ferrero, Andrea; Chen, Baiyu; Li, Zhoubo; Yu, Lifeng; McCollough, Cynthia

    2017-05-01

    To compare algorithms performing material decomposition and classification in dual-energy CT, it is desirable to know the ground truth of the lesion to be analyzed in real patient data. In this work, we developed and validated a framework to insert digital lesions of arbitrary chemical composition into patient projection data acquired on a dual-source, dual-energy CT system. A model that takes into account beam-hardening effects was developed to predict the CT number of objects with known chemical composition. The model utilizes information about the x-ray energy spectra, the patient/phantom attenuation, and the x-ray detector energy response. The beam-hardening model was validated on samples of iodine (I) and calcium (Ca) for a second-generation dual-source, dual-energy CT scanner for all tube potentials available and a wide range of patient sizes. The seven most prevalent mineral components of renal stones were modeled and digital stones were created with CT numbers computed for each patient/phantom size and x-ray energy spectra using the developed beam-hardening model. Each digital stone was inserted in the dual-energy projection data of a water phantom scanned on a dual-source scanner and reconstructed with the routine algorithms in use in our practice. The geometry of the forward projection for dual-energy data was validated by comparing CT number accuracy and high-contrast resolution of simulated dual-energy CT data of the ACR phantom with experimentally acquired data. The beam-hardening model and forward projection method accurately predicted the CT number of I and Ca over a wide range of tube potentials and phantom sizes. The images reconstructed after the insertion of digital kidney stones were consistent with the images reconstructed from the scanner, and the CT number ratios for different kidney stone types were consistent with data in the literature. A sample application of the proposed tool was also demonstrated. A framework was developed and validated

  7. 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…

  8. 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.

  9. 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…

  10. Myxoma Virus Expressing Human Interleukin-12 Does Not Induce Myxomatosis in European Rabbits▿

    Science.gov (United States)

    Stanford, Marianne M.; Barrett, John W.; Gilbert, Philippe-Alexandre; Bankert, Richard; McFadden, Grant

    2007-01-01

    Myxoma virus (MV) is a candidate for oncolytic virotherapy due to its ability to selectively infect and kill tumor cells, yet MV is a species-specific pathogen that causes disease only in European rabbits. To assess the ability of MV to deliver cytokines to tumors, we created an MV (vMyxIL-12) that expresses human interleukin-12 (IL-12). vMyxIL-12 replicates similarly to wild-type MV, and virus-infected cells secrete bioactive IL-12. Yet, vMyxIL-12 does not cause myxomatosis, despite expressing the complete repertoire of MV proteins. Thus, vMyxIL-12 exhibits promise as an oncolytic candidate and is safe in all known vertebrate hosts, including lagomorphs. PMID:17728229

  11. Myxoma virus expressing human interleukin-12 does not induce myxomatosis in European rabbits.

    Science.gov (United States)

    Stanford, Marianne M; Barrett, John W; Gilbert, Philippe-Alexandre; Bankert, Richard; McFadden, Grant

    2007-11-01

    Myxoma virus (MV) is a candidate for oncolytic virotherapy due to its ability to selectively infect and kill tumor cells, yet MV is a species-specific pathogen that causes disease only in European rabbits. To assess the ability of MV to deliver cytokines to tumors, we created an MV (vMyxIL-12) that expresses human interleukin-12 (IL-12). vMyxIL-12 replicates similarly to wild-type MV, and virus-infected cells secrete bioactive IL-12. Yet, vMyxIL-12 does not cause myxomatosis, despite expressing the complete repertoire of MV proteins. Thus, vMyxIL-12 exhibits promise as an oncolytic candidate and is safe in all known vertebrate hosts, including lagomorphs.

  12. 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.

  13. 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…

  14. 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

  15. 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.)

  16. 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.

  17. Dual energy CT for the assessment of lung perfusion-Correlation to scintigraphy

    International Nuclear Information System (INIS)

    Thieme, Sven F.; Becker, Christoph R.; Hacker, Marcus; Nikolaou, Konstantin; Reiser, Maximilian F.; Johnson, Thorsten R.C.

    2008-01-01

    Purpose of this study was to determine the diagnostic value of dual energy CT in the assessment of pulmonary perfusion with reference to pulmonary perfusion scintigraphy. Thirteen patients received both dual energy CT (DECT) angiography (Somatom Definition, Siemens) and ventilation/perfusion scintigraphy. Median time between scans was 3 days (range, 0-90). DECT perfusion maps were generated based on the spectral properties of iodine. Two blinded observes assessed DECT angiograms, perfusion maps and scintigrams for presence and location of perfusion defects. The results were compared by patient and by segment, and diagnostic accuracy of DECT perfusion imaging was calculated regarding scintigraphy as standard of reference. Diagnostic accuracy per patient showed 75% sensitivity, 80% specificity and a negative predictive value of 66%. Sensitivity per segment amounted to 83% with 99% specificity, with 93% negative predictive value. Peripheral parts of the lungs were not completely covered by the 80 kVp detector in 85% of patients. CTA identified corresponding emboli in 66% of patients with concordant perfusion defects in DECT and scintigraphy. Dual energy CT perfusion imaging is able to display pulmonary perfusion defects with good agreement to scintigraphic findings. DECT can provide a pulmonary CT angiogram, high-resolution morphology of the lung parenchyma and perfusion information in one single exam

  18. Dual energy CT for the assessment of lung perfusion-Correlation to scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Thieme, Sven F.; Becker, Christoph R. [Department of Clinical Radiology, Ludwig-Maximilians-University of Munich (Germany); Hacker, Marcus [Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich (Germany); Nikolaou, Konstantin; Reiser, Maximilian F. [Department of Clinical Radiology, Ludwig-Maximilians-University of Munich (Germany); Johnson, Thorsten R.C. [Department of Clinical Radiology, Ludwig-Maximilians-University of Munich (Germany)], E-mail: thorsten.johnson@med.uni-muenchen.de

    2008-12-15

    Purpose of this study was to determine the diagnostic value of dual energy CT in the assessment of pulmonary perfusion with reference to pulmonary perfusion scintigraphy. Thirteen patients received both dual energy CT (DECT) angiography (Somatom Definition, Siemens) and ventilation/perfusion scintigraphy. Median time between scans was 3 days (range, 0-90). DECT perfusion maps were generated based on the spectral properties of iodine. Two blinded observes assessed DECT angiograms, perfusion maps and scintigrams for presence and location of perfusion defects. The results were compared by patient and by segment, and diagnostic accuracy of DECT perfusion imaging was calculated regarding scintigraphy as standard of reference. Diagnostic accuracy per patient showed 75% sensitivity, 80% specificity and a negative predictive value of 66%. Sensitivity per segment amounted to 83% with 99% specificity, with 93% negative predictive value. Peripheral parts of the lungs were not completely covered by the 80 kVp detector in 85% of patients. CTA identified corresponding emboli in 66% of patients with concordant perfusion defects in DECT and scintigraphy. Dual energy CT perfusion imaging is able to display pulmonary perfusion defects with good agreement to scintigraphic findings. DECT can provide a pulmonary CT angiogram, high-resolution morphology of the lung parenchyma and perfusion information in one single exam.

  19. A Dual Luciferase Reporter System for B. burgdorferi Measures Transcriptional Activity during Tick-Pathogen Interactions

    Directory of Open Access Journals (Sweden)

    Philip P. Adams

    2017-05-01

    Full Text Available Knowledge of the transcriptional responses of vector-borne pathogens at the vector-pathogen interface is critical for understanding disease transmission. Borrelia (Borreliella burgdorferi, the causative agent of Lyme disease in the United States, is transmitted by the bite of infected Ixodes sp. ticks. It is known that B. burgdorferi has altered patterns of gene expression during tick acquisition, persistence and transmission. Recently, we and others have discovered in vitro expression of RNAs found internal, overlapping, and antisense to annotated open reading frames in the B. burgdorferi genome. However, there is a lack of molecular genetic tools for B. burgdorferi for quantitative, strand-specific, comparative analysis of these transcripts in distinct environments such as the arthropod vector. To address this need, we have developed a dual luciferase reporter system to quantify B. burgdorferi promoter activities in a strand-specific manner. We demonstrate that constitutive expression of a B. burgdorferi codon-optimized Renilla reniformis luciferase gene (rlucBb allows normalization of the activity of a promoter of interest when fused to the B. burgdorferi codon-optimized Photinus pyralis luciferase gene (flucBb on the same plasmid. Using the well characterized, differentially regulated, promoters for flagellin (flaBp, outer surface protein A (ospAp and outer surface protein C (ospCp, we document the efficacy of the dual luciferase system for quantitation of promoter activities during in vitro growth and in infected ticks. Cumulatively, the dual luciferase method outlined herein is the first dual reporter system for B. burgdorferi, providing a novel and highly versatile approach for strand-specific molecular genetic analyses.

  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…

  1. Dual emission fluorescent silver nanoclusters for sensitive detection of the biological coenzyme NAD+/NADH.

    Science.gov (United States)

    Yuan, Yufeng; Huang, Kehan; Chang, Mengfang; Qin, Cuifang; Zhang, Sanjun; Pan, Haifeng; Chen, Yan; Xu, Jianhua

    2016-02-01

    Fluorescent silver nanoclusters (Ag NCs) displaying dual-excitation and dual-emission properties have been developed for the specific detection of NAD(+) (nicotinamide adenine dinucleotide, oxidized form). With the increase of NAD(+) concentrations, the longer wavelength emission (with the peak at 550 nm) was gradually quenched due to the strong interactions between the NAD(+) and Ag NCs, whereas the shorter wavelength emission (peaking at 395 nm) was linearly enhanced. More important, the dual-emission intensity ratio (I395/I550), fitting by a single-exponential decay function, can efficiently detect various NAD(+) levels from 100 to 4000 μM, as well as label NAD(+)/NADH (reduced form of NAD) ratios in the range of 1-50. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. 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

  3. 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...

  4. 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

  5. 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

  6. 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;…

  7. 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.

  8. Dual-modal cancer detection based on optical pH sensing and Raman spectroscopy.

    Science.gov (United States)

    Kim, Soogeun; Lee, Seung Ho; Min, Sun Young; Byun, Kyung Min; Lee, Soo Yeol

    2017-10-01

    A dual-modal approach using Raman spectroscopy and optical pH sensing was investigated to discriminate between normal and cancerous tissues. Raman spectroscopy has demonstrated the potential for in vivo cancer detection. However, Raman spectroscopy has suffered from strong fluorescence background of biological samples and subtle spectral differences between normal and disease tissues. To overcome those issues, pH sensing is adopted to Raman spectroscopy as a dual-modal approach. Based on the fact that the pH level in cancerous tissues is lower than that in normal tissues due to insufficient vasculature formation, the dual-modal approach combining the chemical information of Raman spectrum and the metabolic information of pH level can improve the specificity of cancer diagnosis. From human breast tissue samples, Raman spectra and pH levels are measured using fiber-optic-based Raman and pH probes, respectively. The pH sensing is based on the dependence of pH level on optical transmission spectrum. Multivariate statistical analysis is performed to evaluate the classification capability of the dual-modal method. The analytical results show that the dual-modal method based on Raman spectroscopy and optical pH sensing can improve the performance of cancer classification. (2017) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).

