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Sample records for hsv-tk armed oncolytic

  1. In vivo image of radioiodinated IVDU and IVFRU in HSV-TK gene tranduced hepatocellular carcinoma bearing buffalo rat

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    Lee, Tae Sup; Choi, T. H.; Ahn, S. H.; Woo, K. S.; Chung, W. S.; Lee, S. J.; Choi, C. W. [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

    2000-07-01

    The extent of gene delivery and expression in gene therapy with suicide genes such as herpes simplex virus thymidine kinase (HSV-tk) is assessed with measurement of selective localization of radioiodinated HSV-tk substrates in HSV-tk expressing tumor. We compared n vitro uptake of {sup 125}I-IVDU, IVFRU and in vivo image of HSV-tk gene tranduced hepatocellular carcinoma model. Using H{sub 2}O{sub 2}(hydrogen peroxide), IVDU and IVFRU was radiolabeled as carrier free form. The uptake of {sup 125}I-IVDU IVFRU was determined with increasing incubation periods in MCA-tk and MCA cell line (1X10{sup 6}cell/flask). The cell harvested and counted after incubation of 15, 30, 60, 120, 240, 480 minutes. For estimating accumulation of radiolabelled IVDU, IVFRU in HSV-tk expressing tumor, MCA-tk cells (1 X 10{sup 6}/100 {mu}l) injected intramuscularly into right thigh of buffalo rats. To determine selective localization of radiolabelled IVDU, IVFRU in HSV-tk expressing hepatocellular carcinoma bearing buffalo rats, MCA-tk cells (1X 10{sup 7} cell/100 {mu}l) were injected subcutaneously into both shoulders of buffalo rats. Established tumor mass implanted into liver of buffalo rats using intra-hepatic tumor injection. Two weeks later, {sup 123}I labelled IVDU, IVFRU(7.4 X 10{sup 7}Bq/200 {mu}l) injected intravenously into tail veins of each buffalo rats. Gamma camera used as revealing localization of {sup 123}I-IVDU, IVFRU in MCA-tk cells grafts rats and in vivo image was taken 2 hrs, 24 hrs after injection. radioiodinated IVDU, IVFRU were radiolabeled with {sup 123}I as labeling yield 70%, {sup 125}I as 84%. Two compounds showed minimal uptake in MCA cell line, but in MCA-tk cell line, increased uptake was observed. The ratio of MCA-tk to MCA was up to 116-fold in {sup 125}I-IVDU, up to 37-fold in {sup 125}I-IVFRU at 480 min. The uptake of IVDU was 4 times higher than IVFRU in MCA-tk cells. Gamma camera images of HSV-tk gene tranduced MCA tumor showed accumulation of {sup 123}I

  2. Study on constructing retroviral vector carrying HSV-tk gene and its antitumor effect in vitro

    International Nuclear Information System (INIS)

    Pan Yujun; Hui Guozhen; Hu Jin

    1997-01-01

    The author reports the construction of retroviral vector PLNTK carrying HsV-tk gene driven by pgk promoter and the successful transferring into cells NBA 2 and SHG 44 respectively as shown by PCR. In vitro study, HSV-tk-expressed-cells prove to be more sensitive to ACV than parent cells. The sensitivity of SHGLNTK and NBALNTK to ACV is 1000 and 500 times that of their parent cells respectively. 3 H-TdR test demonstrated that the DNA replication in gene modified cells is more suppressed than that of parent cells when treated with ACV. Moreover, the ACV sensitivity level of parent cells is enhanced when co-cultured with gene modified cells, which suggests the existence of the bystander effect

  3. In vivo and in vitro experimental study on cervix cancer with combination of HSV-TK/GCV suicide gene therapy system and 60Co radiotherapy

    International Nuclear Information System (INIS)

    Chen Daozhen; Xue Wenqun; Zhan Huiying; Zhu Yunxia; Yang Youyi; Liu Lu; Tang Qiusha

    2006-01-01

    Objective: To evaluate the killing effect of HSV-TK/GCV suicide gene therapy system combined with 60 Co radiotherapy on human cervical cancer HeLa cell line in vivo and in vitro, and to explore radiosensitization by the HSV-TK/GCV system. Methods: The HSV-TK/GCV suicide gene therapy system and 60 Co radiotherapy were used separately or in combination for human cervical cancer HeLa cell line in vivo and in vitro to compare their effects. Colony formation test and the rate of radiosensitization effect(E/O) were employed to observed the radiosensitization by the HSV-TK/GCV system. Results: The HSV-TK/GCV suicide gene therapy system showed strong therapeutic effects on HeLa cells both in vitro and in vivo (the inhibition rates were 45.8% and 39.5%, respectively). Moreover, the combined application of gene therapy and radiotherapy exhibited stronger therapeutic effects in vitro and in vivo (the inhibition rate was 87.5% in vitro, and was 87.9% in vivo) (P 1.4), indicating the HSV-TK/GCV system could exert a sensitizing effect on 60 Co radiotherapy of the transplanted human cervical cancer cells in nude mice. Conclusion: The HSV-TK/GCV system has radiosensitizationaction. Gene therapy combined with radiotherapy may be a good supplementary method for synthetic treatment of cervical cancer. (authors)

  4. An experimental study on cervix cancer with combination of HSV-TK/GCV suicide gene therapy system and 60Co radiotherapy

    International Nuclear Information System (INIS)

    Chen, Daozhen; Tang, Qiusha

    2010-01-01

    To evaluate the killing effect of HSV-TK/GCV suicide gene therapy system combined with 60 Co radiotherapy on human cervical cancer Hela cell line in vitro and in vivo, and to explore the radiosensitization by HSV-TK/GCV system. HSV-TK/GCV suicide gene therapy system and 60 Co radiotherapy were used separately or in combination on human cervical cancer Hela cell line in vitro and in vivo to compare their effects. Colony formation test and the rate of radiosensitization effect (E/O) were employed to observed the radiosensitization by HSV-TK/GCV system. HSV-TK/GCV suicide gene therapy system had strong therapeutic effects on Hela cells in vitro and in vivo (the inhibition rates were 45.8% and 39.5%, respectively), moreover, the combined administration of gene therapy and radiotherapy had stronger therapeutic effects in vitro and in vivo (the inhibition rate was 87.5% in vitro, and the inhibition rate was 87.9% in vivo) (P < 0.01). The inhibition rate by radiotherapy alone was 42.4% in vitro and 35.8% in vivo. The sensitivity of combined therapy to radiotherapy increased more than that of therapy alone, the ability of colony formation decreased (P < 0.01). The rate of radiosensitivity effect (E/O) was 3.17(> 1.4), indicating HSV-TK/GCV system could exert a sensitizing effect on 60 Co radiotherapy of the transplanted human cervical cancer cell in nude mice. HSV-TK/GCV system had radiosensitization. Gene therapy combined with radiotherapy may be a good supplementary method for cervix cancer synthetic treatment

  5. Enhanced therapeutic effect of multiple injections of HSV-TK + GCV gene therapy in combination with ionizing radiation in a mouse mammary tumor model

    International Nuclear Information System (INIS)

    Vlachaki, Maria T.; Chhikara, Madhu; Aguilar, Laura; Zhu Xiaohong; Chiu, Kam J.; Woo, Shiao; Teh, Bin S.; Thompson, Timothy C.; Butler, E. Brian; Aguilar-Cordova, Estuardo

    2001-01-01

    Purpose: Standard therapies for breast cancer lack tumor specificity and have significant risk for recurrence and toxicities. Herpes simplex virus-thymidine kinase (HSV-tk) gene therapy combined with radiation therapy (XRT) may be effective because of complementary mechanisms and distinct toxicity profiles. HSV-tk gene therapy followed by systemic administration of ganciclovir (GCV) enhances radiation-induced DNA damage by generating high local concentrations of phosphorylated nucleotide analogs that increase radiation-induced DNA breaks and interfere with DNA repair mechanisms. In addition, radiation-induced membrane damage enhances the 'bystander effect' by facilitating transfer of nucleotide analogs to neighboring nontransduced cells and by promoting local and systemic immune responses. This study assesses the effect of single and multiple courses of HSV-tk gene therapy in combination with ionizing radiation in a mouse mammary cancer model. Methods and Materials: Mouse mammary TM40D tumors transplanted s.c. in syngeneic immunocompetent BALB-c mice were treated with either adenoviral-mediated HSV-tk gene therapy or local radiation or the combination of gene and radiation therapy. A vector consisting of a replication-deficient (E1-deleted) adenovirus type 5 was injected intratumorally to administer the HSV-tk gene, and GCV was initiated 24 h later for a total of 6 days. Radiation was given as a single dose of 5 Gy 48 h after the HSV-tk injection. A metastatic model was developed by tail vein injection of TM40D cells on the same day that the s.c. tumors were established. Systemic antitumor effect was evaluated by counting the number of lung nodules after treating only the primary tumors with gene therapy, radiation, or the combination of gene and radiation therapy. To assess the therapeutic efficacy of multiple courses of this combinatorial approach, one, two, and three courses of HSV-tk + GCV gene therapy, in combination with radiation, were compared to HSV-tk or

  6. Noninvasive theranostic imaging of HSV-TK/GCV suicide gene therapy in liver cancer by folate-targeted quantum dot-based liposomes

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    Shao, D.; Li, J.; Pan, Y.; Zhang, X.; Zheng, X.; Wang, Z.; Zhang, M.; Zhang, H.; Chen, L.

    2015-01-01

    Theranostics is emerging as a popular strategy for cancer therapy; thanks to the development of nano-technology. In this work, we have combined an HSV-TK/GCV suicide gene system and near-infrared quantum dots, as the former is quite effective in liver cancer treatment and the latter facilitates

  7. Long term follow up of patients after allogeneic stem cell transplantation and transfusion of HSV-Tk transduced T-cells.

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    Eva Maria Weissinger

    2015-04-01

    Full Text Available Allogeneic stem cell transplantation (allo-HSCT is one of the curative treatments for hematologic malignancies, but is hampered by severe complications, such as acute or chronic graft-versus-host-disease (aGvHD; cGvHD and infections. CD34-selcetion of stem cells reduces the risk of aGvHD, but also leads to increased infectious complications and relapse. Thus, we studied the efficacy, safety and feasibility of transfer of gene modified donor T-cells shortly after allo-HSCT in two clinical trials between 2002 and 2007 and here we compare the results to unmodified donor leukocyte transfusion (DLI. The aim of these trials was to provide patients with the protection of T-cells after T-cell-depleted allo-HSCT in the matched or mismatched donor setting with an option to delete transduced T-cells, if severe aGvHD occurred within the trial period. Donor-T-cells were transduced with the replication-deficient retrovirus SFCMM-3, expressing HSV-Tk and the truncated LNGFR for selection of transduced cells. Transduced cells were transfused either after day +60 (matched donors or on day +42 (haploidentical donors.Nine patients were included in the first trial (MHH; 2002 until 2007 2 were included in TK007 (2005-2009 and 6 serve as a control group for outcome after haploidentical transplantation without HSV-TK-transduced DLI. Three patients developed acute GvHD, two had grade I of the skin, one had aGvHD on day +131 (post-HSCT; +89 post-HSV-Tk DLI grade II, which was successfully controlled by ganciclovir (GCV. Donor chimerism was stabilized after transfusion of the transduced cells in all patients treated. Functionality of HSV-Tk gene expressing T-cells was shown by loss of bcr-abl gene expression as well as by control of cytomegalovirus-reactivation. To date, 6patients have relapsed and died, 2 after a second HSCT without T-cell depletion or administration of unmodified T-cells. Eleven patients (7 post-HSV-Tk DLI are alive and well to date.

  8. GAP junctional intercellular communication confers an enhanced bystander effect as well as a protective effect in HSV-TK/gancyclovir mediated cytotoxicity

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    Wygoda, Marc R.; Rehemtulla, Alnawaz; Davis, Mary A.; Lawrence, Theodore S.

    1996-01-01

    Purpose/Objective: The 'Bystander Effect' is the phenomenon by which cells which are not transduced with the Herpes Simplex Virus - Thymidine Kinase (HSV-TK) gene are killed by the guanosine analog Gancyclovir (GCV) when they are nearby HSV-TK positive cells. Since currently available gene transfer technologies have a low efficiency (typically less than 10% of cells are transduced), a better understanding of the mechanism underlying the bystander effect is crucial for the success of the HSV-TK/GCV enzyme prodrug gene therapy approach. Gap junctions, which are specialized cell membrane channels allowing the passage of molecules < 1000 daltons in size directly from cell to cell, have been proposed as a possible mediator of the bystander effect. In particular, gap junctions could permit the transfer of toxic metabolites from the HSV-TK positive cells to the bystander cells. Our aim was to assess the role of gap junctional intercellular communication (GJIC) in the bystander effect. Materials and Methods: Co-culture of an HSV-TK transduced rat liver epithelial cell line (WB-TK), with either its communication competent parental cell line (WB), or an isogenic cell line differing by its communication incompetence (aB1). The ratios of effector cells (WB-TK) to bystander cells (WB or aB1), were (100(0)), (50(50)), (5(95)), or(0(100)) . These various mixed populations were exposed for 24 hours to 10μM GCV and thereafter placed at clonal density into selective media, allowing for growth of either the bystander (TK negative) cells or the effector (TK-positive) cells. Results: 1) When the effector/bystander ratio was (50(50)) the surviving fraction of the bystander cells was 3.5% and 37% for the WB and aB1, respectively. When the effector/bystander ratio was (5(95)), the surviving fraction was 51% and 65% for the WB and aB1, respectively. Either cell line (WB or aB1) cultured alone was unaffected by GCV. These results demonstrate that the bystander effect is much higher when

  9. Novel radiosynthesis of PET HSV-tk gene reporter probes [18F]FHPG and [18F]FHBG employing dual Sep-Pak SPE techniques.

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    Wang, Ji-Quan; Zheng, Qi-Huang; Fei, Xiangshu; Mock, Bruce H; Hutchins, Gary D

    2003-11-17

    Positron emission tomography (PET) herpes simplex virus thymidine kinase (HSV-tk) gene reporter probes 9-[(3-[(18)F]fluoro-1-hydroxy-2-propoxy)methyl]guanine ([(18)F]FHPG) and 9-(4-[(18)F]fluoro-3-hydroxymethylbutyl)guanine ([(18)F]FHBG) were prepared by nucleophilic substitution of the appropriate tosylated precursors with [(18)F]KF/Kryptofix 2.2.2 followed by a quick deprotection reaction and purification with a simplified dual Silica Sep-Pak solid-phase extraction (SPE) method in 15-30% radiochemical yield.

  10. Introduction of Exogenous HSV-TK Suicide Gene Increases Safety of Keratinocyte-Derived Induced Pluripotent Stem Cells by Providing Genetic “Emergency Exit” Switch

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    Maciej Sułkowski

    2018-01-01

    Full Text Available Since their invention in 2006, induced Pluripotent Stem (iPS cells remain a great promise for regenerative medicine circumventing the ethical issues linked to Embryonic Stem (ES cell research. iPS cells can be generated in a patient-specific manner as an unlimited source of various cell types for in vitro drug screening, developmental biology studies and regenerative use. Having the capacity of differentiating into the cells of all three primary germ layers, iPS cells have high potential to form teratoma tumors. This remains their main disadvantage and hazard which, until resolved, prevents utilization of iPS cells in clinic. Here, we present an approach for increasing iPS cells safety by introducing genetic modification—exogenous suicide gene Herpes Simplex Virus Thymidine Kinase (HSV-TK. Its expression results in specific vulnerability of genetically modified cells to prodrug—ganciclovir (GCV. We show that HSV-TK expressing cells can be eradicated both in vitro and in vivo with high specificity and efficiency with low doses of GCV. Described strategy increases iPS cells safety for future clinical applications by generating “emergency exit” switch allowing eradication of transplanted cells in case of their malfunction.

  11. Introduction of Exogenous HSV-TK Suicide Gene Increases Safety of Keratinocyte-Derived Induced Pluripotent Stem Cells by Providing Genetic "Emergency Exit" Switch.

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    Sułkowski, Maciej; Konieczny, Paweł; Chlebanowska, Paula; Majka, Marcin

    2018-01-09

    Since their invention in 2006, induced Pluripotent Stem (iPS) cells remain a great promise for regenerative medicine circumventing the ethical issues linked to Embryonic Stem (ES) cell research. iPS cells can be generated in a patient-specific manner as an unlimited source of various cell types for in vitro drug screening, developmental biology studies and regenerative use. Having the capacity of differentiating into the cells of all three primary germ layers, iPS cells have high potential to form teratoma tumors. This remains their main disadvantage and hazard which, until resolved, prevents utilization of iPS cells in clinic. Here, we present an approach for increasing iPS cells safety by introducing genetic modification-exogenous suicide gene Herpes Simplex Virus Thymidine Kinase ( HSV-TK ). Its expression results in specific vulnerability of genetically modified cells to prodrug-ganciclovir (GCV). We show that HSV-TK expressing cells can be eradicated both in vitro and in vivo with high specificity and efficiency with low doses of GCV. Described strategy increases iPS cells safety for future clinical applications by generating "emergency exit" switch allowing eradication of transplanted cells in case of their malfunction.

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

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    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

  13. 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)

  14. 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.

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

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    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.

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

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    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.

  17. 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.

  18. 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.

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    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.

  19. Synthesis of 2'-deoxy-2'-[{sup 18}F]-fluoro-5-ethyl-1-{beta}-D-arabinofuranosyluracil ([{sup 18}F]-FEAU) and micro-PET imaging of HSV-tk gene expression in tumor-bearing nude mice

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    Alauddin, M.M.; Shahinian, A.; Park, R.; Tohme, M.; Fissekis, J.D.; Conti, P.S. [Univ. of Southern California, Los Angeles, CA (United States). PET Imaging Science Center

    2004-07-01

    Herpes simplex virus type-1 thymidine kinase (HSV1-tk) is being used as a suicide gene for gene therapy of cancer. An in vivo method to assess the HSV1-tk enzyme activity after gene transfer is desirable to monitor gene expression as an indicator of gene delivery. Imaging of the HSV1-tk reporter gene along with various reporter probes is of current interest. We originally developed [{sup 18}F]-FHPG and [{sup 18}F]-FHBG for PET imaging of HSV1-tk gene expression and demonstrated that [{sup 18}F]-FHBG is more useful than [{sup 18}F]-FHPG for this purpose. [{sup 124}I]-FIAU has been shown to be a potential PET imaging agent for HSV1-tk gene expression, and is superior to [{sup 18}F]-FHPG and [{sup 18}F]-FHBG. We also demonstrated that radiolabeled FMAU can be used as a marker for HSV-tk gene expression, and is superior to [{sup 18}F]-FHPG and [{sup 18}F]-FHBG. Earlier we reported a synthesis for 2'-deoxy-2'-[{sup 18}F]fluoro-5-methyl-1-{beta}-D-arabinofuranosyluracil ([{sup 18}F]-FMAU) and some other 5-substituted nucleosides. We have synthesized now [{sup 18}F]-FEAU, used the tracer for micro-PET imaging of suicide gene expression in tumor-bearing nude mice, and compared the results with earlier studies using [{sup 14}C]-FMAU. (orig.)

  20. 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.

  1. 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.

  2. 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.

  3. Immunostimulatory Gene Therapy Using Oncolytic Viruses as Vehicles

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    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.

  4. 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.

  5. Designing herpes viruses as oncolytics

    Science.gov (United States)

    Peters, Cole; Rabkin, Samuel D

    2015-01-01

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

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

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    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.

  7. 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

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

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    Timothy P Cripe

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

  10. 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

  11. 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.

  12. 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

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

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    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.

  14. Oncolytic virotherapy in upper gastrointestinal tract cancers

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    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

  15. 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

  16. 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

  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. 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.

  19. 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

  20. Oncolytic vaccinia therapy of squamous cell carcinoma

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    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.

  1. 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

  2. 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 

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

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    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. 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 

  5. 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.

  6. Oncolytic Viruses: Therapeutics With an Identity Crisis

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    Caroline J. Breitbach

    2016-07-01

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

  7. 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

  8. 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

  9. 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

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

    Science.gov (United States)

    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.

  11. 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.

  12. 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.

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

    Directory of Open Access Journals (Sweden)

    Sarah Aref

    2016-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Hutzen B

    2015-08-01

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

  15. Oncolytic Replication of E1b-Deleted Adenoviruses

    Directory of Open Access Journals (Sweden)

    Pei-Hsin Cheng

    2015-11-01

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

  16. 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.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Lundstrom K

    2018-02-01

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

  19. 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

  20. 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

  1. Prospective Randomized Phase 2 Trial of Intensity Modulated Radiation Therapy With or Without Oncolytic Adenovirus-Mediated Cytotoxic Gene Therapy in Intermediate-Risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Freytag, Svend O., E-mail: sfreyta1@hfhs.org [Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan (United States); Stricker, Hans [Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan (United States); Lu, Mei [Public Health Sciences, Henry Ford Health System, Detroit, Michigan (United States); Elshaikh, Mohamed; Aref, Ibrahim; Pradhan, Deepak; Levin, Kenneth; Kim, Jae Ho [Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan (United States); Peabody, James [Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan (United States); Siddiqui, Farzan; Barton, Kenneth; Pegg, Jan; Zhang, Yingshu; Cheng, Jingfang [Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan (United States); Oja-Tebbe, Nancy; Bourgeois, Renee [Public Health Sciences, Henry Ford Health System, Detroit, Michigan (United States); Gupta, Nilesh; Lane, Zhaoli [Pathology, Henry Ford Health System, Detroit, Michigan (United States); Rodriguez, Ron [Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); DeWeese, Theodore [Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); and others

    2014-06-01

    Purpose: To assess the safety and efficacy of combining oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) with intensity modulated radiation therapy (IMRT) in intermediate-risk prostate cancer. Methods and Materials: Forty-four men with intermediate-risk prostate cancer were randomly assigned to receive either OAMCGT plus IMRT (arm 1; n=21) or IMRT only (arm 2; n=23). The primary phase 2 endpoint was acute (≤90 days) toxicity. Secondary endpoints included quality of life (QOL), prostate biopsy (12-core) positivity at 2 years, freedom from biochemical/clinical failure (FFF), freedom from metastases, and survival. Results: Men in arm 1 exhibited a greater incidence of low-grade influenza-like symptoms, transaminitis, neutropenia, and thrombocytopenia than men in arm 2. There were no significant differences in gastrointestinal or genitourinary events or QOL between the 2 arms. Two-year prostate biopsies were obtained from 37 men (84%). Thirty-three percent of men in arm 1 were biopsy-positive versus 58% in arm 2, representing a 42% relative reduction in biopsy positivity in the investigational arm (P=.13). There was a 60% relative reduction in biopsy positivity in the investigational arm in men with <50% positive biopsy cores at baseline (P=.07). To date, 1 patient in each arm exhibited biochemical failure (arm 1, 4.8%; arm 2, 4.3%). No patient developed hormone-refractory or metastatic disease, and none has died from prostate cancer. Conclusions: Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer.

  2. Prospective Randomized Phase 2 Trial of Intensity Modulated Radiation Therapy With or Without Oncolytic Adenovirus-Mediated Cytotoxic Gene Therapy in Intermediate-Risk Prostate Cancer

    International Nuclear Information System (INIS)

    Freytag, Svend O.; Stricker, Hans; Lu, Mei; Elshaikh, Mohamed; Aref, Ibrahim; Pradhan, Deepak; Levin, Kenneth; Kim, Jae Ho; Peabody, James; Siddiqui, Farzan; Barton, Kenneth; Pegg, Jan; Zhang, Yingshu; Cheng, Jingfang; Oja-Tebbe, Nancy; Bourgeois, Renee; Gupta, Nilesh; Lane, Zhaoli; Rodriguez, Ron; DeWeese, Theodore

    2014-01-01

    Purpose: To assess the safety and efficacy of combining oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) with intensity modulated radiation therapy (IMRT) in intermediate-risk prostate cancer. Methods and Materials: Forty-four men with intermediate-risk prostate cancer were randomly assigned to receive either OAMCGT plus IMRT (arm 1; n=21) or IMRT only (arm 2; n=23). The primary phase 2 endpoint was acute (≤90 days) toxicity. Secondary endpoints included quality of life (QOL), prostate biopsy (12-core) positivity at 2 years, freedom from biochemical/clinical failure (FFF), freedom from metastases, and survival. Results: Men in arm 1 exhibited a greater incidence of low-grade influenza-like symptoms, transaminitis, neutropenia, and thrombocytopenia than men in arm 2. There were no significant differences in gastrointestinal or genitourinary events or QOL between the 2 arms. Two-year prostate biopsies were obtained from 37 men (84%). Thirty-three percent of men in arm 1 were biopsy-positive versus 58% in arm 2, representing a 42% relative reduction in biopsy positivity in the investigational arm (P=.13). There was a 60% relative reduction in biopsy positivity in the investigational arm in men with <50% positive biopsy cores at baseline (P=.07). To date, 1 patient in each arm exhibited biochemical failure (arm 1, 4.8%; arm 2, 4.3%). No patient developed hormone-refractory or metastatic disease, and none has died from prostate cancer. Conclusions: Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Matthew O. Old

    2016-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Shashi Ashok Gujar

    2014-04-01

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

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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...

  11. 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...

  12. 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...

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

    Directory of Open Access Journals (Sweden)

    Marijke van Rikxoort

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

  14. Arm Pain

    Science.gov (United States)

    ... be a sign of a heart attack. Seek emergency treatment if you have: Arm, shoulder or back ... http://www.mayoclinic.org/symptoms/arm-pain/basics/definition/SYM-20050870 . Mayo Clinic Footer Legal Conditions and ...

  15. 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.

  16. 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.

  17. 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

  18. High-throughput screening to enhance oncolytic virus immunotherapy

    Directory of Open Access Journals (Sweden)

    Allan KJ

    2016-04-01

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

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

    Directory of Open Access Journals (Sweden)

    Janice Kim

    2015-11-01

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

  20. Robotic arm

    International Nuclear Information System (INIS)

    Kwech, H.