  9. Dual-modal cancer detection based on optical pH sensing and Raman spectroscopy

    Science.gov (United States)

    Kim, Soogeun; Lee, Seung Ho; Min, Sun Young; Byun, Kyung Min; Lee, Soo Yeol

    2017-10-01

    A dual-modal approach using Raman spectroscopy and optical pH sensing was investigated to discriminate between normal and cancerous tissues. Raman spectroscopy has demonstrated the potential for in vivo cancer detection. However, Raman spectroscopy has suffered from strong fluorescence background of biological samples and subtle spectral differences between normal and disease tissues. To overcome those issues, pH sensing is adopted to Raman spectroscopy as a dual-modal approach. Based on the fact that the pH level in cancerous tissues is lower than that in normal tissues due to insufficient vasculature formation, the dual-modal approach combining the chemical information of Raman spectrum and the metabolic information of pH level can improve the specificity of cancer diagnosis. From human breast tissue samples, Raman spectra and pH levels are measured using fiber-optic-based Raman and pH probes, respectively. The pH sensing is based on the dependence of pH level on optical transmission spectrum. Multivariate statistical analysis is performed to evaluate the classification capability of the dual-modal method. The analytical results show that the dual-modal method based on Raman spectroscopy and optical pH sensing can improve the performance of cancer classification.

  10. "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"…

  11. Detecting Intracranial Hemorrhage Using Automatic Tube Current Modulation With Advanced Modeled Iterative Reconstruction in Unenhanced Head Single- and Dual-Energy Dual-Source CT.

    Science.gov (United States)

    Scholtz, Jan-Erik; Wichmann, Julian L; Bennett, Dennis W; Leithner, Doris; Bauer, Ralf W; Vogl, Thomas J; Bodelle, Boris

    2017-05-01

    The purpose of our study was to determine diagnostic accuracy, image quality, and radiation dose of low-dose single- and dual-energy unenhanced third-generation dual-source head CT for detection of intracranial hemorrhage (ICH). A total of 123 patients with suspected ICH were examined using a dual-source 192-MDCT scanner. Standard-dose 120-kVp single-energy CT (SECT; n = 36) and 80-kVp and 150-kVp dual-energy CT (DECT; n = 30) images were compared with low-dose SECT (n = 32) and DECT (n = 25) images obtained using automated tube current modulation (ATCM). Advanced modeled iterative reconstruction (ADMIRE) was used for all protocols. Detection of ICH was performed by three readers who were blinded to the image acquisition parameters of each image series. Image quality was assessed both quantitatively and qualitatively. Interobserver agreement was calculated using the Fleiss kappa. Radiation dose was measured as dose-length product (DLP). Detection of ICH was excellent (sensitivity, 94.9-100%; specificity, 94.7-100%) in all protocols (p = 1.00) with perfect interobserver agreement (0.83-0.96). Qualitative ratings showed significantly better ratings for both standard-dose protocols regarding gray matter-to-white matter contrast (p ≤ 0.014), whereas highest gray matter-to-white matter contrast-to-noise ratio was observed with low-dose DECT images (p ≥ 0.057). The lowest posterior fossa artifact index was measured for standard-dose DECT, which showed significantly lower values compared with low-dose protocols (p ≤ 0.034). Delineation of ventricular margins and sharpness of subarachnoidal spaces were rated excellent in all protocols (p ≥ 0.096). Low-dose techniques lowered radiation dose by 26% for SECT images (DLP, 575.0 ± 72.3 mGy · cm vs 771.5 ± 146.8 mGy · cm; p dual-source CT while allowing significant radiation dose reduction.

  12. 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.

  13. A Differentially Driven Dual-Polarized Dual-Wideband Complementary Antenna for 2G/3G/LTE Applications

    Directory of Open Access Journals (Sweden)

    Botao Feng

    2014-01-01

    Full Text Available A novel differentially driven dual-polarized dual-wideband complementary patch antenna with high isolation is proposed for 2G/3G/LTE applications. In order to generate dual-polarization and dual-wideband properties, a pair of biorthogonal dual-layer η-shaped tapered line feeding structures is utilized to feed two pairs of dual-layer U-shaped patches, respectively. The upper-layer U-shaped patches mainly serve the upper frequency band, while the lower-layer ones chiefly work for the lower frequency band. Besides, a horned reflector is introduced to improve radiation patterns and provide stable gain. The prototype antenna can achieve a bandwidth of 25.7% (0.78 GHz–1.01 GHz with a stable gain of 7.8±0.7 dBi for the lower band, and a bandwidth of 45.7% (1.69 GHz–2.69 GHz with a gain of 9.5±1.1 dBi for the upper band. Input isolation exceeding 30 dB has been obtained in the wide bandwidth. Thus, it can be potentially used as a base station antenna for 2G/3G/LTE networks.

  14. 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...

  15. Utility of dual echo T2-weighted turbo spin echo MR imaging for differentiation of solid, malignant hepatic lesions from nonsolid, benign hepatic lesions

    International Nuclear Information System (INIS)

    Yang, Dal Mo; Yoon, Myung Hwan; Kim, Hak Soo; Lee, Eun Joo; Kim, Jong Ho; Kim, Hyung Sik; Chung, Jin Woo

    1999-01-01

    To evaluate the additive value of multiphasic contrast-enhanced dynamic MR imaging as a supplement to dual-echo T2-weighted TSE MR imaging for the differentiation of solid, malignant hepatic lesions from nonsolid, benign hepatic lesions. Two radiologists retrospectively reviewed dual-echo T2-weighted TSE MR images and gadolinium-enhanced MR images in 51 patients with hepatic lesions (28 malignant, 69 benign). For the differentiation of malignant from benign lesions, as seen on dual-echo T2-weighted TSE MR images, we evaluated sensitivity, specificity, and accuracy, and compared with the results with those for dual echo T2-weighted MR images plus multiphasic contrast-enhanced dynamic MR images. In addition, Az values for dual echo T2-weighted MR images were compared with those for dual echo T2-weighted MR images plus multiphasic contrast-enhanced dynamic MR images. For the differentiation of malignant from benign hepatic lesions, as seen on dual-echo T2-weighted TSE images, sensitivity, specificity, and accuracy were 80.0%, 97.5%, and 93.9%, respectively, for lesions less than 3cm in diameter, and 92.3%, 95.0%, and 93.5%, respectively, for those that were 3cm or larger. The results for dual-echo T2-weighted MR imaging plus multiphasic contrast-enhanced dynamic MR imaging were 86.7%, 100.0%, and 97.3%, respectively, for lesions less than 3cm, and 92.3%, 100.0%, and 95.7%, respectively for those that were 3cm or larger. There were no significant differences in sensitivity, specificity, or accuracy between the results obtained using dual-echo T2-weighted MR imaging and those obtained with dual-echo T2-weighted MR imaging plus multiphasic contrast-enhanced dynamic MR imaging. Nor were these statistically significant differences in Az values between the two groups. For the differentiation of solid, malignant hepatic lesions from nonsolid, benign hepatic lesions, there is no difference in accuracy between dual-echo T2-weighted TSE MR imaging and the additional use of

  16. 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....

  17. 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.

  18. A new semantic vigilance task: vigilance decrement, workload, and sensitivity to dual-task costs.

    Science.gov (United States)

    Epling, Samantha L; Russell, Paul N; Helton, William S

    2016-01-01

    Cognitive resource theory is a common explanation for both the performance decline in vigilance tasks, known as the vigilance decrement, and the limited ability to perform multiple tasks simultaneously. The limited supply of cognitive resources may be utilized faster than they are replenished resulting in a performance decrement, or may need to be allocated among multiple tasks with some performance cost. Researchers have proposed both domain-specific, for example spatial versus verbal processing resources, and domain general cognitive resources. One challenge in testing the domain specificity of cognitive resources in vigilance is the current lack of difficult semantic vigilance tasks which reliably produce a decrement. In the present research, we investigated whether the vigilance decrement was found in a new abbreviated semantic discrimination vigilance task, and whether there was a performance decrement in said vigilance task when paired with a word recall task, as opposed to performed individually. As hypothesized, a vigilance decrement in the semantic vigilance task was found in both the single-task and dual-task conditions, along with reduced vigilance performance in the dual-task condition and reduced word recall in the dual-task condition. This is consistent with cognitive resource theory. The abbreviated semantic vigilance task will be a useful tool for researchers interested in determining the specificity of cognitive resources utilized in vigilance tasks.

  19. Model independent approach to studies of the confining dual Abrikosov vortex in SU(2) lattice gauge theory

    International Nuclear Information System (INIS)

    Haymaker, Richard W.; Matsuki, Takayuki

    2007-01-01

    We address the problem of determining the type I, type II or borderline dual superconductor behavior in maximal Abelian gauge SU(2) through the study of the dual Abrikosov vortex. We find that significant electric currents in the simulation data call into question the use of the dual Ginzburg-Landau Higgs model in interpreting the data. Further, two definitions of the penetration depth parameter take two different values. The splitting of this parameter into two is intricately connected to the existence of electric currents. It is important in our approach that we employ definitions of flux and electric and magnetic currents that respect Maxwell equations exactly for lattice averages independent of lattice spacings. Applied to specific Wilson loop sizes, our conclusions differ from those that use the dual GLH model

  20. An integrated treatment model for dual diagnosis of psychosis and addiction.

    Science.gov (United States)

    Minkoff, K

    1989-10-01

    A model that integrates the treatment of patients with a dual diagnosis of psychosis and addiction has been developed on a general hospital psychiatric unit. The model emphasizes the parallels between the standard biopsychosocial illness-and-rehabilitation model for treatment of serious psychiatric disorders and the 12-step disease-and-recovery model of Alcoholics Anonymous for treatment of addiction. Dual-diagnosis patients are viewed as having two primary, chronic, biologic mental illnesses, each requiring specific treatment to stabilize acute symptoms and engage the patient in a recovery process. An integrated treatment program is described, as are the steps taken to alleviate psychiatric clinicians' concerns about patient involvement in AA and addiction clinicians' discomfort with patients' use of medication.

  1. Dual p16 and Ki-67 Expression in Liquid-Based Cervical Cytological Samples Compared to Pap Cytology Findings, Biopsies, and HPV Testing in Cervical Cancer Screening: A Diagnostic Accuracy Study.

    Science.gov (United States)

    Prigenzi, Karla Calaça Kabbach; Heinke, Thaís; Salim, Rafael Calil; Focchi, Gustavo Rubino de Azevedo

    2018-01-01

    Our objective was to verify the sensitivity and specificity of dual immunocytochemistry staining for p16 and Ki-67 in liquid-based samples (the "dual" assay) for cervical lesion screening, compared to biopsy findings and human papillomavirus (HPV) DNA molecular detection. Sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values for the "dual immunocytochemistry assay" were calculated and compared to histopathological results and to high-risk HPV DNA detection in adult women or teenagers submitted to cervical cancer screening. A total of 151 women were included. The majority (96.2%) of those with negative dual assay results had lower biopsy grades (p cytology results suggestive of cervical cancer had positive dual immunocytochemistry assay results more frequently (p < 0.001), and these positive results were also significantly associated with biopsy findings (p < 0.001) and with high-risk genotype HPV infection (p = 0.007). Specificity and PPV for the dual assay were 0.972 (0.855-0.999) and 0.800 (0.284-0.995), respectively, and 1.000 (0.590-1.000) and 1.000 (0.631-1.000) for HPV detection. The dual immunocytochemistry assay had high specificity and PPV. It reveals a persistent HPV infection, avoiding the need for new tissue collections for biopsies or hybrid capture. © 2018 S. Karger AG, Basel.