    1989-01-01

    A robotic arm positionable within a nuclear vessel by access through a small diameter opening and having a mounting tube supported within the vessel and mounting a plurality of arm sections for movement lengthwise of the mounting tube as well as for movement out of a window provided in the wall of the mounting tube is disclosed. An end effector, such as a grinding head or welding element, at an operating end of the robotic arm, can be located and operated within the nuclear vessel through movement derived from six different axes of motion provided by mounting and drive connections between arm sections of the robotic arm. The movements are achieved by operation of remotely-controllable servo motors, all of which are mounted at a control end of the robotic arm to be outside the nuclear vessel. 23 figs

  1. Robotic arm

    Science.gov (United States)

    Kwech, Horst

    1989-04-18

    A robotic arm positionable within a nuclear vessel by access through a small diameter opening and having a mounting tube supported within the vessel and mounting a plurality of arm sections for movement lengthwise of the mounting tube as well as for movement out of a window provided in the wall of the mounting tube. An end effector, such as a grinding head or welding element, at an operating end of the robotic arm, can be located and operated within the nuclear vessel through movement derived from six different axes of motion provided by mounting and drive connections between arm sections of the robotic arm. The movements are achieved by operation of remotely-controllable servo motors, all of which are mounted at a control end of the robotic arm to be outside the nuclear vessel.

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

    Directory of Open Access Journals (Sweden)

    Andrew eNguyen

    2014-06-01

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

  3. 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

  4. Broken Arm

    Science.gov (United States)

    ... of falling — including football, soccer, gymnastics, skiing and skateboarding — also increases the risk of a broken arm. ... for high-risk activities, such as in-line skating, snowboarding, rugby and football. Don't smoke. Smoking ...

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. 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.

  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. 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.

  13. 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...

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

    Science.gov (United States)

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

    2018-04-03

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

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

    Directory of Open Access Journals (Sweden)

    Tien V. Nguyen

    2017-08-01

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

  16. 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 ...

  17. 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

  18. 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.

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

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    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.

  20. 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.

  1. 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...

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

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    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.

  3. 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.

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

    Science.gov (United States)

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

    2017-01-01

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

  5. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

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    Hannah Burgess

    2018-03-01

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

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

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    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 

  9. 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.

  10. 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.

  11. 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.

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

    Directory of Open Access Journals (Sweden)

    Ramírez M

    2015-10-01

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

  13. 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.

  14. 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

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

    Directory of Open Access Journals (Sweden)

    Catherine Dold

    2016-01-01

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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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.)

  7. 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.)

  8. 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.

  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

    International Nuclear Information System (INIS)

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

    2010-01-01

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

  10. JPRS Report Arms Control

    National Research Council Canada - National Science Library

    1993-01-01

    Table of Contents: (1) COMMONWEALTH OF INDEPENDENT STATES - (A) GENERAL Flaws in U.S.-Russian SSD Agreement Viewed, Khariton - Espionage Not Crucial in Soviet Nuclear Arms Development, Further on Espionage Role in Nuclear Arms Projects...

  11. Evolution of robotic arms.

    Science.gov (United States)

    Moran, Michael E

    2007-01-01

    The foundation of surgical robotics is in the development of the robotic arm. This is a thorough review of the literature on the nature and development of this device with emphasis on surgical applications. We have reviewed the published literature and classified robotic arms by their application: show, industrial application, medical application, etc. There is a definite trend in the manufacture of robotic arms toward more dextrous devices, more degrees-of-freedom, and capabilities beyond the human arm. da Vinci designed the first sophisticated robotic arm in 1495 with four degrees-of-freedom and an analog on-board controller supplying power and programmability. von Kemplen's chess-playing automaton left arm was quite sophisticated. Unimate introduced the first industrial robotic arm in 1961, it has subsequently evolved into the PUMA arm. In 1963 the Rancho arm was designed; Minsky's Tentacle arm appeared in 1968, Scheinman's Stanford arm in 1969, and MIT's Silver arm in 1974. Aird became the first cyborg human with a robotic arm in 1993. In 2000 Miguel Nicolalis redefined possible man-machine capacity in his work on cerebral implantation in owl-monkeys directly interfacing with robotic arms both locally and at a distance. The robotic arm is the end-effector of robotic systems and currently is the hallmark feature of the da Vinci Surgical System making its entrance into surgical application. But, despite the potential advantages of this computer-controlled master-slave system, robotic arms have definite limitations. Ongoing work in robotics has many potential solutions to the drawbacks of current robotic surgical systems.

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

    Science.gov (United States)

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

    2010-12-15

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

  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. 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

  15. Powered manipulator control arm

    International Nuclear Information System (INIS)

    Le Mouee, Theodore; Vertut, Jean; Marchal, Paul; Germon, J.C.; Petit, Michel

    1975-01-01

    A remote operated control arm for powered manipulators is described. It includes an assembly allowing several movements with position sensors for each movement. The number of possible arm movements equals the number of possible manipulator movements. The control systems may be interrupted as required. One part of the arm is fitted with a system to lock it with respect to another part of the arm without affecting the other movements, so long as the positions of the manipulator and the arm have not been brought into complete coincidence. With this system the locking can be ended when complete concordance is achieved [fr

  16. The arms race control

    International Nuclear Information System (INIS)

    Nemo, J.

    2010-01-01

    Written in 1961, this paper presents the content of a book entitled 'The arms race control' where the author outlined the difference between disarmament and arms control, described the economic and moral role of arms race, the importance of force balance for international security. He wandered whether arms control could ensure this balance and whether nuclear balance meant force balance. Force balance then appears to be a precarious and unsteady component of international security. He commented the challenges of disarmament, recalled some arguments for a nuclear disarmament. Then he discussed what would be an arms control with or without disarmament (either nuclear or conventional)

  17. 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

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

    Science.gov (United States)

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

    2018-02-07

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

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

    Directory of Open Access Journals (Sweden)

    Lockley Michelle

    2010-07-01

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

  20. 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 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

  2. 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.

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

    Science.gov (United States)

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

    2009-01-01

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

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

    Science.gov (United States)

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

    2009-03-01

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

  5. 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...

  6. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  8. 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.

  9. 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.

  10. 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.

  11. Arms control and disarmament

    International Nuclear Information System (INIS)

    Acton, P.

    1992-01-01

    Article VI of the Non-Proliferation Treaty commits each party to work towards nuclear disarmament and to negotiations to stop the nuclear arms race. All parties to the Treaty are included and a wide range of arms control and disarmament issues are covered. However the main focus at Treaty review conferences has been on nuclear disarmament by the nuclear weapon states which are party to the Treaty. This has led to bilateral United States - Soviet Union negotiations resulting in the Intermediate-range Nuclear Forces Treaty in December 1987 and the Strategic Arms Reduction Treaty (START) in July followed by unilateral arms control measures in September and October 1991. (UK)

  12. ARM Mentor Selection Process

    Energy Technology Data Exchange (ETDEWEB)

    Sisterson, D. L. [Argonne National Lab. (ANL), Argonne, IL (United States)

    2015-10-01

    The Atmospheric Radiation Measurement (ARM) Program was created in 1989 with funding from the U.S. Department of Energy (DOE) to develop several highly instrumented ground stations to study cloud formation processes and their influence on radiative transfer. In 2003, the ARM Program became a national scientific user facility, known as the ARM Climate Research Facility. This scientific infrastructure provides for fixed sites, mobile facilities, an aerial facility, and a data archive available for use by scientists worldwide through the ARM Climate Research Facility—a scientific user facility. The ARM Climate Research Facility currently operates more than 300 instrument systems that provide ground-based observations of the atmospheric column. To keep ARM at the forefront of climate observations, the ARM infrastructure depends heavily on instrument scientists and engineers, also known as lead mentors. Lead mentors must have an excellent understanding of in situ and remote-sensing instrumentation theory and operation and have comprehensive knowledge of critical scale-dependent atmospheric processes. They must also possess the technical and analytical skills to develop new data retrievals that provide innovative approaches for creating research-quality data sets. The ARM Climate Research Facility is seeking the best overall qualified candidate who can fulfill lead mentor requirements in a timely manner.

  13. Security and arms control

    International Nuclear Information System (INIS)

    Kolodziej, E.A.; Morgan, P.M.

    1989-01-01

    This book attempts to clarify and define selected current issues and problems related to security and arms control from an international perspective. The chapters are organized under the following headings. Conflict and the international system, Nuclear deterrence, Conventional warfare, Subconventional conflict, Arms control and crisis management

  14. Managing new arms races

    International Nuclear Information System (INIS)

    Segal, G.

    1992-01-01

    The management of new arms races in the region of Asia-Pacific includes considerations of weapons trade and transfer in the region, with an emphasis on nuclear weapons proliferation. It deals with the problem of controlling the arms trade and the efforts to control conventional weapons and underlines the possible role and influence of Conference on Cooperation and Security in Europe (CSCE)

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. Nonspecific Arm Pain

    Directory of Open Access Journals (Sweden)

    Ali Moradi

    2013-12-01

    Full Text Available Nonspecific activity-related arm pain is characterized by an absence of objective physical findings and symptoms that do not correspond with objective pathophysiology. Arm pain without strict diagnosis is often related to activity, work-related activity in particular, and is often seen in patients with physically demanding work. Psychological factors such as catastrophic thinking, symptoms of depression, and heightened illness concern determine a substantial percentage of the disability associated with puzzling hand and arm pains. Ergonomic modifications can help to control symptoms, but optimal health may require collaborative management incorporating psychosocial and psychological elements of illness.

  3. Nonspecific Arm Pain

    Directory of Open Access Journals (Sweden)

    Ali Moradi

    2013-12-01

    Full Text Available   Nonspecific activity-related arm pain is characterized by an absence of objective physical findings and symptoms that do not correspond with objective pathophysiology. Arm pain without strict diagnosis is often related to activity, work-related activity in particular, and is often seen in patients with physically demanding work. Psychological factors such as catastrophic thinking, symptoms of depression, and heightened illness concern determine a substantial percentage of the disability associated with puzzling hand and arm pains. Ergonomic modifications can help to control symptoms, but optimal health may require collaborative management incorporating psychosocial and psychological elements of illness.

  4. Arms Trafficking and Colombia

    National Research Council Canada - National Science Library

    Cragin, Kim; Hoffman, Bruce

    2003-01-01

    ... to traditional definitions of a security threat. For this analysis, the term "small arms" refers to man-portable personal and military weapons, ranging from handguns to assault rifles to surface-to-air missiles (SAMs...

  5. 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.

  6. Arms Races and Negotiations

    OpenAIRE

    Sandeep Baliga; Tomas Sjostrom

    2003-01-01

    Two players simultaneously decide whether or not to acquire new weapons in an arms race game. Each player's type determines his propensity to arm. Types are private information, and are independently drawn from a continuous distribution. With probability close to one, the best outcome for each player is for neither to acquire new weapons (although each prefers to acquire new weapons if he thinks the opponent will). There is a small probability that a player is a dominant strategy type who alw...

  7. Hello to Arms

    Science.gov (United States)

    2005-01-01

    This image highlights the hidden spiral arms (blue) that were discovered around the nearby galaxy NGC 4625 by the ultraviolet eyes of NASA's Galaxy Evolution Explorer. The image is composed of ultraviolet and visible-light data, from the Galaxy Evolution Explorer and the California Institute of Technology's Digitized Sky Survey, respectively. Near-ultraviolet light is colored green; far-ultraviolet light is colored blue; and optical light is colored red. As the image demonstrates, the lengthy spiral arms are nearly invisible when viewed in optical light while bright in ultraviolet. This is because they are bustling with hot, newborn stars that radiate primarily ultraviolet light. The youthful arms are also very long, stretching out to a distance four times the size of the galaxy's core. They are part of the largest ultraviolet galactic disk discovered so far. Located 31 million light-years away in the constellation Canes Venatici, NGC 4625 is the closest galaxy ever seen with such a young halo of arms. It is slightly smaller than our Milky Way, both in size and mass. However, the fact that this galaxy's disk is forming stars very actively suggests that it might evolve into a more massive and mature galaxy resembling our own. The armless companion galaxy seen below NGC 4625 is called NGC 4618. Astronomers do not know why it lacks arms but speculate that it may have triggered the development of arms in NGC 4625.

  8. 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...

  9. 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.

  10. Armed conflict and child health.

    Science.gov (United States)

    Rieder, Michael; Choonara, Imti

    2012-01-01

    Armed conflict has a major impact on child health throughout the world. One in six children worldwide lives in an area of armed conflict and civilians are more likely to die than soldiers as a result of the conflict. In stark contrast to the effect on children, the international arms trade results in huge profits for the large corporations involved in producing arms, weapons and munitions. Armed conflict is not inevitable but is an important health issue that should be prevented.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-07-10

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

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

    International Nuclear Information System (INIS)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    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. 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

  15. PHENIX Muon Arms

    International Nuclear Information System (INIS)

    Akikawa, H.; Al-Jamel, A.; Archuleta, J.B.; Archuleta, J.R.; Armendariz, R.; Armijo, V.; Awes, T.C.; Baldisseri, A.; Barker, A.B.; Barnes, P.D.; Bassalleck, B.; Batsouli, S.; Behrendt, J.; Bellaiche, F.G.; Bland, A.W.; Bobrek, M.; Boissevain, J.G.; Borel, H.; Brooks, M.L.; Brown, A.W.; Brown, D.S.; Bruner, N.; Cafferty, M.M.; Carey, T.A.; Chai, J.-S.; Chavez, L.L.; Chollet, S.; Choudhury, R.K.; Chung, M.S.; Cianciolo, V.; Clark, D.J.; Cobigo, Y.; Dabrowski, C.M.; Debraine, A.; DeMoss, J.; Dinesh, B.V.; Drachenberg, J.L.; Drapier, O.; Echave, M.A.; Efremenko, Y.V.; En'yo, H.; Fields, D.E.; Fleuret, F.; Fried, J.; Fujisawa, E.; Funahashi, H.; Gadrat, S.; Gastaldi, F.; Gee, T.F.; Glenn, A.; Gogiberidze, G.; Gonin, M.; Gosset, J.; Goto, Y.; Granier de Cassagnac, R.; Hance, R.H.; Hart, G.W.; Hayashi, N.; Held, S.; Hicks, J.S.; Hill, J.C.; Hoade, R.; Hong, B.; Hoover, A.; Horaguchi, T.; Hunter, C.T.; Hurst, D.E.; Ichihara, T.; Imai, K.; Isenhower, L.D.L. Davis; Isenhower, L.D.L. Donald; Ishihara, M.; Jang, W.Y.; Johnson, J.; Jouan, D.; Kamihara, N.; Kamyshkov, Y.; Kang, J.H.; Kapoor, S.S.; Kim, D.J.; Kim, D.-W.; Kim, G.-B.; Kinnison, W.W.; Klinksiek, S.; Kluberg, L.; Kobayashi, H.; Koehler, D.; Kotchenda, L.; Kuberg, C.H.; Kurita, K.; Kweon, M.J.; Kwon, Y.; Kyle, G.S.; LaBounty, J.J.; Lajoie, J.G.; Lee, D.M.; Lee, S.; Leitch, M.J.; Li, Z.; Liu, M.X.; Liu, X.; Liu, Y.; Lockner, E.; Lopez, J.D.; Mao, Y.; Martinez, X.B.; McCain, M.C.; McGaughey, P.L.; Mioduszewski, S.; Mischke, R.E.; Mohanty, A.K.; Montoya, B.C.; Moss, J.M.; Murata, J.; Murray, M.M.; Nagle, J.L.; Nakada, Y.; Newby, J.; Obenshain, F.; Palounek, A.P.T.; Papavassiliou, V.; Pate, S.F.; Plasil, F.; Pope, K.; Qualls, J.M.; Rao, G.; Read, K.F.; Robinson, S.H.; Roche, G.; Romana, A.; Rosnet, P.; Roth, R.; Saito, N.; Sakuma, T.; Sandhoff, W.F.; Sanfratello, L.; Sato, H.D.; Savino, R.; Sekimoto, M.; Shaw, M.R.; Shibata, T.-A.; Sim, K.S.; Skank, H.D.; Smith, D.E.; Smith, G.D.; Sondheim, W.E.; Sorensen, S.; Staley, F.; Stankus, P.W.; Steffens, S.; Stein, E.M.; Stepanov, M.; Stokes, W.; Sugioka, M.; Sun, Z.; Taketani, A.; Taniguchi, E.; Tepe, J.D.; Thornton, G.W.; Tian, W.; Tojo, J.; Torii, H.; Towell, R.S.; Tradeski, J.; Vassent, M.; Velissaris, C.; Villatte, L.; Wan, Y.; Watanabe, Y.; Watkins, L.C.; Whitus, B.R.; Williams, C.; Willis, P.S.; Wong-Swanson, B.G.; Yang, Y.; Yoneyama, S.; Young, G.R.; Zhou, S.

    2003-01-01

    The PHENIX Muon Arms detect muons at rapidities of |y|=(1.2-2.4) with full azimuthal acceptance. Each muon arm must track and identify muons and provide good rejection of pions and kaons (∼10 -3 ). In order to accomplish this we employ a radial field magnetic spectrometer with precision tracking (Muon Tracker) followed by a stack of absorber/low resolution tracking layers (Muon Identifier). The design, construction, testing and expected run parameters of both the muon tracker and the muon identifier are described

  16. PHENIX Muon Arms

    Energy Technology Data Exchange (ETDEWEB)

    Akikawa, H.; Al-Jamel, A.; Archuleta, J.B.; Archuleta, J.R.; Armendariz, R.; Armijo, V.; Awes, T.C.; Baldisseri, A.; Barker, A.B.; Barnes, P.D.; Bassalleck, B.; Batsouli, S.; Behrendt, J.; Bellaiche, F.G.; Bland, A.W.; Bobrek, M.; Boissevain, J.G.; Borel, H.; Brooks, M.L.; Brown, A.W.; Brown, D.S.; Bruner, N.; Cafferty, M.M.; Carey, T.A.; Chai, J.-S.; Chavez, L.L.; Chollet, S.; Choudhury, R.K.; Chung, M.S.; Cianciolo, V.; Clark, D.J.; Cobigo, Y.; Dabrowski, C.M.; Debraine, A.; DeMoss, J.; Dinesh, B.V.; Drachenberg, J.L.; Drapier, O.; Echave, M.A.; Efremenko, Y.V.; En' yo, H.; Fields, D.E.; Fleuret, F.; Fried, J.; Fujisawa, E.; Funahashi, H.; Gadrat, S.; Gastaldi, F.; Gee, T.F.; Glenn, A.; Gogiberidze, G.; Gonin, M.; Gosset, J.; Goto, Y.; Granier de Cassagnac, R.; Hance, R.H.; Hart, G.W.; Hayashi, N.; Held, S.; Hicks, J.S.; Hill, J.C.; Hoade, R.; Hong, B.; Hoover, A.; Horaguchi, T.; Hunter, C.T.; Hurst, D.E.; Ichihara, T.; Imai, K.; Isenhower, L.D.L. Davis; Isenhower, L.D.L. Donald; Ishihara, M.; Jang, W.Y.; Johnson, J.; Jouan, D.; Kamihara, N.; Kamyshkov, Y.; Kang, J.H.; Kapoor, S.S.; Kim, D.J.; Kim, D.-W.; Kim, G.-B.; Kinnison, W.W.; Klinksiek, S.; Kluberg, L.; Kobayashi, H.; Koehler, D.; Kotchenda, L.; Kuberg, C.H.; Kurita, K.; Kweon, M.J.; Kwon, Y.; Kyle, G.S.; LaBounty, J.J.; Lajoie, J.G.; Lee, D.M.; Lee, S.; Leitch, M.J.; Li, Z.; Liu, M.X.; Liu, X.; Liu, Y.; Lockner, E.; Lopez, J.D.; Mao, Y.; Martinez, X.B.; McCain, M.C.; McGaughey, P.L.; Mioduszewski, S.; Mischke, R.E.; Mohanty, A.K.; Montoya, B.C.; Moss, J.M.; Murata, J.; Murray, M.M.; Nagle, J.L.; Nakada, Y.; Newby, J.; Obenshain, F.; Palounek, A.P.T.; Papavassiliou, V.; Pate, S.F.; Plasil, F.; Pope, K.; Qualls, J.M.; Rao, G.; Read, K.F. E-mail: readkf@ornl.gov; Robinson, S.H.; Roche, G.; Romana, A.; Rosnet, P.; Roth, R.; Saito, N.; Sakuma, T.; Sandhoff, W.F.; Sanfratello, L.; Sato, H.D.; Savino, R.; Sekimoto, M.; Shaw, M.R.; Shibata, T.-A.; Sim, K.S.; Skank, H.D.; Smith, D.E.; Smith, G.D. [and others

    2003-03-01

    The PHENIX Muon Arms detect muons at rapidities of |y|=(1.2-2.4) with full azimuthal acceptance. Each muon arm must track and identify muons and provide good rejection of pions and kaons ({approx}10{sup -3}). In order to accomplish this we employ a radial field magnetic spectrometer with precision tracking (Muon Tracker) followed by a stack of absorber/low resolution tracking layers (Muon Identifier). The design, construction, testing and expected run parameters of both the muon tracker and the muon identifier are described.

  17. Worldwide Report, Arms Control

    Science.gov (United States)

    1986-02-28

    NACHRICHTEN , 18 Oct 85) 39 Presummit Polish Reporting on SDI Issues (Warsaw RZECZPOSPOLITA, 19-20 Oct 85; Warsaw ZYCIE WARSZAWY, 15 Oct 85) 42...28 February 1986 SDI AND SPACE ARMS MEETING REVEALS SOME SUPPORT FOR EUREKA LINK TO MILITARY Puesseldbrf VDI NACHRICHTEN in German 18 Oct 85 p 10

  18. Worldwide Report, Arms Control.

    Science.gov (United States)

    1986-02-04

    8217Unpredictable Consequences’ of SDI (Moscow PRAVDA, 7 Dec 85) 22 Moscow TV on ASTEC Meeting, Military Monopolies, SDI (Tomas Kolesnichenko; Moscow...planet. /8309 CSO: 5200/1228 22 JPRS-TAO86*014 4 February 1986 SDI AND SPACE ARMS MOSCOW TV ON ASTEC MEETING, MILITARY MONOPOLIES, SDI

  19. Affine pairings on ARM

    NARCIS (Netherlands)

    Acar, T.; Lauter, K.; Naehrig, M.; Shumow, D.; Abdalla, M.; Lange, T.

    2013-01-01

    We report on relative performance numbers for affine and projective pairings on a dual-core Cortex A9 ARM processor. Using a fast inversion in the base field and doing inversion in extension fields by using the norm map to reduce to inversions in smaller fields, we find a very low ratio of

  20. Arms Trafficking and Colombia

    Science.gov (United States)

    2003-01-01

    chronology of the intensification of violence in the area, see Noche Y Niebla: Panorama De Derechos Humanos Y Violencia Politica En Colombia, Bogotá...Arms, London, UK: Zed Books, 2000, pp. 155–178. Noche Y Niebla: Panorama De Derechos Humanos Y Violencia Politica En Colombia, Bogotá: Cinep & Justicia

  1. Modernization of African Armed Forces

    DEFF Research Database (Denmark)

    Mandrup, Thomas

    2015-01-01

    Concept paper framing the debate at the Dakar Forum Workshop on Modernization of Armed forces in Africa.......Concept paper framing the debate at the Dakar Forum Workshop on Modernization of Armed forces in Africa....

  2. Understanding the conventional arms trade

    Science.gov (United States)

    Stohl, Rachel

    2017-11-01

    The global conventional arms trade is worth tens of billions of dollars every year and is engaged in by every country in the world. Yet, it is often difficult to control the legal trade in conventional arms and there is a thriving illicit market, willing to arm unscrupulous regimes and nefarious non-state actors. This chapter examines the international conventional arms trade, the range of tools that have been used to control it, and challenges to these international regimes.

  3. Safeguarding arms control

    International Nuclear Information System (INIS)

    Flanagan, S.J.

    1988-01-01

    This essay reviews the evolution of various safeguards concepts associated with U.S. Soviet arms control negotiations over the past twenty-five years. It explore in some detail the origins, nature, and effectiveness of the safeguards packages associated with six agreements: the Limited Test Ban Treaty (1963), the SALT I Interim Agreement (1972), the Anti-Ballistic Missile (ABM) Treaty (1972), the Threshold Test Ban Treaty (1974), the Peaceful Nuclear Explosions Treaty (1976) and the SALT II Treaty (1979). Finally, the implications of this historical record for developing future nuclear and conventional arms control accords and for shoring up existing pacts, such as the ABM Treaty, are assessed with a view towards practicable prescriptions for Western policymakers. The treaty eliminating intermediate-range nuclear forces (INF) incorporates several verification safeguards, and it is very likely that analogous measures would be attached to any accord constraining conventional forces in Europe

  4. Coat of Arms.

    Science.gov (United States)

    Smith, Bryan

    1998-01-01

    Describes an activity, the "coat of arms," that can serve as an ice-breaker or warm-up for the first day of an English-as-a-Second/Foreign-Language class, as a motivating start to the week, or act as an innovative segue between skill lessons. The technique can be adapted for students ranging from elementary school to adult language learners of all…

  5. Arms Production in Venezuela.

    Science.gov (United States)

    1987-12-01

    studied engineering in the United States. Cardoen produces a wide spectrum of munitions, security equipment and especially armored vehicles, and has...capabilities are: a. The amount of capital available for investment. Arms industry development requires enormous amounts of capital, especially if the...Naval Postgraduate School Monterey, CA 93943-5100 5. Director de Educacion de La Armada 1 Comandancia General de La Armada Av. Vollmer, Urb. San

  6. Scientific coats of arms.

    Science.gov (United States)

    Fara, Patricia

    2005-09-01

    With their mythical creatures and arcane symbolism, coats of arms seem to have little connection with modern science. Yet despite its chivalric origins, the ancient language of heraldry has long fascinated famous scientists. Although this idiosyncratic tradition was parodied by Victorian geologists, who laughingly replaced unicorns and griffins with images of dinosaurs that they had recently discovered, it has been perpetuated since by Ernest Rutherford, who liked to present himself as a new alchemist.

  7. Liposuction of arm lymphoedema.

    OpenAIRE

    Brorson, Håkan

    2003-01-01

    Breast cancer is the most common disease in women, and up to 38% develop lymphedema of the arm following mastectomy, standard axillary node dissection and postoperative irradiation. Limb reductions have been reported utilising various conservative therapies such as manual lymph and pressure therapy. Some patients with long-standing pronounced lymphedema do not respond to these conservative treatments because slow or absent lymph flow causes the formation of excess subcutaneous adipose tissue....