  2. 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

  3. The Stiffness and Damping Characteristics of a Dual-Chamber Air Spring Device Applied to Motion Suppression of Marine Structures

    Directory of Open Access Journals (Sweden)

    Xiaohui Zeng

    2016-03-01

    Full Text Available Dual-chamber air springs are used as a key component for vibration isolation in some industrial applications. The working principle of the dual-chamber air spring device as applied to motion suppression of marine structures is similar to that of the traditional air spring, but they differ in their specific characteristics. The stiffness and damping of the dual-chamber air spring device determine the extent of motion suppression. In this article, we investigate the stiffness and damping characteristics of a dual-chamber air spring device applied to marine structure motion suppression using orthogonal analysis and an experimental method. We measure the effects of volume ratio, orifice ratio, excitation amplitude, and frequency on the stiffness and damping of the dual-chamber vibration absorber. Based on the experimental results, a higher-order non-linear regression method is obtained. We achieve a rapid calculation model for dual-chamber air spring stiffness and damping, which can provide guidance to project design.

  4. 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…

  5. 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.)

  6. 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.)

  7. GPM GROUND VALIDATION DUAL-FREQUENCY DUAL-POLARIZED DOPPLER RADAR (D3R) IFLOODS V1

    Data.gov (United States)

    National Aeronautics and Space Administration — The GPM Ground Validation Dual-frequency Dual-polarized Doppler Radar (D3R) IFloodS data set contain radar reflectivity and doppler velocity measurements. The D3R...

  8. Dual layer hollow fiber sorbents for trace H2S removal from gas streams

    KAUST Repository

    Bhandari, Dhaval A.; Bessho, Naoki; Koros, William J.

    2013-01-01

    Hollow fiber sorbents are pseudo monolithic materials with potential use in various adsorption based applications. Dual layer hollow fiber sorbents have the potential to allow thermal regeneration without direct contact of the regeneration fluid with the sorbent particles. This paper considers the application of dual layer hollow fiber sorbents for a case involving trace amounts of H2S removal from a simulated gas stream and offers a comparison with single layer hollow fiber sorbents. The effect of spin dope composition and core layer zeolite loading on the gas flux, H2S transient sorption capacity and pore structure are also studied. This work can be used as a guide to develop and optimize dual layer hollow fiber sorbent properties beyond the specific example considered here. © 2013 Elsevier Ltd.

  9. Dual layer hollow fiber sorbents for trace H2S removal from gas streams

    KAUST Repository

    Bhandari, Dhaval A.

    2013-05-01

    Hollow fiber sorbents are pseudo monolithic materials with potential use in various adsorption based applications. Dual layer hollow fiber sorbents have the potential to allow thermal regeneration without direct contact of the regeneration fluid with the sorbent particles. This paper considers the application of dual layer hollow fiber sorbents for a case involving trace amounts of H2S removal from a simulated gas stream and offers a comparison with single layer hollow fiber sorbents. The effect of spin dope composition and core layer zeolite loading on the gas flux, H2S transient sorption capacity and pore structure are also studied. This work can be used as a guide to develop and optimize dual layer hollow fiber sorbent properties beyond the specific example considered here. © 2013 Elsevier Ltd.

  10. Preliminary study of single contrast enhanced dual energy heart imaging using dual-source CT

    International Nuclear Information System (INIS)

    Peng Jin; Zhang Longjiang; Zhou Changsheng; Lu Guangming; Ma Yan; Gu Haifeng

    2009-01-01

    Objective: To evaluate the feasibility and preliminary applications of single contrast enhanced dual energy heart imaging using dual-source CT (DSCT). Methods: Thirty patients underwent dual energy heart imaging with DSCT, of which 6 cases underwent SPECT or DSA within one week. Two experienced radiologists assessed image quality of coronary arteries and iodine map of myocardium. and correlated the coronary artery stenosis with the perfusion distribution of iodine map. Results: l00% (300/300) segments reached diagnostic standards. The mean score of image for all patients was 4.68±0.57. Mural coronary artery was present in 10 segments in S cases, atherosclerotic plaques in 32 segments in 12 cases, of which 20 segments having ≥50% stenosis, 12 segments ≤50% stenosis; dual energy CT coronary angiography was consistent with the DSA in 3 patients. 37 segmental perfusion abnormalities on iodine map were found in 15 cases, including 28 coronary blood supply segment narrow segment and 9 no coronary stenosis (including three negative segments in SPECD. Conclusion: Single contrast enhanced dual energy heart imaging can provide good coronary artery and myocardium perfusion images in the patients with appropriate heart rate, which has a potential to be used in the clinic and further studies are needed. (authors)

  11. Dual education and industrial cooperation in electrical engineering

    Science.gov (United States)

    Váradiné Szarka, A.

    2016-11-01

    Dual education in higher education is a new system in Hungary introduced by Mercedes Benz with cooperation of Kecskemet College. In the new system companies support certain number of students and provide them strong practical education in their field. Students applying successfully for dual education study together with non-dual students at the university, so they go through the same university courses as their non-dual colleagues, but while non-dual students’ academic year includes 2×14 weeks active semester and 2×6 weeks exam session, all over 40 weeks, dual students have 48 working weeks including study at the university and practicing at the company. The main question of the success which one is the most effective model to be applied. This paper summarises 2 models of dual education with their advantages and disadvantages and also it presents practical realization at the University of Debrecen with special attention to measurement and instrumentation. Dual education in BSc level electrical engineering course cooperates with 6 multinational companies of the region in four specialization. Dual education also has great impact to the modernisation of engineering education. Detailed study of dual education in field of instrumentation and measurement is provided in the paper.

  12. 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).

  13. 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.

  14. Short-term memory and dual task performance

    Science.gov (United States)

    Regan, J. E.

    1982-01-01

    Two hypotheses concerning the way in which short-term memory interacts with another task in a dual task situation are considered. It is noted that when two tasks are combined, the activity of controlling and organizing performance on both tasks simultaneously may compete with either task for a resource; this resource may be space in a central mechanism or general processing capacity or it may be some task-specific resource. If a special relationship exists between short-term memory and control, especially if there is an identity relationship between short-term and a central controlling mechanism, then short-term memory performance should show a decrement in a dual task situation. Even if short-term memory does not have any particular identity with a controlling mechanism, but both tasks draw on some common resource or resources, then a tradeoff between the two tasks in allocating resources is possible and could be reflected in performance. The persistent concurrence cost in memory performance in these experiments suggests that short-term memory may have a unique status in the information processing system.

  15. Managing multiple roles - Personality, stress, and work-family interference in dual-earner couples

    NARCIS (Netherlands)

    Wierda-Boer, H.H.; Gerris, J.R.M.; Vermulst, A.A.

    2009-01-01

    Today many parents have multiple roles. This study examined how personality, domain-specific stress, and work-family interference are interrelated. Questionnaire data of 276 Dutch dual-earner couples with young children were analyzed using structural equation modeling. Findings demonstrated that job

  16. 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

  17. Are factors related to dual-task performance in people with Parkinson's disease dependent on the type of dual task?

    Science.gov (United States)

    Strouwen, Carolien; Molenaar, Esther A L M; Keus, Samyra H J; Münks, Liesbeth; Heremans, Elke; Vandenberghe, Wim; Bloem, Bastiaan R; Nieuwboer, Alice

    2016-02-01

    Impaired dual-task performance significantly impacts upon functional mobility in people with Parkinson's disease (PD). The aim of this study was to identify determinants of dual-task performance in people with PD in three different dual tasks to assess their possible task-dependency. We recruited 121 home-dwelling patients with PD (mean age 65.93 years; mean disease duration 8.67 years) whom we subjected to regular walking (control condition) and to three dual-task conditions: walking combined with a backwards Digit Span task, an auditory Stroop task and a Mobile Phone task. We measured dual-task gait velocity using the GAITRite mat and dual-task reaction times and errors on the concurrent tasks as outcomes. Motor, cognitive and descriptive variables which correlated to dual-task performance (p task gait velocity and executive function, tested by the alternating intake test, was significantly associated with gait velocity during the Digit Span (R(2) = 0.65; p task (R(2) = 0.62; p task. Age was a surplus determinant of gait velocity while using a mobile phone. Single-task gait velocity and executive function as measured by a verbal fluency switching task were independent determinants of dual-task gait performance in people with PD. In contrast to expectation, these factors were the same across different tasks, supporting the robustness of the findings. Future study needs to determine whether these factors predict dual-task abnormalities prospectively. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. 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.

  19. Vesicular stomatitis virus expressing a chimeric Sindbis glycoprotein containing an Fc antibody binding domain targets to Her2/neu overexpressing breast cancer cells

    International Nuclear Information System (INIS)

    Bergman, Ira; Whitaker-Dowling, Patricia; Gao Yanhua; Griffin, Judith A.; Watkins, Simon C.

    2003-01-01

    Vesicular stomatitis virus (VSV) is a candidate for development for cancer therapy. It is an oncolytic virus that is safe in humans. Recombinant virus can be made directly from plasmid components. We attempted to create a virus that targeted specifically to breast cancer cells. Nonreplicating and replicating pseudotype VSV were created whose only surface glycoprotein (gp) was a Sindbis gp, called Sindbis-ZZ, modified to severely reduce its native binding function and to contain the Fc-binding domain of Staphylococcus aureus protein A. When titered on Her2/neu overexpressing SKBR3 human breast cancer cells, pseudotype VSV coated with Sindbis-ZZ had 5 /ml. This work demonstrates the ability to easily create, directly from plasmid components, an oncolytic replicating VSV with a restricted host cell range

  20. Optimal and fast E/B separation with a dual messenger field

    Science.gov (United States)

    Kodi Ramanah, Doogesh; Lavaux, Guilhem; Wandelt, Benjamin D.

    2018-05-01

    We adapt our recently proposed dual messenger algorithm for spin field reconstruction and showcase its efficiency and effectiveness in Wiener filtering polarized cosmic microwave background (CMB) maps. Unlike conventional preconditioned conjugate gradient (PCG) solvers, our preconditioner-free technique can deal with high-resolution joint temperature and polarization maps with inhomogeneous noise distributions and arbitrary mask geometries with relative ease. Various convergence diagnostics illustrate the high quality of the dual messenger reconstruction. In contrast, the PCG implementation fails to converge to a reasonable solution for the specific problem considered. The implementation of the dual messenger method is straightforward and guarantees numerical stability and convergence. We show how the algorithm can be modified to generate fluctuation maps, which, combined with the Wiener filter solution, yield unbiased constrained signal realizations, consistent with observed data. This algorithm presents a pathway to exact global analyses of high-resolution and high-sensitivity CMB data for a statistically optimal separation of E and B modes. It is therefore relevant for current and next-generation CMB experiments, in the quest for the elusive primordial B-mode signal.

  1. Photoacoustic/ultrasound dual-modality contrast agent and its application to thermotherapy.

    Science.gov (United States)

    Wang, Yu-Hsin; Liao, Ai-Ho; Chen, Jui-Hao; Wang, Churng-Ren Chris; Li, Pai-Chi

    2012-04-01

    This study investigates a photoacoustic/ultrasound dual-modality contrast agent, including extending its applications from image-contrast enhancement to combined diagnosis and therapy with site-specific targeting. The contrast agent comprises albumin-shelled microbubbles with encapsulated gold nanorods (AuMBs). The gas-filled microbubbles, whose diameters range from submicrometer to several micrometers, are not only echogenic but also can serve as drug-delivery vehicles. The gold nanorods are used to enhance the generation of both photoacoustic and photothermal signals. The optical absorption peak of the gold nanorods is tuned to 760 nm and is invariant after microbubble encapsulation. Dual-modality contrast enhancement is first described here, and the applications to cellular targeting and laser-induced thermotherapy in a phantom are demonstrated. Photoacoustic imaging can be used to monitor temperature increases during the treatment. The targeting capability of AuMBs was verified, and the temperature increased by 26°C for a laser power of 980 mW, demonstrating the potential of combined diagnosis and therapy with the dual-modality agent. Targeted photo- or acoustic-mediated delivery is also possible.

  2. 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.

  3. One dimensional modeling of a diesel-CNG dual fuel engine

    Science.gov (United States)

    Azman, Putera Adam; Fawzi, Mas; Ismail, Muammar Mukhsin; Osman, Shahrul Azmir

    2017-04-01

    Some of the previous studies have shown that the use of compressed natural gas (CNG) in diesel engines potentially produce engine performance improvement and exhaust gas emission reduction, especially nitrogen oxides, unburned hydrocarbons, and carbon dioxide. On the other hand, there are other researchers who claimed that the use of CNG increases exhaust gas emissions, particularly nitrogen oxides. In this study, a one-dimensional model of a diesel-CNG dual fuel engine was made based on a 4-cylinder 2.5L common rail direct injection diesel engine. The software used is GT-Power, and it was used to analyze the engine performance and exhaust gas emissions of several diesel-CNG dual fuel blend ratios, i.e. 100:0, 90:10, 80:20, 70:30, 60:40 and 50:50. The effect of 100%, 75%, 50% engine loads on the exhaust gas emissions were also studied. The result shows that all diesel-CNG fuel blends produces higher brake torque and brake power at engine speed of 2000-3000 rpm compared with 100% diesel. The 50:50 diesel-CNG blend produces the highest brake torque and brake power, but also has the highest brake specific fuel consumption. As a higher percentage of CNG added to the dual fuel blend, unburned hydrocarbons and carbon monoxide emission increased while carbon dioxide emission decreased. The nitrogen oxides emission concentration is generally unaffected by any change of the dual fuel ratio.

  4. Interference of Spin-2 Self-Dual Modes

    OpenAIRE

    Ilha, Anderson; Wotzasek, Clovis

    2001-01-01

    We study the effects of interference between the self-dual and anti self-dual massive modes of the linearized Einstein-Chern-Simons topological gravity. The dual models to be used in the interference process are carefully analyzed with special emphasis on their propagating spectrum. We identify the opposite dual aspects, necessary for the application of the interference formalism on this model. The soldered theory so obtained displays explicitly massive modes of the Proca type. It may also be...

  5. Contexts of cigarette and e-cigarette use among dual users: a qualitative study.

    Science.gov (United States)

    Pokhrel, Pallav; Herzog, Thaddeus A; Muranaka, Nicholas; Regmi, Sakshi; Fagan, Pebbles

    2015-09-04

    Not much is currently understood regarding the contexts of cigarette and e-cigarette use among dual users. Proper application of e-cigarettes to smoking cessation or tobacco harm reduction would require an understanding of when and why dual users use cigarettes versus e-cigarettes. This study sought to elucidate the contexts of cigarette versus e-cigarette use among dual users. Twelve focus group discussions were conducted with 62 young adult current daily e-cigarette users [63% men; mean age = 25.1 (Standard Deviation = 5.5)]. Almost all participants either concurrently smoked cigarettes or had been recent dual users. Data were analyzed following principles of inductive deduction. Results indicated that dual users' use of cigarettes is influenced by particular activities (e.g., before/after eating), strong craving or need for stimulation (e.g., in response to stress), places/situations (e.g., when cigarette smokers are nearby; outdoors), use of other substances (alcohol, coffee), and unavailability of an e-cigarette when needed. In addition to particular activities and places/situations that are conducive to e-cigarette use, use of e-cigarette when cigarette is not available or where cigarette smoking is not permitted emerged as contexts specific to e-cigarette use. For habitual cigarette smokers wanting to quit tobacco smoking, switching over completely to e-cigarettes may require skills of cognitive-behavioral management. Future research needs to ascertain the characteristics of dual users who use e-cigarettes as cessation aids versus as cigarette alternative when cigarette is unavailable or smoking is not permitted.

  6. Effects of dual-task balance training on postural performance in patients with Multiple Sclerosis: a double-blind, randomized controlled pilot trial.

    Science.gov (United States)

    Monjezi, Saeideh; Negahban, Hossein; Tajali, Shirin; Yadollahpour, Nava; Majdinasab, Nastaran

    2017-02-01

    To investigate the effects of dual-task balance training on postural performance in patients with multiple sclerosis as compared with single-task balance training. Double-blind, pretest-posttest, randomized controlled pilot trial. Local Multiple Sclerosis Society. A total of 47 patients were randomly assigned to two equal groups labeled as single-task training and dual-task training groups. All patients received supervised balance training sessions, 3 times per week for 4 weeks. The patients in the single-task group performed balance activities, alone. However, patients in dual-task group practiced balance activities while simultaneously performing cognitive tasks. The 10-Meter Walk Test and Timed Up-and-Go under single-task and dual-task conditions, in addition to Activities-specific Balance Confidence, Berg Balance Scale, and Functional Gait Assessment were assessed pre-, and post intervention and also 6-weeks after the end of intervention. Only 38 patients completed the treatment plan. There was no difference in the amount of improvement seen between the two study groups. In both groups there was a significant effect of time for dual-10 Meter Walk Test (F 1, 36 =11.33, p=0.002) and dual-Timed Up-and-Go (F 1, 36 =14.27, p=0.001) but not for their single-tasks. Moreover, there was a significant effect of time for Activities-specific Balance Confidence, Berg Balance Scale, and Functional Gait Assessment ( Ppilot study did not show more benefits from undertaking dual-task training than single-task training. A power analysis showed 71 patients per group would be needed to determine whether there was a clinically relevant difference for dual-task gait speed between the groups.

  7. 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

  8. Aerial Triangulation Close-range Images with Dual Quaternion

    Directory of Open Access Journals (Sweden)

    SHENG Qinghong

    2015-05-01

    Full Text Available A new method for the aerial triangulation of close-range images based on dual quaternion is presented. Using dual quaternion to represent the spiral screw motion of the beam in the space, the real part of dual quaternion represents the angular elements of all the beams in the close-range area networks, the real part and the dual part of dual quaternion represents the line elements corporately. Finally, an aerial triangulation adjustment model based on dual quaternion is established, and the elements of interior orientation and exterior orientation and the object coordinates of the ground points are calculated. Real images and large attitude angle simulated images are selected to run the experiments of aerial triangulation. The experimental results show that the new method for the aerial triangulation of close-range images based on dual quaternion can obtain higher accuracy.

  9. Beyond patchwork precaution in the dual-use governance of synthetic biology.

    Science.gov (United States)

    Kelle, Alexander

    2013-09-01

    The emergence of synthetic biology holds the potential of a major breakthrough in the life sciences by transforming biology into a predictive science. The dual-use characteristics of similar breakthroughs during the twentieth century have led to the application of benignly intended research in e.g. virology, bacteriology and aerobiology in offensive biological weapons programmes. Against this background the article raises the question whether the precautionary governance of synthetic biology can aid in preventing this techno-science witnessing the same fate? In order to address this question, this paper proceeds in four steps: it firstly introduces the emerging techno-science of synthetic biology and presents some of its potential beneficial applications. It secondly analyses contributions to the bioethical discourse on synthetic biology as well as precautionary reasoning and its application to life science research in general and synthetic biology more specifically. The paper then identifies manifestations of a moderate precautionary principle in the emerging synthetic biology dual-use governance discourse. Using a dual-use governance matrix as heuristic device to analyse some of the proposed measures, it concludes that the identified measures can best be described as "patchwork precaution" and that a more systematic approach to construct a web of dual-use precaution for synthetic biology is needed in order to guard more effectively against the field's future misuse for harmful applications.

  10. Dual fuel mode operation in diesel engines using renewable fuels: Rubber seed oil and coir-pith producer gas

    Energy Technology Data Exchange (ETDEWEB)

    Ramadhas, A.S.; Jayaraj, S.; Muraleedharan, C. [Department of Mechanical Engineering, National Institute of Technology Calicut, Calicut-673601 (India)

    2008-09-15

    Partial combustion of biomass in the gasifier generates producer gas that can be used as supplementary or sole fuel for internal combustion engines. Dual fuel mode operation using coir-pith derived producer gas and rubber seed oil as pilot fuel was analyzed for various producer gas-air flow ratios and at different load conditions. The engine is experimentally optimized with respect to maximum pilot fuel savings in the dual fuel mode operation. The performance and emission characteristics of the dual fuel engine are compared with that of diesel engine at different load conditions. Specific energy consumption in the dual-fuel mode of operation with oil-coir-pith operation is found to be in the higher side at all load conditions. Exhaust emission was found to be higher in the case of dual fuel mode of operation as compared to neat diesel/oil operation. Engine performance characteristics are inferior in fully renewable fueled engine operation but it suitable for stationary engine application, particularly power generation. (author)

  11. 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.

  12. Mechanisms of Practice-Related Reductions of Dual-Task Interference with Simple Tasks: Data and Theory

    Science.gov (United States)

    Strobach, Tilo; Torsten, Schubert

    2017-01-01

    In dual-task situations, interference between two simultaneous tasks impairs performance. With practice, however, this impairment can be reduced. To identify mechanisms leading to a practice-related improvement in sensorimotor dual tasks, the present review applied the following general hypothesis: Sources that impair dual-task performance at the beginning of practice are associated with mechanisms for the reduction of dual-task impairment at the end of practice. The following types of processes provide sources for the occurrence of this impairment: (a) capacity-limited processes within the component tasks, such as response-selection or motor response stages, and (b) cognitive control processes independent of these tasks and thus operating outside of component-task performance. Dual-task practice studies show that, under very specific conditions, capacity-limited processes within the component tasks are automatized with practice, reducing the interference between two simultaneous tasks. Further, there is evidence that response-selection stages are shortened with practice. Thus, capacity limitations at these stages are sources for dual-task costs at the beginning of practice and are overcome with practice. However, there is no evidence demonstrating the existence of practice-related mechanisms associated with capacity-limited motor-response stages. Further, during practice, there is an acquisition of executive control skills for an improved allocation of limited attention resources to two tasks as well as some evidence supporting the assumption of improved task coordination. These latter mechanisms are associated with sources of dual-task interference operating outside of component task performance at the beginning of practice and also contribute to the reduction of dual-task interference at its end. PMID:28439319

  13. Evaluation of Myc Gene Amplification in Prostate Cancer Using a Dual Color Chromogenic in-Situ Hybridization (Dual CISH) Assay

    OpenAIRE

    Daniel Lerda; Marta Cabrera; Jorge Flores; Luis Gutierrez; Armando Chierichetti; Martin Revol; Hernan Garcia Onto

    2013-01-01

    Objetive: The overall purpose of the study was to demonstrate applicability of the Dako dual-color chromogenic in situ hybridization (CISH) assay (DAKO Denmark, Glostrup) with respect to fluorescence in situ hybridization (FISH) probes MYC-C. Methods: MYC gene amplification by FISH and Dako dual-color CISH Results: The study showed that the dual-color CISH assay can convert Texas red and fluorescein isothiocyanate (FITC) signals into chromogenic signals. The dual –color CISH assay was p...

  14. 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.

  15. 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....