  8. Kiikuv maja / Anu Arm

    Index Scriptorium Estoniae

    Arm, Anu

    2006-01-01

    Eesti Kunstiakadeemia esimese kursuse arhitektuuriüliõpilaste II semestri töö. Juhendaja arhitekt Andres Alver, ehitamise Pedaspeale organiseeris suvepraktika juhendaja arhitekt Jaan Tiidemann. Autor Anu Arm, kaasa töötasid ja valmis ehitasid: Ott Alver, Maarja Elm, Mari Hunt, Alvin Järving, Marten Kaevats, Riho Kerge, Reedik Poopuu, Anu Põime, Helen Rebane, Kaisa Saarva, Martin Tago, Reet Volt. Valmis: 19. VIII 2006

  9. Strategic arms limitation

    Science.gov (United States)

    Allen Greb, G.; Johnson, Gerald W.

    1983-10-01

    Following World War II, American scientists and politicians proposed in the Baruch plan a radical solution to the problem of nuclear weapons: to eliminate them forever under the auspices of an international nuclear development authority. The Soviets, who as yet did not possess the bomb, rejected this plan. Another approach suggested by Secretary of War Henry Stimson to negotiate directly with the Soviet Union was not accepted by the American leadership. These initial arms limitation failures both reflected and exacerbated the hostile political relationship of the superpowers in the 1950s and 1960s. Since 1969, the more modest focus of the Soviet-American arms control process has been on limiting the numbers and sizes of both defensive and offensive strategic systems. The format for this effort has been the Strategic Arms Limitatins Talks (Salt) and more recently the Strategic Arms Reduction Talks (START). Both sides came to these negotiations convinced that nuclear arsenals had grown so large that some for of mutual restraint was needed. Although the SALT/START process has been slow and ponderous, it has produced several concrete the agreements and collateral benefits. The 1972 ABM Treaty restricts the deployment of ballistic missile defense systems, the 1972 Interim Agreement places a quantitative freeze on each side's land based and sea based strategic launchers, and the as yet unratified 1979 SALT II Treaty sets numerical limits on all offensive strategic systems and sublimits on MIRVed systems. Collateral benefits include improved verification procedures, working definitions and counting rules, and permanent bureaucratic apparatus which enhance stability and increase the chances for achieving additional agreements.

  10. Worldwide Report, Arms Control.

    Science.gov (United States)

    1985-11-22

    dinosaurs (and a large number of other species which disappeared "simultaneously") might have become extinct because a large comet hit the earth’s...clear yet aeain the reasons why Washington is in such haste in the arms race for "star wars" and why it refuses to assume a commitment not to be...Kolesnichenko says: [Begin Kolesnichenko recording in Russian with English translation] In an effort to calm the American public and provide a logical reason

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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 

  16. 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.

  17. 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

  18. Armed conflict and child health

    OpenAIRE

    Rieder, Michael; Choonara, Imti

    2012-01-01

    Armed conflict has a major impact on child health\\ud throughout the world. One in six children worldwide lives\\ud in an area of armed conflict and civilians are more likely\\ud to die than soldiers as a result of the conflict. In stark\\ud contrast to the effect on children, the international arms\\ud trade results in huge profits for the large corporations\\ud involved in producing arms, weapons and munitions.\\ud Armed conflict is not inevitable but is an important\\ud health issue that should be...

  19. 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.

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

    Science.gov (United States)

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

    2017-09-16

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

  1. Removable molar power arm

    Directory of Open Access Journals (Sweden)

    Raj Kumar Verma

    2013-01-01

    Full Text Available Attachment of force elements from the gingival hook of maxillary molar tubes during the retraction of the anterior teeth is very common in orthodontic practice. As the line of force passes below the center of resistance (CR of molar, it results its mesial tipping and also anchorage loss. To overcome this problem, the line of force should pass along the CR of molar. This article highlights a method to overcome this problem by attaching a removable power arm to the headgear tube of molar tube during the retraction of the anterior teeth.

  2. Disarmament and arms control

    International Nuclear Information System (INIS)

    Elzen, B.

    1979-01-01

    This report discusses how far science and technology can provide methods of making arms control and disarmament agreements more controlable in an objective way. Two case studies have been considered, the test ban treaty and the verification of the number of strategic nuclear weapons. These lead to the conclusion that both science and politics are closely interwoven and that within what appear to be scientific arguments, political positions are being defended. Consequently scientists and technologists and the contexts in which they work, play a prominent role. (C.F.)

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. Nature of galaxy spiral arms

    International Nuclear Information System (INIS)

    Efremov, Yu.N.

    1984-01-01

    The nature of galaxy spiral arms is discussed in a popular form. Two approaches in the theory of spiral arms are considered; they are related to the problem of differential galaxy rotation and the spiral structure wave theory. The example of Galaxy M31 is considered to compare the structural peculiarity of its spiral arms with the wave theory predictions. The situation in the central and south-eastern part of arm S4 in Galaxy M31 noted to be completely explained by the wave theory and modern concepts on the origin of massive stars

  9. Nuclear arms cleanup

    International Nuclear Information System (INIS)

    Cooper, M.H.

    1994-01-01

    The Soviet Union's demise five years ago brought an end to the Cold War, the 45-year arms race between the Soviet superpower and the United States. The euphoria that greeted the end of this bloodless conflict has dampened somewhat, however, as U.S. officials and their counterparts in the former Soviet republics come to grips with its legacy: thousands of highly toxic and politically destabilizing nuclear weapons. With no more perceived need for much of their vast arsenals, the governments have agreed to dismantle large numbers of nuclear warheads. But the agencies involved in this task face a daunting technical and political problem: what to do with the thousands of tons of plutonium and uranium that are the main ingredients of nuclear weapons

  10. The Neanderthal lower arm.

    Science.gov (United States)

    De Groote, Isabelle

    2011-10-01

    Neanderthal forearms have been described as being very powerful. Different individual features in the lower arm bones have been described to distinguish Neanderthals from modern humans. In this study, the overall morphology of the radius and ulna is considered, and morphological differences among Neanderthals, Upper Paleolithic Homo sapiens and recent H. sapiens are described. Comparisons among populations were made using a combination of 3D geometric morphometrics and standard multivariate methods. Comparative material included all available complete radii and ulnae from Neanderthals, early H. sapiens and archaeological and recent human populations, representing a wide geographical and lifestyle range. There are few differences among the populations when features are considered individually. Neanderthals and early H. sapiens fell within the range of modern human variation. When the suite of measurements and shapes were analyzed, differences and similarities became apparent. The Neanderthal radius is more laterally curved, has a more medially placed radial tuberosity, a longer radial neck, a more antero-posteriorly ovoid head and a well-developed proximal interosseous crest. The Neanderthal ulna has a more anterior facing trochlear notch, a lower M. brachialis insertion, larger relative mid-shaft size and a more medio-lateral and antero-posterior sinusoidal shaft. The Neanderthal lower arm morphology reflects a strong cold-adapted short forearm. The forearms of H. sapiens are less powerful in pronation and supination. Many differences between Neanderthals and H. sapiens can be explained as a secondary consequence of the hyper-polar body proportions of the Neanderthals, but also as retentions of the primitive condition of other hominoids. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Have Third-World Arms Industries Reduced Arms Imports?

    OpenAIRE

    Looney, R.E.

    1989-01-01

    Current Research on Peace and Violence, no. 1, 1989. Refereed Journal Article In 1945 only Argentina, Brazil, India and South Africa in the Third World possessed domestic arms industries which produced weapons systems other than small arms and ammunition (SIPRI, 1987, 76).

  12. 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

  13. 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

  14. 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.

  15. Nuclear Arms Race and Environment

    OpenAIRE

    Li, Anpeng

    2012-01-01

    This paper introduces a new factor, environment, into nuclear arms race model. In this model, nuclear weapons produce larger defense power compared with conventional arms, but hurt the environment meanwhile. In the global welfare maximum level, both conventional and nuclear weapons budget are zero. However, the competitive equilibrium may not achieve the optimum. I give the condition to jump out of the prisoner's dilemma.

  16. Arménie

    Directory of Open Access Journals (Sweden)

    François Verdier

    2012-04-01

    Full Text Available L’Arménie est une petite république du Caucase, à la limite sud–est de l’Europe, qui a gagné son autonomie en 1990 après l’ouverture du bloc soviétique. Le nouveau Ministère du Patrimoine a sollicité la coopération de la France pour mettre en place une nouvelle politique culturelle. Tout d’abord, une évaluation sur place de la situation dans les domaines des monuments historiques, de l’archéologie et de l’Inventaire a permis d’envisager les réponses à proposer. Pour la demande d’informatisation des dossiers d’inventaire déjà réalisés sous l’autorité de l’Académie de Saint–Petersbourg, nous avons proposé de former des chercheurs arméniens aux méthodes et techniques de l’Inventaire général. L’accueil d’une stagiaire pendant trois mois au service régional de l’Inventaire de Haute–Normandie a été suivi par la mise en place d’un équipement informatique à Yérévan, puis par l’accueil et la formation de techniciens informaticiens et photographes arméniens. De retour dans leur pays ils ont commencé à remettre en place un service d’inventaire dont le programme comprend la création d’une base de données patrimoniales, le recensement de la ville de Yérévan, la numérisation d’images pour la publication d’un indicateur du patrimoine et la préparation de dossiers de protection au titre du patrimoine mondial.The Armenian heritage comprises both archaeological remains of towns destroyed by never–ending wars and a number of old churches from the eleventh and twelfth centuries. Yerevan, the capital of Armenia, was founded three thousand years ago and is one of Europe’s oldest capitals. From 1925 it has developed according to an ambitious urban planning project. After the major political upheavals of 1991, a special ministry was created to look after the architectural and movable heritage of the country and to promote the Armenian national identity. A mission in Yerevan was

  17. How do octopuses use their arms?

    Science.gov (United States)

    Mather, J A

    1998-09-01

    A taxonomy of the movement patterns of the 8 flexible arms of octopuses is constructed. Components consist of movements of the arm itself, the ventral suckers and their stalks, as well as the relative position of arms and the skin web between them. Within 1 arm, combinations of components result in a variety of behaviors. At the level of all arms, 1 group of behaviors is described as postures, on the basis of the spread of all arms and the web to make a 2-dimensional surface whose position differs in the 3rd dimension. Another group of arm behaviors is actions, more or less coordinated and involving several to all arms. Arm control appears to be based on radial symmetry, relative equipotentiality of all arms, relative independence of each arm, and separability of components within the arm. The types and coordination of arm behaviors are discussed with relationship to biomechanical limits, muscle structures, and neuronal programming.

  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. 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.

  20. 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.

  1. 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.

  2. International security and arms control

    International Nuclear Information System (INIS)

    Ekeus, R.

    2000-01-01

    The end of the cold war also ended the focus on the bilateral approach to arms control and disarmament. Key concepts of security needed to be revisited, along with their implications for the disarmament and arms control agenda. Though there is currently a unipolar global security environment, there remain important tasks on the multilateral arms control agenda. The major task is that of reducing and eliminating weapons of mass destruction, especially nuclear weapons. The author contends that maintaining reliance on the nuclear-weapons option makes little sense in a time when the major Powers are strengthening their partnerships in economics, trade, peacemaking and building. (author)

  3. 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.

  4. 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.

  5. 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.

  6. Borehole tool outrigger arm displacement control mechanism

    International Nuclear Information System (INIS)

    Lee, A.G.

    1985-01-01

    As the outrigger arms of a borehole logging tool are flexed inwardly and outwardly according to the diameter of the borehole opening through which they pass, the corresponding axial displacements of the ends of the arms are controlled to determine the axial positions of the arms relative to the tool. Specifically, as the arm ends move, they are caused to rotate by a cam mechanism. The stiffness of the arms causes the arm ends to rotate in unison, and the exact positions of the arms on the tool are then controlled by the differential movements of the arm ends in the cams

  7. Technology and the arms race

    International Nuclear Information System (INIS)

    MacKenzie, D.

    1988-01-01

    This article makes a review of the book Innovation and the Arms Race: How the United States and the Soviet Union Develop New Military Technologies written by Matthew Evangelista. For at least the last two decades, scholars have struggled to come to grips with the role of technological change in the arms race. Possible relationships between theories on technology and politics are examined. The contrasts between U.S. and Soviet approaches are highlighted

  8. Changing patterns of arms transfers

    International Nuclear Information System (INIS)

    Wulf, H.

    1998-01-01

    Three factors in the international system have been of importance for the trade of arms: the role of the main actors on the supply side and since 1970 on the demand side, the permanently increasing importance of economics, and the balance trade, industrial capacity and jobs in supplier countries and purchasing power of potential importers. Two political events in 1991 had lasting effect on the development of the trade in arms: the dissolution of Soviet Union and the Gulf War

  9. Unequal-Arms Michelson Interferometers

    Science.gov (United States)

    Tinto, Massimo; Armstrong, J. W.

    2000-01-01

    Michelson interferometers allow phase measurements many orders of magnitude below the phase stability of the laser light injected into their two almost equal-length arms. If, however, the two arms are unequal, the laser fluctuations can not be removed by simply recombining the two beams. This is because the laser jitters experience different time delays in the two arms, and therefore can not cancel at the photo detector. We present here a method for achieving exact laser noise cancellation, even in an unequal-arm interferometer. The method presented in this paper requires a separate readout of the relative phase in each arm, made by interfering the returning beam in each arm with a fraction of the outgoing beam. By linearly combining the two data sets with themselves, after they have been properly time shifted, we show that it is possible to construct a new data set that is free of laser fluctuations. An application of this technique to future planned space-based laser interferometer detector3 of gravitational radiation is discussed.