  16. The functional neuroanatomy of multitasking: combining dual tasking with a short term memory task.

    Science.gov (United States)

    Deprez, Sabine; Vandenbulcke, Mathieu; Peeters, Ron; Emsell, Louise; Amant, Frederic; Sunaert, Stefan

    2013-09-01

    Insight into the neural architecture of multitasking is crucial when investigating the pathophysiology of multitasking deficits in clinical populations. Presently, little is known about how the brain combines dual-tasking with a concurrent short-term memory task, despite the relevance of this mental operation in daily life and the frequency of complaints related to this process, in disease. In this study we aimed to examine how the brain responds when a memory task is added to dual-tasking. Thirty-three right-handed healthy volunteers (20 females, mean age 39.9 ± 5.8) were examined with functional brain imaging (fMRI). The paradigm consisted of two cross-modal single tasks (a visual and auditory temporal same-different task with short delay), a dual-task combining both single tasks simultaneously and a multi-task condition, combining the dual-task with an additional short-term memory task (temporal same-different visual task with long delay). Dual-tasking compared to both individual visual and auditory single tasks activated a predominantly right-sided fronto-parietal network and the cerebellum. When adding the additional short-term memory task, a larger and more bilateral frontoparietal network was recruited. We found enhanced activity during multitasking in components of the network that were already involved in dual-tasking, suggesting increased working memory demands, as well as recruitment of multitask-specific components including areas that are likely to be involved in online holding of visual stimuli in short-term memory such as occipito-temporal cortex. These results confirm concurrent neural processing of a visual short-term memory task during dual-tasking and provide evidence for an effective fMRI multitasking paradigm. © 2013 Elsevier Ltd. All rights reserved.

  17. Gait, dual task and history of falls in elderly with preserved cognition, mild cognitive impairment, and mild Alzheimer's disease.

    Science.gov (United States)

    Ansai, Juliana H; Andrade, Larissa P; Rossi, Paulo G; Takahashi, Anielle C M; Vale, Francisco A C; Rebelatto, José R

    Studies with functional and applicable methods and new cognitive demands involving executive function are needed to improve screening, prevention and rehabilitation of cognitive impairment and falls. to identify differences in gait, dual task performances, and history of falls between elderly people with preserved cognition, mild cognitive impairment and mild Alzheimer's disease. A cross-sectional study was conducted. The sample consisted of 40 community-dwelling older adults with preserved cognition, 40 older adults with mild cognitive impairment, and 38 older adults with mild Alzheimer's disease. The assessment consisted of anamneses, gait (measured by the 10-meter walk test), dual task (measured by the Timed Up and Go Test associated with the motor-cognitive task of calling a phone number), and history of falls in the past year. There were no differences among all groups for all variables. However, the Alzheimer's disease Group performed significantly worse in the dual task than the other groups. No item of dual task could distinguish people with preserved cognition from those with mild cognitive impairment. The groups with cognitive impairment included more fallers, and specific characteristics in history of falls between groups were identified. Dual task could distinguish Alzheimer's disease patients specifically from other cognitive profiles. Copyright © 2017 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia. Publicado por Elsevier Editora Ltda. All rights reserved.

  18. [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.

  19. 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)

  20. Switchable dual-wavelength single-longitudinal-mode erbium fiber laser utilizing a dual-ring scheme with a saturable absorber

    Science.gov (United States)

    Yang, Zi-Qing; Huang, Tzu-Jung; Chang, Yao-Jen; Yeh, Chien-Hung; Chow, Chi-Wai; Chen, Jing-Heng; Chen, Kun-Huang

    2018-06-01

    In this work, we propose and demonstrate a switchable dual-wavelength erbium-doped fiber (EDF) ring laser with stable single-longitudinal-mode (SLM) output. Here, a dual-ring (DR) structure with an unpumped EDF of 2 m is designed to achieve SLM oscillation. Five fiber Bragg gratings (FBGs) are applied in the laser cavity serving as the reflective element to generate different dual-wavelength outputs. In the measurement, six sets of generated dual-wavelengths with various mode-spacing (Δλ) can be achieved via the five FBGs. Additionally, the stability performance of the proposed EDF DR laser is also demonstrated.

  1. Data sharing and dual-use issues.

    Science.gov (United States)

    Bezuidenhout, Louise

    2013-03-01

    The concept of dual-use encapsulates the potential for well-intentioned, beneficial scientific research to also be misused by a third party for malicious ends. The concept of dual-use challenges scientists to look beyond the immediate outcomes of their research and to develop an awareness of possible future (mis)uses of scientific research. Since 2001 much attention has been paid to the possible need to regulate the dual-use potential of the life sciences. Regulation initiatives fall under two broad categories-those that develop the ethical education of scientists and foster an awareness and responsibility of dual-use issues, and those which assess the regulation of information being generated by current research. Both types of initiatives are premised on a cautious, risk-adverse philosophy which advocates careful examination of all future endpoints of research endeavors. This caution advocated within initiatives such as pre-publication review of journal articles contrasts to the obligation to share underpinning data sharing discussions. As the dual-use debate has yet to make a significant impact on data sharing discussions (and vice versa) it is possible that these two areas of knowledge control may present areas of ethical conflict for scientists, and thus need to be more closely examined. This paper examines the tension between the obligation to share exemplified by data sharing principles and the concerns raised by the risk-cautious culture of the dual-use debates. The paper concludes by reflecting on the issues of responsibility as raised by dual-use as relating to data sharing, such as the chain of custody for shared data.

  2. Unraveling Executive Functioning in Dual Diagnosis.

    Science.gov (United States)

    Duijkers, Judith C L M; Vissers, Constance Th W M; Egger, Jos I M

    2016-01-01

    In mental health, the term dual-diagnosis is used for the co-occurrence of Substance Use Disorder (SUD) with another mental disorder. These co-occurring disorders can have a shared cause, and can cause/intensify each other's expression. Forming a threat to health and society, dual-diagnosis is associated with relapses in addiction-related behavior and a destructive lifestyle. This is due to a persistent failure to control impulses and the maintaining of inadequate self-regulatory behavior in daily life. Thus, several aspects of executive functioning like inhibitory, shifting and updating processes seem impaired in dual-diagnosis. Executive (dys-)function is currently even seen as a shared underlying key component of most mental disorders. However, the number of studies on diverse aspects of executive functioning in dual-diagnosis is limited. In the present review, a systematic overview of various aspects of executive functioning in dual-diagnosis is presented, striving for a prototypical profile of patients with dual-diagnosis. Looking at empirical results, inhibitory and shifting processes appear to be impaired for SUD combined with schizophrenia, bipolar disorder or cluster B personality disorders. Studies involving updating process tasks for dual-diagnosis were limited. More research that zooms in to the full diversity of these executive functions is needed in order to strengthen these findings. Detailed insight in the profile of strengths and weaknesses that underlies one's behavior and is related to diagnostic classifications, can lead to tailor-made assessment and indications for treatment, pointing out which aspects need attention and/or training in one's self-regulative abilities.

  3. 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.

  4. 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.

  5. Accuracy of contrast-enhanced dual-energy MDCT for the assessment of iodine uptake in renal lesions.

    Science.gov (United States)

    Mileto, Achille; Marin, Daniele; Ramirez-Giraldo, Juan Carlos; Scribano, Emanuele; Krauss, Bernhard; Mazziotti, Silvio; Ascenti, Giorgio

    2014-05-01

    The objective of our study was to assess the accuracy of iodine-related attenuation and iodine quantification as imaging biomarkers of iodine uptake in renal lesions on a single-phase nephrographic image with dual-energy MDCT. Fifty-nine patients (41 men, 18 women; age range, 28-84 years) with 80 renal lesions underwent contrast-enhanced dual-energy CT during the nephrographic phase of enhancement. Renal lesions were characterized as enhancing or nonenhancing on color-coded iodine overlay maps using iodine-related attenuation (in Hounsfield units) and iodine quantification (in milligrams per milliliter). For iodine-related attenuation the iodine uptake thresholds of 15 and 20 HU were tested; a threshold of 0.5 mg/mL was used for iodine quantification. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of iodine-related attenuation and iodine quantification were calculated from chi-square tests of contingency with histopathology or imaging follow-up as the reference standard. The 95% CIs were calculated from binomial expression. Differences in sensitivity and specificity were assessed by means of McNemar analysis. A significant difference in sensitivity and specificity was found between iodine-related attenuation with the thresholds of 15 HU (sensitivity, 91.4%; specificity, 93.3%; PPV, 91.4%; NPV, 93.3%) and 20 HU (sensitivity, 77.1%; specificity, 100%; PPV, 100%; NPV, 84.9%) (p = 0.008) and between iodine quantification (sensitivity, 100%; specificity, 97.7%; PPV, 97.2%; NPV, 100%) and iodine-related attenuation with a threshold of 20 HU (p = 0.004). No significant difference in sensitivity and specificity was found between iodine quantification and iodine-related attenuation with a threshold of 15 HU. Contrast-enhanced dual-energy MDCT with iodine-related attenuation and iodine quantification allows accurate evaluation of iodine uptake in renal lesions on a single-phase nephrographic image.

  6. Effects of Early Dual-Eligible Special Needs Plans on Health Expenditure.

    Science.gov (United States)

    Zhang, Yongkang; Diana, Mark L

    2017-10-18

    To examine the effects of the penetration of dual-eligible special needs plans (D-SNPs) on health care spending. Secondary state-level panel data from Medicare-Medicaid Linked Enrollee Analytic Data Source (MMLEADS) public use file and Special Needs Plan Comprehensive Reports, Area Health Resource Files, and Medicaid Managed Care Enrollment Report between 2007 and 2011. A difference-in-difference strategy that adjusts for dual-eligibles' demographic and socioeconomic characteristics, state health resources, beneficiaries' health risk factors, Medicare/Medicaid enrollment, and state- and year-fixed effects. Data from MMLEADS were summarized from Centers for Medicare and Medicaid Services (CMS)'s Chronic Conditions Data Warehouse, which contains 100 percent of Medicare enrollment data, claims for beneficiaries who are enrolled in the fee-for-service (FFS) program, and Medicaid Analytic Extract files. The MMLEADS public use file also includes payment information for managed care. Data in Special Needs Plan Comprehensive Reports were from CMS's Health Plan Management System. Results indicate that D-SNPs penetration was associated with reduced Medicare spending per dual-eligible beneficiary. Specifically, a 1 percent increase in D-SNPs penetration was associated with 0.2 percent reduction in Medicare spending per beneficiary. We found no association between D-SNPs penetration and Medicaid or total spending. Involving Medicaid services in D-SNPs may be crucial to improve coordination between Medicare and Medicaid programs and control Medicaid spending among dual-eligible beneficiaries. Starting from 2013, D-SNPs were mandated to have contracts with state Medicaid agencies. This change may introduce new effects of D-SNPs on health care spending. More research is needed to examine the impact of D-SNPs on dual-eligible spending. © Health Research and Educational Trust.

  7. Musical training, bilingualism, and executive function: a closer look at task switching and dual-task performance.

    Science.gov (United States)

    Moradzadeh, Linda; Blumenthal, Galit; Wiseheart, Melody

    2015-07-01

    This study investigated whether musical training and bilingualism are associated with enhancements in specific components of executive function, namely, task switching and dual-task performance. Participants (n = 153) belonging to one of four groups (monolingual musician, bilingual musician, bilingual non-musician, or monolingual non-musician) were matched on age and socioeconomic status and administered task switching and dual-task paradigms. Results demonstrated reduced global and local switch costs in musicians compared with non-musicians, suggesting that musical training can contribute to increased efficiency in the ability to shift flexibly between mental sets. On dual-task performance, musicians also outperformed non-musicians. There was neither a cognitive advantage for bilinguals relative to monolinguals, nor an interaction between music and language to suggest additive effects of both types of experience. These findings demonstrate that long-term musical training is associated with improvements in task switching and dual-task performance. Copyright © 2014 Cognitive Science Society, Inc.

  8. 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.

  9. 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.

  10. Does Grammatical Structure Accelerate Number Word Learning? Evidence from Learners of Dual and Non-Dual Dialects of Slovenian.

    Directory of Open Access Journals (Sweden)

    Franc Marušič

    Full Text Available How does linguistic structure affect children's acquisition of early number word meanings? Previous studies have tested this question by comparing how children learning languages with different grammatical representations of number learn the meanings of labels for small numbers, like 1, 2, and 3. For example, children who acquire a language with singular-plural marking, like English, are faster to learn the word for 1 than children learning a language that lacks the singular-plural distinction, perhaps because the word for 1 is always used in singular contexts, highlighting its meaning. These studies are problematic, however, because reported differences in number word learning may be due to unmeasured cross-cultural differences rather than specific linguistic differences. To address this problem, we investigated number word learning in four groups of children from a single culture who spoke different dialects of the same language that differed chiefly with respect to how they grammatically mark number. We found that learning a dialect which features "dual" morphology (marking of pairs accelerated children's acquisition of the number word two relative to learning a "non-dual" dialect of the same language.

  11. Dual pancreas- and lung-targeting therapy for local and systemic complications of acute pancreatitis mediated by a phenolic propanediamine moiety.

    Science.gov (United States)

    Li, Jianbo; Zhang, Jinjie; Fu, Yao; Sun, Xun; Gong, Tao; Jiang, Jinghui; Zhang, Zhirong

    2015-08-28

    To inhibit both the local and systemic complications with acute pancreatitis, an effective therapy requires a drug delivery system that can efficiently overcome the blood-pancreas barrier while achieving lung-specific accumulation. Here, we report the first dual pancreas- and lung-targeting therapeutic strategy mediated by a phenolic propanediamine moiety for the treatment of acute pancreatitis. Using the proposed dual-targeting ligand, an anti-inflammatory compound Rhein has been tailored to preferentially accumulate in the pancreas and lungs with rapid distribution kinetics, excellent tissue-penetrating properties and minimum toxicity. Accordingly, the drug-ligand conjugate remarkably downregulated the proinflammatory cytokines in the target organs thus effectively inhibiting local pancreatic and systemic inflammation in rats. The dual-specific targeting therapeutic strategy may help pave the way for targeted drug delivery to treat complicated inflammatory diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. An Efficient Construction of Self-Dual Codes

    OpenAIRE

    Lee, Yoonjin; Kim, Jon-Lark

    2012-01-01

    We complete the building-up construction for self-dual codes by resolving the open cases over $GF(q)$ with $q \\equiv 3 \\pmod 4$, and over $\\Z_{p^m}$ and Galois rings $\\GR(p^m,r)$ with an odd prime $p$ satisfying $p \\equiv 3 \\pmod 4$ with $r$ odd. We also extend the building-up construction for self-dual codes to finite chain rings. Our building-up construction produces many new interesting self-dual codes. In particular, we construct 945 new extremal self-dual ternary $[32,16,9]$ codes, each ...

  13. Dual Kidney Allocation Score: A Novel Algorithm Utilizing Expanded Donor Criteria for the Allocation of Dual Kidneys in Adults.

    Science.gov (United States)

    Johnson, Adam P; Price, Thea P; Lieby, Benjamin; Doria, Cataldo

    2016-09-08

    BACKGROUND Dual kidney transplantation (DKT) of expanded-criteria donors is a cost-intensive procedure that aims to increase the pool of available deceased organ donors and has demonstrated equivalent outcomes to expanded-criteria single kidney transplantation (eSKT). The objective of this study was to develop an allocation score based on predicted graft survival from historical dual and single kidney donors. MATERIAL AND METHODS We analyzed United Network for Organ Sharing (UNOS) data for 1547 DKT and 26 381 eSKT performed between January 1994 and September 2013. We utilized multivariable Cox regression to identify variables independently associated with graft survival in dual and single kidney transplantations. We then derived a weighted multivariable product score from calculated hazard ratios to model the benefit of transplantation as dual kidneys. RESULTS Of 36 donor variables known at the time of listing, 13 were significantly associated with graft survival. The derived dual allocation score demonstrated good internal validity with strong correlation to improved survival in dual kidney transplants. Donors with scores less than 2.1 transplanted as dual kidneys had a worsened median survival of 594 days (24%, p-value 0.031) and donors with scores greater than 3.9 had improved median survival of 1107 days (71%, p-value 0.002). There were 17 733 eSKT (67%) and 1051 DKT (67%) with scores in between these values and no differences in survival (p-values 0.676 and 0.185). CONCLUSIONS We have derived a dual kidney allocation score (DKAS) with good internal validity. Future prospective studies will be required to demonstrate external validity, but this score may help to standardize organ allocation for dual kidney transplantation.

  14. The high-energy dual-beam facility

    International Nuclear Information System (INIS)

    Kaletta, D.

    1984-07-01

    This proposal presents a new experimental facility at the Kernforschungszentrum Karlsruhe (KfK) to study the effects of irradiation on the first wall and blanket materials of a fusion reactor. A special effort is made to demonstrate the advantages of the Dual Beam Technique (DBT) as a future research tool for materials development within the European Fusion Technology Programme. The Dual-Beam-Technique allows the production both of helium and of damage in thick metal and ceramic specimens by simultaneous irradiation with high energy alpha particles and protons produced by the two KfK cyclotrons. The proposal describes the Dual Beam Technique the planned experimental activities and the design features of the Dual Beam Facility presently under construction. (orig.) [de

  15. 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...

  16. 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....

  17. Technique and Feasibility of a Dual Staining Method for Estrogen Receptors and AgNORs

    Directory of Open Access Journals (Sweden)

    Lukas Günther

    2000-01-01

    Full Text Available A new staining method for dual demonstration of Estrogen receptors (ER and argyrophilc Nucleolus‐Organizer Regions (AgNORs was developed. To rule out possible reciprocal effects, serial slides of 10 invasive ductale breast cancers were stained with either the single staining method or the simultaneous ER/AgNOR‐staining method and investigated comparatively. By measuring the slides with the image analysis system AMBA, reciprocal effects could be excluded. It was proven that dual staining of both markers results in a reproducible and specific staining result. We concluded that it is justified to measure AgNORs in immunohistochemically stained cells.

  18. 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…

  19. Emission, efficiency, and influence in a diesel n-butanol dual-injection engine

    International Nuclear Information System (INIS)

    Zhu, Yanchun; Chen, Zheng; Liu, Jingping

    2014-01-01

    Highlights: • Dual-injection combustion for diesel n-butanol dual-fuel is investigated. • Higher EGR rate results in lower NOx and ITE, but higher smoke, HC and CO. • Larger butanol fraction results in lower smoke and ITE, but higher NOx, HC and CO. • Advanced injection can decrease smoke, HC and CO, and increase ITE. • Coupling of butanol fraction, EGR and injection timing makes for a better performance. - Abstract: In this work, a dual-injection combustion mode for diesel n-butanol dual-fuel, combined direct injection (DI) of diesel with port fuel injection (PFI) of n-butanol, was introduced. Effects of n-butanol fraction, EGR rate and injection timing on this mode were studied on a modified single-cylinder diesel engine at the speed of 1400 r/min and the IMEP of 1.0 MPa. The results indicate that with increased EGR rate, NOx emissions reduce, but smoke emissions increase. As n-butanol fraction is increased, smoke emissions decrease with a small increase in NOx. However, higher HC and CO emissions, higher indicated specific fuel consumption (ISFC) and lower indicated thermal efficiency (ITE) have to be paid with increased n-butanol fraction, especially at high EGR condition. Advancing diesel injection timing suitably has the capacity of mitigating those costs and further decreasing smoke emissions with a small penalty in NOx emissions. Coupling of large butanol fraction, high EGR rate, and advanced injection suitably contributes to a better balance between emissions and efficiency in the diesel n-butanol dual-injection engine

  20. 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)

  1. Dual-source dual-energy CT for the differentiation of urinary stone composition: preliminary study

    International Nuclear Information System (INIS)

    Yang Qifang; Zhang Wanshi; Meng Limin; Shi Huiping; Wang Dong; Bi Yongmin; Li Xiangsheng; Fang Hong; Guo Heqing; Yan Jingmin

    2011-01-01

    Objective: To evaluate dual-source dual-energy CT (DSCT) for the differentiation of' urinary stone composition in vitro. Methods: Ninety-seven urinary stones were obtained by endoscopic lithotripsy and scanned using dual-source dual-energy CT. The stones were divided into six groups according to infrared spectroscopy stone analysis: uric acid (UA) stones (n=10), cystine stones (n=5), struvite stones (n=6), calcium oxalate (CaOx) stones (n=22), mixed UA stones (n=7) and mixed calcium stones (n=47). Hounsfield units (HU) of each stone were recorded for the 80 kV and the 140 kV datasets by hand-drawing method. HU difference, HU ratio and dual energy index (DEI) were calculated and compared among the stone groups with one-way ANOVA. Using dual energy software to determine the composition of all stones, results were compared to infrared spectroscopy analysis. Results: There were statistical differences in HU difference [(-17±13), (229±34), (309±45), (512±97), (201±64) and (530±71) HU respectively], in HU ratio (0.96±0.03, 1.34±0.04, 1.41±0.03, 1.47±0.03, 1.30±0.07, and 1.49±0.03 respectively), and DEI (-0.006±0.004, 0.064±0.007, 0.080± 0.007, 0.108±0.011, 0.055±0.014 and 0.112±0.008 respectively) among different stone groups (F= 124.894, 407.028, 322.864 respectively, P<0.01). There were statistical differences in HU difference, HU ratio and DEI between UA stones and the other groups (P<0.01). There were statistical differences in HU difference, HU ratio and DEI between CaOx or mixed calcium stones and the other four groups (P< 0.01). There was statistical difference in HU ratio between cystine and struvite stones (P<0.01). There were statistical differences in HU difference, HU ratio and DEI between struvite and mixed UA stones (P< 0.05). Dual energy software correctly characterized 10 UA stones, 4 cystine stones, 22 CaOx stones and 6 mixed UA stones. Two struvite stones were considered to contain cystine. One cystine stone, 1 mixed UA stone, 4

  2. Dual method use among long-acting reversible contraceptive users.

    Science.gov (United States)

    Bernard, Caitlin; Zhao, Qiuhong; Peipert, Jeffrey F

    2018-03-27

    To compare rates of dual method use (concurrent use of condoms and an effective method of contraception) in long-acting reversible contraceptive (LARC) and non-LARC hormonal contraceptive users, and to determine factors associated with dual method use. We conducted a secondary analysis of the Contraceptive CHOICE Project, an observational, prospective cohort study of 9256 women in St. Louis, MO, USA. Our sample included 6744 women who initiated a contraceptive method within 3 months of enrollment, continued use at 6 months post-enrollment, and responded regarding dual method use. Our primary outcome was the rate of dual method use at 6 months post-enrollment. Dual method use was reported by 32% of LARC and 45% of non-LARC hormonal contraceptive users (p dual method use (RR adj 0.76, 95% CI 0.70-0.83). Factors associated with dual method use in our multivariable analysis were age dual method use, baseline diagnosis of sexually transmitted infection (STI), greater partner willingness to use a condom, and higher condom self-efficacy score. LARC users are less likely to report dual method use compared to non-LARC hormonal contraceptive users, but other factors also impact dual method use. Further studies should be performed to determine whether this lower dual method use increases the risk of STI. Clinicaltrials.gov Identifier NCT01986439.

  3. 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.

  4. 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.

  5. A Triangulated Qualitative Study of Veteran Decision-Making to Seek Care During Heart Failure Exacerbation: Implications of Dual Health System Use

    Science.gov (United States)

    Pope, Charlene A.; Davis, Boyd H.; Wine, Leticia; Nemeth, Lynne S.; Axon, Robert N.