  10. 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

    Wild-type mammalian orthoreovirus serotype 3 Dearing (T3wt) is nonpathogenic in humans but preferentially infects and kills cancer cells in culture and demonstrates promising antitumor activity in vivo. Using forward genetics, we previously isolated two variants of reovirus, T3v1 and T3v2, with increased infectivity toward a panel of cancer cell lines and improved in vivo oncolysis in a murine melanoma model relative to that of T3wt. Our current study explored how mutations in T3v1 and T3v2 promote infectivity. Reovirions contain trimers of σ1, the reovirus cell attachment protein, at icosahedral capsid vertices. Quantitative Western blot analysis showed that purified T3v1 and T3v2 virions had ∼ 2- and 4-fold-lower levels of σ1 fiber than did T3wt virions. Importantly, using RNA interference to reduce σ1 levels during T3wt production, we were able to generate wild-type reovirus with reduced levels of σ1 per virion. As σ1 levels were reduced, virion infectivity increased by 2- to 5-fold per cell-bound particle, demonstrating a causal relationship between virion σ1 levels and the infectivity of incoming virions. During infection of tumorigenic L929 cells, T3wt, T3v1, and T3v2 uncoated the outer capsid proteins σ3 and μ1C at similar rates. However, having started with fewer σ1 molecules, a complete loss of σ1 was achieved sooner for T3v1 and T3v2. Distinct from intracellular uncoating, chymotrypsin digestion, as a mimic of natural enteric infection, resulted in more rapid σ3 and μ1C removal, unique disassembly intermediates, and a rapid loss of infectivity for T3v1 and T3v2 compared to T3wt. Optimal infectivity toward natural versus therapeutic niches may therefore require distinct reovirus structures and σ1 levels. Wild-type reovirus is currently in clinical trials as a potential cancer therapy. Our molecular studies on variants of reovirus with enhanced oncolytic activity in vitro and in vivo now show that distinct reovirus structures promote

  11. Algorithms for Unequal-Arm Michelson Interferometers

    Science.gov (United States)

    Giampieri, Giacomo; Hellings, Ronald W.; Tinto, Massimo; Bender, Peter L.; Faller, James E.

    1994-01-01

    A method of data acquisition and data analysis is described in which the performance of Michelson-type interferometers with unequal arms can be made nearly the same as interferometers with equal arms. The method requires a separate readout of the relative phase in each arm, made by interfering the returning beam in each arm with a fraction of the outgoing beam.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. Proprioceptive Interaction between the Two Arms in a Single-Arm Pointing Task.

    Directory of Open Access Journals (Sweden)

    Kazuyoshi Kigawa

    Full Text Available Proprioceptive signals coming from both arms are used to determine the perceived position of one arm in a two-arm matching task. Here, we examined whether the perceived position of one arm is affected by proprioceptive signals from the other arm in a one-arm pointing task in which participants specified the perceived position of an unseen reference arm with an indicator paddle. Both arms were hidden from the participant's view throughout the study. In Experiment 1, with both arms placed in front of the body, the participants received 70-80 Hz vibration to the elbow flexors of the reference arm (= right arm to induce the illusion of elbow extension. This extension illusion was compared with that when the left arm elbow flexors were vibrated or not. The degree of the vibration-induced extension illusion of the right arm was reduced in the presence of left arm vibration. In Experiment 2, we found that this kinesthetic interaction between the two arms did not occur when the left arm was vibrated in an abducted position. In Experiment 3, the vibration-induced extension illusion of one arm was fully developed when this arm was placed at an abducted position, indicating that the brain receives increased proprioceptive input from a vibrated arm even if the arm was abducted. Our results suggest that proprioceptive interaction between the two arms occurs in a one-arm pointing task when the two arms are aligned with one another. The position sense of one arm measured using a pointer appears to include the influences of incoming information from the other arm when both arms were placed in front of the body and parallel to one another.

  20. Neck and arm pain syndromes

    DEFF Research Database (Denmark)

    de las Peñas, César Fernández; Cleland, Joshua; Huijbregts, Peter

    approaches.It uniquely addresses the expanding role of the various health care professions which require increased knowledge and skills in screening for contra-indications and recognizing the need for medical-surgical referral. Neck and Arm Pain Syndromes also stresses the integration of experiential......The first of its kind, Neck and Arm Pain Syndromes is a comprehensive evidence- and clinical-based book, covering research-based diagnosis, prognosis and management of neuromusculoskeletal pathologies and dysfunctions of the upper quadrant, including joint, muscle, myofascial and neural tissue...... of the most commonly seen pain syndromes in clinical practice over 800 illustrations demonstrating examination procedures and techniques....

  1. Nuclear physicist, arms control advocate

    CERN Multimedia

    Chang, K

    2002-01-01

    Victor F. Weisskopf, a nuclear physicist who worked on the Manhattan Project to build the first atomic bomb in World War II and later became an ardent advocate of arms control, died Monday at his home in Newton, MA, USA. He was 93 (1 page).

  2. Taxation, stateness and armed groups

    DEFF Research Database (Denmark)

    Hoffmann, Kasper; Vlassenroot, Koen; Marchais, Gauthier

    2016-01-01

    of authority and practices of rule that originate in the colonial era. In particular, the article shows that by appealing to both local customary and national forms of political community and citizenship, armed groups are able to assume public authority to tax civilians. However, their public authority may...

  3. Distinguishing targets in armed conflict

    African Journals Online (AJOL)

    The main object of international humanitarian law (IHL) is the amelioration of the effect of armed conflict on the populace. It seeks to accomplish this by establishing rules that ensure that objects the destruction of which will not give military advantage e are protected; thus, such objects are not to be targeted or destroyed.

  4. How Computers are Arming biology!

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 23; Issue 1. In-vitro to In-silico - How Computers are Arming biology! Geetha Sugumaran Sushila Rajagopal. Face to Face Volume 23 Issue 1 January 2018 pp 83-102. Fulltext. Click here to view fulltext PDF. Permanent link:

  5. Blood pressure measurement: one arm or both arm?

    Science.gov (United States)

    Kulkarni, Prasad K; Shekhar, Susheela; Reddy, B N; Nirmala, B C

    2011-09-01

    Guidelines for measuring blood pressure includes measurement of blood pressure on both arms but it is often ignored. Our case report aims at highlighting the need follow the guidelines. A 60 year old 59 kg weighing male asymptomatic patient without any comobidities was posted for bilateral inguinal hernia repair. The interarm blood pressure difference was discovered incidentally during his preanaesthetic evalution. On further evaluation patient was found to be having subclavian stenosis on left side which was asymptomatic. Intraoperative and post operative period was uneventful. Blood pressure measurement should be done in accordance with the stipulated guidelines. Inter arm blood pressure difference should be noted in all patients as not only for diagnosis and treatment of hypertension but also as a tool to diagnose asymptomatic peripheral vascular disesase.

  6. Controlling robot arm with the mind

    National Science Foundation

    2017-05-31

    Full Text Available Research test subjects at the University of Minnesota who were fitted with a specialized noninvasive brain cap were able to move a robotic arm just by imagining moving their own arms.

  7. Chaotic evolution of arms races

    Science.gov (United States)

    Tomochi, Masaki; Kono, Mitsuo

    1998-12-01

    A new set of model equations is proposed to describe the evolution of the arms race, by extending Richardson's model with special emphases that (1) power dependent defensive reaction or historical enmity could be a motive force to promote armaments, (2) a deterrent would suppress the growth of armaments, and (3) the defense reaction of one nation against the other nation depends nonlinearly on the difference in armaments between two. The set of equations is numerically solved to exhibit stationary, periodic, and chaotic behavior depending on the combinations of parameters involved. The chaotic evolution is realized when the economic situation of each country involved in the arms race is quite different, which is often observed in the real world.

  8. Regenerator cross arm seal assembly

    Science.gov (United States)

    Jackman, Anthony V.

    1988-01-01

    A seal assembly for disposition between a cross arm on a gas turbine engine block and a regenerator disc, the seal assembly including a platform coextensive with the cross arm, a seal and wear layer sealingly and slidingly engaging the regenerator disc, a porous and compliant support layer between the platform and the seal and wear layer porous enough to permit flow of cooling air therethrough and compliant to accommodate relative thermal growth and distortion, a dike between the seal and wear layer and the platform for preventing cross flow through the support layer between engine exhaust and pressurized air passages, and air diversion passages for directing unregenerated pressurized air through the support layer to cool the seal and wear layer and then back into the flow of regenerated pressurized air.

  9. Dual arm master controller concept

    International Nuclear Information System (INIS)

    Kuban, D.P.; Perkins, G.S.

    1984-01-01

    The Advanced Servomanipulator (ASM) slave was designed with an anthropomorphic stance, gear/torque tube power drives, and modular construction. These features resulted in increased inertia, friction, and backlash relative to tape-driven manipulators. Studies were performed which addressed the human factors design and performance trade-offs associated with the corresponding master controller best suited for the ASM. The results of these studies, as well as the conceptual design of the dual arm master controller, are presented. 6 references, 3 figures

  10. Dual arm master controller development

    Science.gov (United States)

    Kuban, D. P.; Perkins, G. S.

    1985-01-01

    The advanced servomanipulator (ASM) slave was designed with an anthropomorphic stance gear/torque tube power drives, and modular construction. These features resulted in increased inertia, friction, and backlash relative to tape driven manipulators. Studies were performed which addressed to human factor design and performance tradeoffs associated with the corresponding master controller best suited for the ASM. The results of these studies, as well as the conceptual design of the dual arm master controller, are presented.

  11. 21 CFR 890.3640 - Arm sling.

    Science.gov (United States)

    2010-04-01

    ... arm sling is a device intended for medical purposes to immobilize the arm, by means of a fabric band... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Arm sling. 890.3640 Section 890.3640 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES...

  12. Limited consensus around ARM information protection practices ...

    African Journals Online (AJOL)

    An existing enterprise IP SoP was adapted to ARM through literature analysis and produced a draft ARM SoP. The draft ARM SoP was applied in a rote fashion to a small sample of government-operated archives to identify likely areas of consensus and lack of consensus surrounding the various elements of the SoP.

  13. The MVACS Robotic Arm Camera

    Science.gov (United States)

    Keller, H. U.; Hartwig, H.; Kramm, R.; Koschny, D.; Markiewicz, W. J.; Thomas, N.; Fernades, M.; Smith, P. H.; Reynolds, R.; Lemmon, M. T.; Weinberg, J.; Marcialis, R.; Tanner, R.; Boss, B. J.; Oquest, C.; Paige, D. A.

    2001-08-01

    The Robotic Arm Camera (RAC) is one of the key instruments newly developed for the Mars Volatiles and Climate Surveyor payload of the Mars Polar Lander. This lightweight instrument employs a front lens with variable focus range and takes images at distances from 11 mm (image scale 1:1) to infinity. Color images with a resolution of better than 50 μm can be obtained to characterize the Martian soil. Spectral information of nearby objects is retrieved through illumination with blue, green, and red lamp sets. The design and performance of the camera are described in relation to the science objectives and operation. The RAC uses the same CCD detector array as the Surface Stereo Imager and shares the readout electronics with this camera. The RAC is mounted at the wrist of the Robotic Arm and can characterize the contents of the scoop, the samples of soil fed to the Thermal Evolved Gas Analyzer, the Martian surface in the vicinity of the lander, and the interior of trenches dug out by the Robotic Arm. It can also be used to take panoramic images and to retrieve stereo information with an effective baseline surpassing that of the Surface Stereo Imager by about a factor of 3.

  14. Performance of arm locking in LISA

    International Nuclear Information System (INIS)

    McKenzie, Kirk; Spero, Robert E.; Shaddock, Daniel A.

    2009-01-01

    For the Laser Interferometer Space Antenna (LISA) to reach its design sensitivity, the coupling of the free-running laser frequency noise to the signal readout must be reduced by more than 14 orders of magnitude. One technique employed to reduce the laser frequency noise will be arm locking, where the laser frequency is locked to the LISA arm length. In this paper we detail an implementation of arm locking. We investigate orbital effects (changing arm lengths and Doppler frequencies), the impact of errors in the Doppler knowledge that can cause pulling of the laser frequency, and the noise limit of arm locking. Laser frequency pulling is examined in two regimes: at lock acquisition and in steady state. The noise performance of arm locking is calculated with the inclusion of the dominant expected noise sources: ultrastable oscillator (clock) noise, spacecraft motion, and shot noise. We find that clock noise and spacecraft motion limit the performance of dual arm locking in the LISA science band. Studying these issues reveals that although dual arm locking [A. Sutton and D. A. Shaddock, Phys. Rev. D 78, 082001 (2008)] has advantages over single (or common) arm locking in terms of allowing high gain, it has disadvantages in both laser frequency pulling and noise performance. We address this by proposing a modification to the dual arm-locking sensor, a hybrid of common and dual arm-locking sensors. This modified dual arm-locking sensor has the laser frequency pulling characteristics and low-frequency noise coupling of common arm locking, but retains the control system advantages of dual arm locking. We present a detailed design of an arm-locking controller and perform an analysis of the expected performance when used with and without laser prestabilization. We observe that the sensor phase changes beneficially near unity-gain frequencies of the arm-locking controller, allowing a factor of 10 more gain than previously believed, without degrading stability. With a time

  15. 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

  16. 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.