    2018-01-01

    Among Veterans, heart failure (HF) contributes to frequent emergency department visits and hospitalization. Dual health care system use (dual use) occurs when Veterans Health Administration (VA) enrollees also receive care from non-VA sources. Mounting evidence suggests that dual use decreases efficiency and patient safety. This qualitative study used constructivist grounded theory and content analysis to examine decision making among 25 Veterans with HF, for similarities and differences between all-VA users and dual users. In general, all-VA users praised specific VA providers, called services helpful, and expressed positive capacity for managing HF. In addition, several Veterans who described inadvertent one-time non-VA health care utilization in emergent situations more closely mirrored all-VA users. By contrast, committed dual users more often reported unmet needs, nonresponse to VA requests, and faster services in non-VA facilities. However, a primary trigger for dual use was VA telephone referral for escalating symptoms, instead of care coordination or primary/specialty care problem-solving. PMID:29482411

  6. The dual of the Carroll-Field-Jackiw model

    International Nuclear Information System (INIS)

    Guimaraes, M.S.; Grigorio, L.; Wotzasek, C.

    2006-01-01

    In this work we apply different duality techniques, both the dual projection, based on the soldering formalism and the master action, in order to obtain and study the dual description of the Carroll- Field-Jackiw model [1], a theory with a Chern-Simons-like explicitly Lorentz and CPT violating term, including the interaction with external charges. This Maxwell-Chern-Simons-like model may be rewritten in terms of the interacting modes of a massless scalar model and a topologically massive model [2], that are mapped, through duality, into interacting massless Maxwell and massive self-dual modes [3]. It is also shown that these dual modes might be represented into an unified rank-two self-dual model that represents the direct dual of the vector Maxwell-Chern-Simons-like model

  7. The organotypic multicellular spheroid is a relevant three-dimensional model to study adenovirus replication and penetration in human tumors in vitro

    NARCIS (Netherlands)

    Grill, Jacques; Lamfers, Martine L. M.; van Beusechem, Victor W.; Dirven, Clemens M.; Pherai, D. Shareen; Kater, Mathijs; van der Valk, Paul; Vogels, Ronald; Vandertop, W. Peter; Pinedo, Herbert M.; Curiel, David T.; Gerritsen, Winald R.

    2002-01-01

    The use of adenoviruses for gene transfer and as oncolytic agents is currently receiving widespread attention. As specific constraints to adenovirus distribution and spread cannot be studied in cell cultures, there is a need for an in vitro three-dimensional (3D) model mimicking the in vivo biology

  8. The design and analysis of AVTMR (all voting triple modular redundancy) and dual-duplex system

    International Nuclear Information System (INIS)

    Kim, Hyunki; Lee, Hyeuntae; Lee, Keyseo

    2005-01-01

    In this paper, we design AVTMR (All Voting Triple Modular Redundancy) and dual-duplex system which have a fault-tolerant characteristic, and two systems are compared in the evaluation of RAMS (Reliability, Availability, Maintainability and Safety) and MTTF (Mean Time To Failure). AVTMR system is designed in a triplicated voter technique and dual-duplex system in a comparator, and two systems are based on MC68000. To evaluate system characteristic, Markov modeling method is designed for reliability, availability, safety and MTTF (Mean Time To Failure), and RELEX6.0 tool is used for the calculation of failure rate of electrical components that is based on MILSPEC-217F. In this paper, we can see two systems are more high dependability than a single system, and AVTMR or dual-duplex system can be selected for a specific application system. Especially, because AVTMR and dual-duplex system have high RAMS better than a single system, they can be applied to life critical system such as an airplane and a high-speed railway system

  9. High levels of time contraction in young children in dual tasks are related to their limited attention capacities.

    Science.gov (United States)

    Hallez, Quentin; Droit-Volet, Sylvie

    2017-09-01

    Numerous studies have shown that durations are judged shorter in a dual-task condition than in a simple-task condition. The resource-based theory of time perception suggests that this is due to the processing of temporal information, which is a demanding cognitive task that consumes limited attention resources. Our study investigated whether this time contraction in a dual-task condition is greater in younger children and, if so, whether this is specifically related to their limited attention capacities. Children aged 5-7years were given a temporal reproduction task in a simple-task condition and a dual-task condition. In addition, different neuropsychological tests were used to assess not only their attention capacities but also their capacities in terms of working memory and information processing speed. The results showed a shortening of perceived time in the dual task compared with the simple task, and this increased as age decreased. The extent of this shortening effect was directly linked to younger children's limited attentional capacities; the lower their attentional capacities, the greater the time contraction. This study demonstrated that children's errors in time judgments are linked to their cognitive capacities rather than to capacities that are specific to time. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology

    DEFF Research Database (Denmark)

    Ikenberg, Hans; Bergeron, Christine; Schmidt, Dietmar

    2013-01-01

    Pap cytology is known to be more specific but less sensitive than testing for human papillomavirus (HPV) for the detection of high-grade cervical intraepithelial neoplasia (CIN2+). We assessed whether p16/Ki-67 dual-stained cytology, a biomarker combination indicative of transforming HPV infections...

  11. Dual-source virtual non-contrast CT of the head: a preliminary study

    International Nuclear Information System (INIS)

    Huang Wei; Xu Yiming; Shao Jin

    2011-01-01

    Objective: To investigate image quality and clinical value of dual-source dual energy virtual non-contrast (VNC) CT of the head. Methods: Sixty-two patients suspected of cerebrovascular diseases underwent conventional non-contrast (CNC) CT and dual energy CTA examination of the head with dual-source CT. Virtual non-contrast images were reconstructed using dual energy software. The CT values of gray matter, white matter, cerebrospinal fluid, hyperdense hemorrhagic lesion and hypodense ischemic lesion were compared between CNC and VNC images. A four-score scale was used to assess image quality subjectively. Image noise, radiation dosage and detection rate were compared between CNC and VNC images. Paired t test, Wilcoxon signed ranks test and Chi-square test (McNemar test and Kappa test) were used. Results: The CT value on CNC and VNC images, were (43.3±1.5) and (33.2±1.3) HU for gray matter (t=46.98, P 0.05, Kappa = 1.000) at per-patient level. Twenty-two patients with hypodense ischemic lesions were found on VNC images with one false positive case and two false negative cases. The sensitivity, specificity, positive predictive value and negative predictive value were 91.3% (21/23), 97.4% (38/39), 95.5% (21/22) and 95.0% (38/40) respectively. No statistical difference was found in detecting hypodense lesions between VNC and CNC images (χ 2 = 0.00, P>0.05, Kappa = 0.895). In per-lesion analysis, 53 hemorrhage lesions were found on VNC images with false negative results of four lesions and no false positive result. The sensitivity, specificity, positive predictive value and negative predictive value were 93.0% (53/57). 100.0% (38/38), 100.0% (53/.53) and 90.5% (38/42) respectively. There was no significant difference in detection rate of hyperdense lesion between VNC and CNC images (χ 2 = 2.25, P>0.05, Kappa = 0.914). Thirty-eight hypodense lesions were found on VNC images with 2 false positive lesions and 13 false negative lesions. The sensitivity, specificity

  12. Self-dual nonsupersymmetric Type II String Compactifications

    International Nuclear Information System (INIS)

    Kachru, Shamit; Silverstein, Eva

    1998-01-01

    It has recently been proposed that certain nonsupersymmetric type II orbifolds have vanishing perturbative contributions to the cosmological constant. We show that techniques of Sen and Vafa allow one to construct dual type II descriptions of these models (some of which have no weakly coupled heterotic dual). The dual type II models are given by the same orbifolds with the string coupling S and a T 2 volume T exchanged. This allows us to argue that in various strongly coupled limits of the original type II models, there are weakly coupled duals which exhibit the same perturbative cancellations as the original models

  13. Evaluation of Myc Gene Amplification in Prostate Cancer Using a Dual Color Chromogenic in-Situ Hybridization (Dual CISH Assay

    Directory of Open Access Journals (Sweden)

    Daniel Lerda

    2013-04-01

    Full Text Available Objetive: The overall purpose of the study was to demonstrate applicability of the Dako dual-color chromogenic in situ hybridization (CISH assay (DAKO Denmark, Glostrup with respect to fluorescence in situ hybridization (FISH probes MYC-C. Methods: MYC gene amplification by FISH and Dako dual-color CISH Results: The study showed that the dual-color CISH assay can convert Texas red and fluorescein isothiocyanate (FITC signals into chromogenic signals. The dual –color CISH assay was performed on 40 cases of prostate cancer. Amplification was identified in 12 of 40 (30% tumors. No amplification was seen in 28 of 40 (70% tumors. FISH data were available in total of 40 tumors. All tumors showed concordant results between dual-color CISH and FISH for classifying a tumor as MYC amplified or not amplified. Conclusions: We conclude that dual-color Dako CISH assay is an accurate method for determining MYC gene amplification with added advantages that make it a more practically useful method. [J Interdiscipl Histopathol 2013; 1(2.000: 81-84

  14. Hepatic MR imaging for in vivo differentiation of steatosis, iron deposition and combined storage disorder: Single-ratio in/opposed phase analysis vs. dual-ratio Dixon discrimination

    International Nuclear Information System (INIS)

    Bashir, Mustafa R.; Merkle, Elmar M.; Smith, Alastair D.; Boll, Daniel T.

    2012-01-01

    Objective: To assess whether in vivo dual-ratio Dixon discrimination can improve detection of diffuse liver disease, specifically steatosis, iron deposition and combined disease over traditional single-ratio in/opposed phase analysis. Methods: Seventy-one patients with biopsy-proven (17.7 ± 17.0 days) hepatic steatosis (n = 16), iron deposition (n = 11), combined deposition (n = 3) and neither disease (n = 41) underwent MR examinations. Dual-echo in/opposed-phase MR with Dixon water/fat reconstructions were acquired. Analysis consisted of: (a) single-ratio hepatic region-of-interest (ROI)-based assessment of in/opposed ratios; (b) dual-ratio hepatic ROI assessment of in/opposed and fat/water ratios; (c) computer-aided dual-ratio assessment evaluating all hepatic voxels. Disease-specific thresholds were determined; statistical analyses assessed disease-dependent voxel ratios, based on single-ratio (a) and dual-ratio (b and c) techniques. Results: Single-ratio discrimination succeeded in identifying iron deposition (I/O Ironthreshold Fatthreshold>1.15 ) from normal parenchyma, sensitivity 70.0%; it failed to detect combined disease. Dual-ratio discrimination succeeded in identifying abnormal hepatic parenchyma (F/W Normalthreshold > 0.05), sensitivity 96.7%; logarithmic functions for iron deposition (I/O Iron d iscriminator (0.01−F/W Iron )/0.48 ) and for steatosis (I/O Fatdiscriminator > e (F/W Fat −0.01)/0.48 ) differentiated combined from isolated diseases, sensitivity 100.0%; computer-aided dual-ratio analysis was comparably sensitive but less specific, 90.2% vs. 97.6%. Conclusion: MR two-point-Dixon imaging using dual-ratio post-processing based on in/opposed and fat/water ratios improved in vivo detection of hepatic steatosis, iron deposition, and combined storage disease beyond traditional in/opposed analysis.

  15. 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.

  16. Multi-species trace gas sensing with dual-wavelength QCLs

    Science.gov (United States)

    Hundt, P. Morten; Tuzson, Béla; Aseev, Oleg; Liu, Chang; Scheidegger, Philipp; Looser, Herbert; Kapsalidis, Filippos; Shahmohammadi, Mehran; Faist, Jérôme; Emmenegger, Lukas

    2018-06-01

    Instrumentation for environmental monitoring of gaseous pollutants and greenhouse gases tends to be complex, expensive, and energy demanding, because every compound measured relies on a specific analytical technique. This work demonstrates an alternative approach based on mid-infrared laser absorption spectroscopy with dual-wavelength quantum cascade lasers (QCLs). The combination of two dual- and one single-DFB QCL yields high-precision measurements of CO (0.08 ppb), CO2 (100 ppb), NH3 (0.02 ppb), NO (0.4 ppb), NO2 (0.1 ppb), N2O (0.045 ppb), and O3 (0.11 ppb) simultaneously in a compact setup (45 × 45 cm2). The lasers are driven time-multiplexed in intermittent continuous wave mode with a repetition rate of 1 kHz. The individual spectra are real-time averaged (1 s) by an FPGA-based data acquisition system. The instrument was assessed for environmental monitoring and benchmarked with reference instrumentation to demonstrate its potential for compact multi-species trace gas sensing.

  17. Dual use research: investigation across multiple science disciplines.

    Science.gov (United States)

    Oltmann, Shannon

    2015-04-01

    Most recent studies of dual use research have focused on the life sciences, although some researchers have suggested that dual use research occurs across many disciplines. This research is an initial investigation into the prevalence of dual use research in other scientific disciplines by surveying senior editors of scientific journals, drawn from Journal Citation Reports. The survey was emailed to 7,500 journal editors with a response rate of 10.1 %. Approximately 4.8 % of life science editors reported they had to consider whether to publish dual use research and 38.9 % said they decided to not publish the research in question. In disciplines other than the life sciences, 7.2 % of editors from other science disciplines reported that they had to consider whether to publish dual use research, and 48.4 % declined to publish it. The survey investigated relationships between dual use and the journal's source of funding and place of publication, but no relationships were found. Further research is needed to better understand the occurrence of dual use research in other science disciplines.

  18. Outage probability of dual-hop FSO fixed gain relay transmission systems

    KAUST Repository

    Zedini, Emna

    2016-12-24

    In this paper, we analyze the end-to-end performance of dual-hop free-space optical (FSO) fixed gain relaying systems in the presence of atmospheric turbulence as well as pointing errors. More specifically, an exact closed-form expression for the outage probability is presented in terms of the bivariate Fox\\'s H function that accounts for both heterodyne detection as well as intensity modulation with direct detection. At high signal-to-noise ratio (SNR) regime, we provide very tight asymptotic result for this performance metric in terms of simple elementary functions. By using dual-hop FSO relaying, we demonstrate a better system performance as compared to the single FSO link. Numerical and Monte-Carlo simulation results are provided to verify the accuracy of the newly proposed results, and a perfect agreement is observed.

  19. 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.

  20. 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)

  1. Recent developments of dual-energy CT in oncology

    Energy Technology Data Exchange (ETDEWEB)

    Simons, David; Schlemmer, Heinz-Peter [Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg (Germany); Kachelriess, Marc [Department of Medical Physics in Radiology, Division of X-ray Imaging and CT, German Cancer Research Center (DKFZ), Heidelberg (Germany)

    2014-04-15

    Dual-energy computed tomography (DECT) can amply contribute to support oncological imaging: the DECT technique offers promising clinical applications in oncological imaging for tumour detection and characterisation while concurrently reducing the radiation dose. Fast image acquisition at two different X-ray energies enables the determination of tissue- or material-specific features, the calculation of virtual unenhanced images and the quantification of contrast medium uptake; thus, tissue can be characterised and subsequently monitored for any changes during treatment. DECT is already widely used, but its potential in the context of oncological imaging has not been fully exploited yet. The technology is the subject of ongoing innovation and increasingly with respect to its clinical potential, particularly in oncology. This review highlights recent state-of-the-art DECT techniques with a strong emphasis on ongoing DECT developments relevant to oncologic imaging, and then focuses on clinical DECT applications, especially its prospective uses in areas of oncological imaging. circle Dual-energy CT (DECT) offers fast, robust, quantitative and functional whole-body imaging. (orig.)

  2. 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.

  3. Dual-targeting immunoliposomes using angiopep-2 and CD133 antibody for glioblastoma stem cells.

    Science.gov (United States)

    Kim, Jung Seok; Shin, Dae Hwan; Kim, Jin-Seok

    2018-01-10

    Glioblastoma stem cells (GSCs), which are identified as subpopulation of CD133 + /ALDH1 + , are known to show resistance to the most of chemotherapy and radiation therapy, leading to the recurrence of tumor in glioblastoma multiforme (GBM) patients. Also, delivery of temozolomide (TMZ), a mainline treatment of GBM, to the GBM site is hampered by various barriers including the blood-brain barrier (BBB). A dual-targeting immunoliposome encapsulating TMZ (Dual-LP-TMZ) was developed by using angiopep-2 (An2) and anti-CD133 monoclonal antibody (CD133 mAb) for BBB transcytosis and specific delivery to GSCs, respectively. The size, zeta potential and drug encapsulation efficiency of Dual-LP-TMZ were 203.4nm in diameter, -1.6mV and 99.2%, respectively. The in vitro cytotoxicity of Dual-LP-TMZ against U87MG GSCs was increased by 425- and 181-folds when compared with that of free TMZ and non-targeted TMZ liposome (LP-TMZ) (10.3μM vs. 4380μM and 1869μM in IC 50 , respectively). Apoptosis and anti-migration ability of Dual-LP-TMZ in U87MG GSCs were also significantly enhanced comparing with those of free TMZ or LP-TMZ. In vivo study clearly showed a significant reduction in tumor size after intravenous administrations of Dual-LP-TMZ to the orthotopically-implanted brain tumor mice when compared with free TMZ or LP-TMZ. Increased life span (ILS) and median survival time (MST) of tumor-bearing mice were also increased when treated with Dual-LP-TMZ (211.2% in ILS and 49.2days in MST) than with free TMZ (0% in ILS and 23.3day in MST). These data indicate that conjugation of both An2 peptide and CD133 mAb to TMZ-encapsulating liposome is very effective in delivering the TMZ to GSCs via BBB, suggesting a potential use of Dual-LP-TMZ as a therapeutic modality for GBM. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Normal values for bone mineral content measured by dual photon absorptiometry in children

    International Nuclear Information System (INIS)

    Tison, F.; Lecouffe, P.; Rousseau, J.; Marchandise, X.; Ythier, H.

    1990-01-01

    The results of dual photon absorptiometry measurements in 43 normal children are analyzed. Results were correlated with age, body weight, and stature. Reference stature-specific values for bone mineral content in children are proposed. Furthermore, the results show that mineralization continues beyond the end of statural growth [fr

  5. Dual resonance models and their currents

    International Nuclear Information System (INIS)

    Johnson, E.A.

    1978-01-01

    It is shown how dual resonance models were rederived from the concept of a string tracing out a surface in space-time. Thus, interacting strings reproduce the dual amplitudes. A scheme for tackling the unitarity problem began to develop. As a consistent theory of hadronic processes began to be built, workers at the same time were naturally led to expect that leptons could be included with hadrons in a unified dual theory. Thus, there is a search for dual amplitudes which would describe interactions between hadrons and currents (for example, electrons), as well as interactions involving only hadrons. Such amplitudes, it is believed, will be the correct ones, describing the real world. Such amplitudes will provide valuable information concerning such things as hadronic form factors. The great difficulties in building current-amplitudes with the required properties of proper factorization on a good spectrum, duality, current algebra, and proper asymptotic behavior are described. Dual models at the present time require for consistency, an intercept value of α 0 = 1 and a dimension value of d = 26 (or d = 10). There have been speculations that the unphysical dimension may be made physical by associating the ''extra dimensions'' with certain internal degrees of freedom. However, it is desired that the theory itself, force the dimension d = 4. It is quite possible that the dimension problem and the intercept problem are tied together and that resolving either problem will resolve the other. Order by order, a new dual current is constructed that is manifestly factorizable and which appears to be valid for arbitrary space-time dimension. The fact that this current is not bound at d = 26, leads to interesting speculations on the nature of dual currents

  6. Enhanced motor learning following task-concurrent dual transcranial direct current stimulation.

    Directory of Open Access Journals (Sweden)

    Sophia Karok

    Full Text Available OBJECTIVE: Transcranial direct current stimulation (tDCS of the primary motor cortex (M1 has beneficial effects on motor performance and motor learning in healthy subjects and is emerging as a promising tool for motor neurorehabilitation. Applying tDCS concurrently with a motor task has recently been found to be more effective than applying stimulation before the motor task. This study extends this finding to examine whether such task-concurrent stimulation further enhances motor learning on a dual M1 montage. METHOD: Twenty healthy, right-handed subjects received anodal tDCS to the right M1, dual tDCS (anodal current over right M1 and cathodal over left M1 and sham tDCS in a repeated-measures design. Stimulation was applied for 10 mins at 1.5 mA during an explicit motor learning task. Response times (RT and accuracy were measured at baseline, during, directly after and 15 mins after stimulation. Motor cortical excitability was recorded from both hemispheres before and after stimulation using single-pulse transcranial magnetic stimulation. RESULTS: Task-concurrent stimulation with a dual M1 montage significantly reduced RTs by 23% as early as with the onset of stimulation (p<0.01 with this effect increasing to 30% at the final measurement. Polarity-specific changes in cortical excitability were observed with MEPs significantly reduced by 12% in the left M1 and increased by 69% in the right M1. CONCLUSION: Performance improvement occurred earliest in the dual M1 condition with a stable and lasting effect. Unilateral anodal stimulation resulted only in trendwise improvement when compared to sham. Therefore, task-concurrent dual M1 stimulation is most suited for obtaining the desired neuromodulatory effects of tDCS in explicit motor learning.

  7. 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).

  8. An investigation of response and stimulus modality transfer effects after dual-task training in younger and older.

    Science.gov (United States)

    Lussier, Maxime; Gagnon, Christine; Bherer, Louis

    2012-01-01

    It has been shown that dual-task training leads to significant improvement in dual-task performance in younger and older adults. However, the extent to which training benefits to untrained tasks requires further investigation. The present study assessed (a) whether dual-task training leads to cross-modality transfer in untrained tasks using new stimuli and/or motor responses modalities, (b) whether transfer effects are related to improved ability to prepare and maintain multiple task-set and/or enhanced response coordination, (c) whether there are age-related differences in transfer effects. Twenty-three younger and 23 older adults were randomly assigned to dual-task training or control conditions. All participants were assessed before and after training on three dual-task transfer conditions; (1) stimulus modality transfer (2) response modality transfer (3) stimulus and response modalities transfer task. Training group showed larger improvement than the control group in the three transfer dual-task conditions, which suggests that training leads to more than specific learning of stimuli/response associations. Attentional costs analyses showed that training led to improved dual-task cost, only in conditions that involved new stimuli or response modalities, but not both. Moreover, training did not lead to a reduced task-set cost in the transfer conditions, which suggests some limitations in transfer effects that can be expected. Overall, the present study supports the notion that cognitive plasticity for attentional control is preserved in late adulthood.

  9. 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)

  10. Field evaluation of a dual rapid diagnostic test for HIV infection and syphilis in Lima, Peru.

    Science.gov (United States)

    Bristow, Claire C; Leon, Segundo R; Huang, Emily; Brown, Brandon J; Ramos, Lourdes B; Vargas, Silver K; Flores, Juan A; Caceres, Carlos F; Klausner, Jeffrey D

    2016-05-01

    Screening for HIV and syphilis in key populations is recommended by the WHO to reduce the morbidity, mortality and transmission associated with undiagnosed and untreated infections. Rapid point-of-care tests t