  17. High precision detector robot arm system

    Science.gov (United States)

    Shu, Deming; Chu, Yong

    2017-01-31

    A method and high precision robot arm system are provided, for example, for X-ray nanodiffraction with an X-ray nanoprobe. The robot arm system includes duo-vertical-stages and a kinematic linkage system. A two-dimensional (2D) vertical plane ultra-precision robot arm supporting an X-ray detector provides positioning and manipulating of the X-ray detector. A vertical support for the 2D vertical plane robot arm includes spaced apart rails respectively engaging a first bearing structure and a second bearing structure carried by the 2D vertical plane robot arm.

  18. To Arm or Not to Arm: The Case Against Arming Vietnam and the Philippines

    Science.gov (United States)

    2015-04-13

    designed to allay 9 Leaf (accessed Oct 24, 2014). 10 Ankit Panda , “What to Expect if the U.S. Lifts...their animated populations. Despite the rhetoric, no ideology or nation is monolithic, thus opportunities exist to improve the U.S.-Sino...Joint Forces Quarterly 2 (2014): 76-80. Panda , Ankit. “What to Expect if the U.S. Lifts Its Vietnam Arms Embargo.” The Diplomat. September 29

  19. The Asteroid Redirect Mission (ARM)

    Science.gov (United States)

    Abell, Paul; Gates, Michele; Johnson, Lindley; Chodas, Paul; Mazanek, Dan; Reeves, David; Ticker, Ronald

    2016-07-01

    To achieve its long-term goal of sending humans to Mars, the National Aeronautics and Space Administration (NASA) plans to proceed in a series of incrementally more complex human spaceflight missions. Today, human flight experience extends only to Low-Earth Orbit (LEO), and should problems arise during a mission, the crew can return to Earth in a matter of minutes to hours. The next logical step for human spaceflight is to gain flight experience in the vicinity of the Moon. These cis-lunar missions provide a "proving ground" for the testing of systems and operations while still accommodating an emergency return path to the Earth that would last only several days. Cis-lunar mission experience will be essential for more ambitious human missions beyond the Earth-Moon system, which will require weeks, months, or even years of transit time. In addition, NASA has been given a Grand Challenge to find all asteroid threats to human populations and know what to do about them. Obtaining knowledge of asteroid physical properties combined with performing technology demonstrations for planetary defense provide much needed information to address the issue of future asteroid impacts on Earth. Hence the combined objectives of human exploration and planetary defense give a rationale for the Asteroid Re-direct Mission (ARM). Mission Description: NASA's ARM consists of two mission segments: 1) the Asteroid Redirect Robotic Mission (ARRM), the first robotic mission to visit a large (greater than ~100 m diameter) near-Earth asteroid (NEA), collect a multi-ton boulder from its surface along with regolith samples, demonstrate a planetary defense technique, and return the asteroidal material to a stable orbit around the Moon; and 2) the Asteroid Redirect Crewed Mission (ARCM), in which astronauts will take the Orion capsule to rendezvous and dock with the robotic vehicle, conduct multiple extravehicular activities to explore the boulder, and return to Earth with samples. NASA's proposed

  20. Dual arm master controller development

    International Nuclear Information System (INIS)

    Kuban, D.P.; Perkins, G.S.

    1985-01-01

    The advanced servomanipulator (ASM) slave was designed with an anthropomorphic stance, gear/torque tube power drives, and modular construction. These features resulted in increased inertia, friction, and backlash relative to tape-driven manipulators. Studies were performed which addressed the human factors design and performance trade-offs associated with the corresponding master controller best suited for the ASM. The results of these studies, as well as the conceptual design of the dual arm master controller, are presented. This work was performed as part of the Consolidated Fuel Reprocessing Program at the Oak Ridge National Laboratory. 5 refs., 7 figs., 1 tab

  1. 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

  2. Arming shoes of the fifteenth century

    OpenAIRE

    Volken Marquita

    2017-01-01

    Military footwear for the fifteenth century includes arming shoes worn under sabatons. Written sources suggest arming shoes and footwear used for fighting were ordinary shoes adapted for the purpose. Archaeological footwear was examined for signs of such modifications. Medieval shoe technology is presented, showing the range of footwear and its uses and gait biomechanics. Based on experiences from re-enactors wearing armours, medieval shoe styles are discussed for appropriateness as arming sh...

  3. Star distribution in the Orion spiral arm

    International Nuclear Information System (INIS)

    Basharina, T.S.; Pavlovskaya, E.D.; Filippova, A.A.

    1985-01-01

    The structure of the Orion spiral arm is studied by numerical experiments, assuming that in each direction considered the star distribution along the line of sight is a combination of two Gaussian laws. The corresponding parameters are evaluated for four Milky Way fields; the bimodal laws now fit the observations by the chi 2 criterion. In the Orion arm the line-of-sight star densities follow asymmetric curves, steeper at the outer edge of the arm

  4. Arms races between and within species.

    Science.gov (United States)

    Dawkins, R; Krebs, J R

    1979-09-21

    An adaptation in one lineage (e.g. predators) may change the selection pressure on another lineage (e.g. prey), giving rise to a counter-adaptation. If this occurs reciprocally, an unstable runaway escalation or 'arms race' may result. We discuss various factors which might give one side an advantage in an arms race. For example, a lineage under strong selection may out-evolve a weakly selected one (' the life-dinner principle'). We then classify arms races in two independent ways. They may be symmetric or asymmetric, and they may be interspecific or intraspecific. Our example of an asymmetric interspecific arms race is that between brood parasites and their hosts. The arms race concept may help to reduce the mystery of why cuckoo hosts are so good at detecting cuckoo eggs, but so bad at detecting cuckoo nestlings. The evolutionary contest between queen and worker ants over relative parental investment is a good example of an intraspecific asymmetric arms race. Such cases raise special problems because the participants share the same gene pool. Interspecific symmetric arms races are unlikely to be important, because competitors tend to diverge rather than escalate competitive adaptations. Intraspecific symmetric arms races, exemplified by adaptations for male-male competition, may underlie Cope's Rule and even the extinction of lineages. Finally we consider ways in which arms races can end. One lineage may drive the other to extinction; one may reach an optimum, thereby preventing the other from doing so; a particularly interesting possibility, exemplified by flower-bee coevolution, is that both sides may reach a mutual local optimum; lastly, arms races may have no stable and but may cycle continuously. We do not wish necessarily to suggest that all, or even most, evolutionary change results from arms races, but we do suggest that the arms race concept may help to resolve three long-standing questions in evolutionary theory.

  5. Preventing Interstate Armed Conflict : whose responsibility?

    OpenAIRE

    Otunba, Ganiyu

    2010-01-01

    This is a study of interstate armed conflict prevention. The concept of conflict, armed conflict and conflict prevention is defined and explained in order to be able to investigate if there is any single institution saddled with the responsibility of preventing interstate armed conflict and also to verify if adequate efforts are been put in this area which is of importance to mankind. The relationship between conflict prevention, conflict management and conflict resolution is also discussed s...

  6. Atmospheric Radiation Measurement Climate Research (ARM)

    Data.gov (United States)

    Federal Laboratory Consortium — With heavily instrumented field sites around the globe, the ARM Climate Research Facility provides the world's most comprehensive outdoor laboratory and data archive...

  7. ICRESH-ARMS 2015 Conference

    CERN Document Server

    Ahmadi, Alireza; Verma, Ajit; Varde, Prabhakar

    2016-01-01

    Containing selected papers from the ICRESH-ARMS 2015 conference in Lulea, Sweden, collected by editors with years of experiences in Reliability and maintenance modeling, risk assessment, and asset management, this work maximizes reader insights into the current trends in Reliability, Availability, Maintainability and Safety (RAMS) and Risk Management. Featuring a comprehensive analysis of the significance of the role of RAMS and Risk Management in the decision making process during the various phases of design, operation, maintenance, asset management and productivity in Industrial domains, these proceedings discuss key issues and challenges in the operation, maintenance and risk management of complex engineering systems and will serve as a valuable resource for those in the field.

  8. 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

  9. 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

  10. Sensory-Feedback Exoskeletal Arm Controller

    Science.gov (United States)

    An, Bin; Massie, Thomas H.; Vayner, Vladimir

    2004-01-01

    An electromechanical exoskeletal arm apparatus has been designed for use in controlling a remote robotic manipulator arm. The apparatus, called a force-feedback exoskeleton arm master (F-EAM) is comfortable to wear and easy to don and doff. It provides control signals from the wearer s arm to a robot arm or a computer simulator (e.g., a virtual-reality system); it also provides force and torque feedback from sensors on the robot arm or from the computer simulator to the wearer s arm. The F-EAM enables the wearer to make the robot arm gently touch objects and finely manipulate them without exerting excessive forces. The F-EAM features a lightweight design in which the motors and gear heads that generate force and torque feedback are made smaller than they ordinarily would be: this is achieved by driving the motors to power levels greater than would ordinarily be used in order to obtain higher torques, and by providing active liquid cooling of the motors to prevent overheating at the high drive levels. The F-EAM (see figure) includes an assembly that resembles a backpack and is worn like a backpack, plus an exoskeletal arm mechanism. The FEAM has five degrees of freedom (DOFs) that correspond to those of the human arm: 1. The first DOF is that of the side-to-side rotation of the upper arm about the shoulder (rotation about axis 1). The reflected torque for this DOF is provided by motor 1 via drum 1 and a planar four-bar linkage. 2. The second DOF is that of the up-and-down rotation of the arm about the shoulder. The reflected torque for this DOF is provided by motor 2 via drum 2. 3. The third DOF is that of twisting of the upper arm about its longitudinal axis. This DOF is implemented in a cable remote-center mechanism (CRCM). The reflected torque for this DOF is provided by motor 3, which drives the upper-arm cuff and the mechanism below it. A bladder inflatable by gas or liquid is placed between the cuff and the wearer s upper arm to compensate for misalignment

  11. Stress analysis for robot arm version 2

    International Nuclear Information System (INIS)

    Anwar Abdul Rahman; Fikri, A.; Salleh, M. S.; Mohd Arif Hamzah; Azraf Azman; Rosli Darmawan; Mohd Rizal Mamat

    2010-01-01

    The design of a robot needs to be analyzed to ensure the specification and requirement by the user is full filled. Therefore, stress analysis has been performed on the robot arm version 2 after its complete fabrication. This paper discusses the result of the analysis and proposed measures to improve the future design of robot arm. (author)

  12. Homosexuality in the Dutch Armed Forces 2006

    NARCIS (Netherlands)

    Anna Adolfsen; Saskia Keuzenkamp; m.m.v. Linda Mans

    2006-01-01

    Original title: Uniform uit de kast. This study looks at the attitudes of defence personnel to homosexuality. How do members of the military view homosexual colleagues? Can gays and lesbians working in the armed forces be open about their sexual preferences? Do they regard the armed forces as

  13. Design of a biomimetic robotic octopus arm.

    Science.gov (United States)

    Laschi, C; Mazzolai, B; Mattoli, V; Cianchetti, M; Dario, P

    2009-03-01

    This paper reports the rationale and design of a robotic arm, as inspired by an octopus arm. The octopus arm shows peculiar features, such as the ability to bend in all directions, to produce fast elongations, and to vary its stiffness. The octopus achieves these unique motor skills, thanks to its peculiar muscular structure, named muscular hydrostat. Different muscles arranged on orthogonal planes generate an antagonistic action on each other in the muscular hydrostat, which does not change its volume during muscle contractions, and allow bending and elongation of the arm and stiffness variation. By drawing inspiration from natural skills of octopus, and by analysing the geometry and mechanics of the muscular structure of its arm, we propose the design of a robot arm consisting of an artificial muscular hydrostat structure, which is completely soft and compliant, but also able to stiffen. In this paper, we discuss the design criteria of the robotic arm and how this design and the special arrangement of its muscular structure may bring the building of a robotic arm into being, by showing the results obtained by mathematical models and prototypical mock-ups.

  14. TOWARDS UNIFORM RULES FOR ARMED CONFLICTS Pieter ...

    African Journals Online (AJOL)

    the two Additional Protocols that followed in 1977, divide armed conflict into two legal categories: ... Wounded, Sick and Shipwrecked Members of Armed Forces at Sea. Third Convention ... Nationalist China; ibid 116. ... 17 Pictet op cit 43; Junod, S 'Additional Protocol II: History and Scope' (1983) 33 The. American ...

  15. Design of a biomimetic robotic octopus arm

    Energy Technology Data Exchange (ETDEWEB)

    Laschi, C; Cianchetti, M [Advanced Robotics Technology and Systems Laboratory, Scuola Superiore Sant' Anna, Pisa (Italy); Mazzolai, B; Dario, P [Italian Institute of Technology, Genova (Italy); Mattoli, V [Centre of Research in Microengineering Laboratory, Scuola Superiore Sant' Anna, Pisa (Italy)], E-mail: cecilia.laschi@sssup.it

    2009-03-01

    This paper reports the rationale and design of a robotic arm, as inspired by an octopus arm. The octopus arm shows peculiar features, such as the ability to bend in all directions, to produce fast elongations, and to vary its stiffness. The octopus achieves these unique motor skills, thanks to its peculiar muscular structure, named muscular hydrostat. Different muscles arranged on orthogonal planes generate an antagonistic action on each other in the muscular hydrostat, which does not change its volume during muscle contractions, and allow bending and elongation of the arm and stiffness variation. By drawing inspiration from natural skills of octopus, and by analysing the geometry and mechanics of the muscular structure of its arm, we propose the design of a robot arm consisting of an artificial muscular hydrostat structure, which is completely soft and compliant, but also able to stiffen. In this paper, we discuss the design criteria of the robotic arm and how this design and the special arrangement of its muscular structure may bring the building of a robotic arm into being, by showing the results obtained by mathematical models and prototypical mock-ups.

  16. Simple model of the arms race

    International Nuclear Information System (INIS)

    Zane, L.I.

    1982-01-01

    A simple model of a two-party arms race is developed based on the principle that the race will continue so long as either side can unleash an effective first strike against the other side. The model is used to examine how secrecy, the ABM, MIRV-ing, and an MX system affect the arms race

  17. Design of a biomimetic robotic octopus arm

    International Nuclear Information System (INIS)

    Laschi, C; Cianchetti, M; Mazzolai, B; Dario, P; Mattoli, V

    2009-01-01

    This paper reports the rationale and design of a robotic arm, as inspired by an octopus arm. The octopus arm shows peculiar features, such as the ability to bend in all directions, to produce fast elongations, and to vary its stiffness. The octopus achieves these unique motor skills, thanks to its peculiar muscular structure, named muscular hydrostat. Different muscles arranged on orthogonal planes generate an antagonistic action on each other in the muscular hydrostat, which does not change its volume during muscle contractions, and allow bending and elongation of the arm and stiffness variation. By drawing inspiration from natural skills of octopus, and by analysing the geometry and mechanics of the muscular structure of its arm, we propose the design of a robot arm consisting of an artificial muscular hydrostat structure, which is completely soft and compliant, but also able to stiffen. In this paper, we discuss the design criteria of the robotic arm and how this design and the special arrangement of its muscular structure may bring the building of a robotic arm into being, by showing the results obtained by mathematical models and prototypical mock-ups

  18. Arm locking with Doppler estimation errors

    Energy Technology Data Exchange (ETDEWEB)

    Yu Yinan; Wand, Vinzenz; Mitryk, Shawn; Mueller, Guido, E-mail: yinan@phys.ufl.ed [Department of Physics, University of Florida, Gainesville, FL 32611 (United States)

    2010-05-01

    At the University of Florida we developed the University of Florida LISA Interferometer Simulator (UFLIS) in order to study LISA interferometry with hardware in the loop at a system level. One of the proposed laser frequency stabilization techniques in LISA is arm locking. Arm locking uses an adequately filtered linear combination of the LISA arm signals as a frequency reference. We will report about experiments in which we demonstrated arm locking using UFLIS. During these experiments we also discovered a problem associated with the Doppler shift of the return beam. The initial arm locking publications assumed that this Doppler shift can perfectly be subtracted inside the phasemeter or adds an insignificant offset to the sensor signal. However, the remaining Doppler knowledge error will cause a constant change in the laser frequency if unaccounted for. Several ways to circumvent this problem have been identified. We performed detailed simulations and started preliminary experiments to verify the performance of the proposed new controller designs.

  19. Picking Robot Arm Trajectory Planning Method

    Directory of Open Access Journals (Sweden)

    Zhang Zhiyong

    2014-01-01

    Full Text Available The picking robot arm is scheduled to complete picking tasks in the working space, to overcome the shaking vibration to improve the picking stability, its movement should follow specific consistence trajectory points. Usually we should give definite multiple feature picking points, map their inverse kinematics to the joint space, establish motion equation for the corresponding point in the joint space, then follow these equations motion for the interpolation on the joint so that we can meet the movement requirements. Trajectory planning is decisive significance for accuracy and stability of controlling robot arm. The key issue that picking arm complete picking task will be come true by trajectory planning, namely, robot arm track the desired trajectory. which based on kinematics and statics picking analysis in a joint space according to the requirements of picking tasks, and obtain the position and orientation for picking robot arm, study and calculate the theory of trajectory parameters timely.

  20. Rolling motions in an inner spiral arm

    International Nuclear Information System (INIS)

    Strauss, F.M.; Poeppel, W.

    1976-01-01

    Hydrogen line observations made at low galactic latitudes for l=318degree, 326degree, 334degree, and 337degree show the presence of velocity gradients in latitude in the nearest inner spiral arm, similar to those found by other observations in different regions. Maximum velocity change is about 10 km s -1 for l=337degree. By generating synthetic line profiles constructed from a model spiral arm, several possible causes of these ''rolling motions'' were studied, such as a vertical displacement or a tilt of the arm (which failed to account for the observations) and rotation or shearing in the arm. It was futher shown that a typical arm can maintain such a motion (approx. =75 km s -1 kpc -1 ) with its own gravitational potential. The results are used to study the origin and tilt of Gould's Belt

  1. Youth Armed Groups in Colombia

    Directory of Open Access Journals (Sweden)

    Linda Dale

    2014-09-01

    Full Text Available For the many years of Colombia’s civil war, youth have been trying to find their way in complicated and dangerous situations. A central component of this is their relationship with armed groups, something that has evolved considerably over the past ten years. This practice note examines the context within which these connections are formed and the implications this has for self/social identity and meaningful resistance. The ideas in this practice note are based on consultations with young Colombians, particularly those displaced from 2000-2013. These sessions included art activities, focus groups and individual interviews. Art activities involved descriptive and expressive projects so that participants could explore their feelings and memories of situations and experiences. This provided a base for group discussions where youth exchanged information and debated issues. A total of 34 workshops were held over a twelve year period. These consultations revealed how war flows all over young people, touching every aspect of their identity. The boundaries between the personal and political no longer exist in today’s civil wars, if indeed they every truly did. Young people growing up inside Colombia’s war understand this at a deep level. An acknowledgement of this pain – showing the connections between the personal and political dimensions of war – is, they would maintain, the basis for their personal healing as well as an important tool for the building of sustainable peace.

  2. CyARM: Haptic Sensing Device for Spatial Localization on Basis of Exploration by Arms

    Directory of Open Access Journals (Sweden)

    Junichi Akita

    2009-01-01

    Full Text Available We introduce a new type of perception aid device based on user's exploration action, which is named as CyARM (acronym of “Cyber Arm”. The user holds this device in her/his arm, the extension of the arm is controlled by tension in wires, which are attached to her/his body according to the distance to the object. This user interface has unique characteristics that give users the illusion of an imaginary arm that extends to existing objects. The implementations of CyARM and our two experiments to investigate the efficiency and effectiveness of CyARM are described. The results show that we could confirm that CyARM can be used to recognize the presence of an object in front of the user and to measure the relative distance to the object.

  3. 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.

  4. 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.

  5. Rosoboroneksport: Arms Sales and the Structure of Russian Defense Industry

    National Research Council Canada - National Science Library

    Blank, Stephen J

    2007-01-01

    In August 2006, the U.S. Government imposed sanctions on Russian arms sellers and producers, Rosoboroneksport, Russia's main arms-selling agency, and Sukhoi, which manufactures aircraft, because of their arms sales to Iran...

  6. ARM Climate Research Facility Annual Report 2005

    Energy Technology Data Exchange (ETDEWEB)

    J. Voyles

    2005-12-31

    Through the ARM Program, the DOE funded the development of several highly instrumented ground stations for studying cloud formation processes and their influence on radiative transfer, and for measuring other parameters that determine the radiative properties of the atmosphere. This scientific infrastructure, and resultant data archive, is a valuable national and international asset for advancing scientific knowledge of Earth systems. In fiscal year (FY) 2003, the DOE designated ARM sites as a national scientific user facility: the ARM Climate Research (ACRF). The ACRF has enormous potential to contribute to a wide range interdisciplinary science in areas such as meteorology, atmospheric aerosols, hydrology, biogeochemical cycling, and satellite validation, to name only a few.

  7. Arming shoes of the fifteenth century

    Directory of Open Access Journals (Sweden)

    Volken Marquita

    2017-12-01

    Full Text Available Military footwear for the fifteenth century includes arming shoes worn under sabatons. Written sources suggest arming shoes and footwear used for fighting were ordinary shoes adapted for the purpose. Archaeological footwear was examined for signs of such modifications. Medieval shoe technology is presented, showing the range of footwear and its uses and gait biomechanics. Based on experiences from re-enactors wearing armours, medieval shoe styles are discussed for appropriateness as arming shoes. The question of why medieval military footwear shows no purposed development is addressed.

  8. ARM Unmanned Aerial Systems Implementation Plan

    Energy Technology Data Exchange (ETDEWEB)

    Schmid, Beat [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Ivey, Mark [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2016-11-01

    Recent advances in Unmanned Aerial Systems (UAS) coupled with changes in the regulatory environment for operations of UAS in the National Airspace increase the potential value of UAS to the U.S. Department of Energy (DOE) Atmospheric Radiation Measurement (ARM) Climate Research Facility. UAS include unmanned aerial vehicles (UAV) and tethered balloon systems (TBS). The roles UAVs and TBSs could play within the ARM Facility, particularly science questions they could help address, have been discussed in several workshops, reports, and vision documents, including: This document describes the implementation of a robust and vigorous program for use of UAV and TBS for the science missions ARM supports.

  9. Passive detection of nuclear-armed SLCMs

    International Nuclear Information System (INIS)

    Sagdeev, R.Z.; Prilutsky, O.F.; Frolov, V.A.

    1992-01-01

    Effective procedures have been developed, using national technical measures (photoreconnaissance satellites, radiointercept stations, etc.), for verification of reductions in land-based intercontinental ballistic missiles, such as marine-based ballistic missiles, and strategic bombers. However, there is agreement on procedures for verifying limitations of numbers of long-range nuclear-armed cruise missiles. The difficulties in developing such procedures are sometimes regarded (by opponents of nuclear disarmament) as a reason why cruise missiles based on ships and submarines ought not to be limited by future arms-reduction treaties. This paper considers the detectability of nuclear-armed cruise missiles through the penetrating radiation emitted spontaneously from their warheads

  10. Arms control, nonproliferation, and US national security

    International Nuclear Information System (INIS)

    Pilat, J.F.

    1985-01-01

    The continuation of the arms race and the failure of arms control and disarmament negotiations lend support to the belief that US and Soviet power, prestige, and security depend upon nuclear weapons. Therefore, the argument goes, the non-nuclear-weapon states (particularly those that are not allied with nuclear-weapon states and do not share their nuclear shield) may conclude that they would be well served by possession of these weapons. In this sense, the failure of nuclear arms reductions could create incentives for further proliferation

  11. 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.

  12. Isolated effects of peripheral arm and central body cooling on arm performance.

    Science.gov (United States)

    Giesbrecht, G G; Wu, M P; White, M D; Johnston, C E; Bristow, G K

    1995-10-01

    Whole body cooling impairs manual arm performance. The independent contributions of local (peripheral) and/or whole body (central) cooling are not known. Therefore, a protocol was developed in which the arm and the rest of the body could be independently cooled. Biceps temperature (Tmus), at a depth of 20 mm, and esophageal temperature (Tes) were measured. Six subjects were immersed to the clavicles in a tank (body tank) of water under 3 conditions: 1) cold body-cold arm (CB-CA); 2) warm body-cold arm (WB-CA); and 3) cold body-warm arm (CB-WA). In the latter two conditions, subjects placed their dominant arm in a separate (arm) tank. Water temperature (Tw) in each tank was independently controlled. In conditions requiring cold body and/or cold arm, Tw in the appropriate tanks was 8 degrees C. In conditions requiring warm body and/or warm arm, Tw in the appropriate tanks was adjusted between 29 and 38 degrees C to maintain body/arm temperature at baseline values. A battery of 6 tests, requiring fine or gross motor movements, were performed immediately before immersion and after 15, 45, and 70 minutes of immersion. In CB-CA, Tes decreased from an average of 37.2 to 35.6 degrees C and Tmus decreased from 34.6 to 22.0 degrees C. In WB-CA, Tmus decreased to 18.1 degrees C (Tes = 37.1 degrees C), and in CB-WA, Tes decreased to 35.8 degrees C (Tmus = 34.5 degrees C). By the end of immersion, there were significant decrements (43-85%) in the performance of all tests in CB-CA and WB-CA (p body and/or the arm elicits large decrements in finger, hand and arm performance. The decrements are due almost entirely to the local effects of arm tissue cooling.

  13. Standing "the Watches" with Armed UAVs

    National Research Council Canada - National Science Library

    McCulloch, Francis

    2002-01-01

    This paper addresses the additional Options available to the operational commander in charge of conducting 'presence and monitoring' missions with the introduction of an armed capability on Unmanned Aerial Vehicles (UAVs...

  14. Science team participation in the ARM program

    International Nuclear Information System (INIS)

    Cess, R.D.

    1993-01-01

    This progress report discusses the Science Team participation in the Atmospheric Radiation Measurement (ARM) Program for the period of October 31, 1992 to November 1, 1993. This report summarized the research accomplishments of six papers

  15. U.S. Arms Sales to Pakistan

    National Research Council Canada - National Science Library

    Grimmett, Richard F

    2008-01-01

    This report briefly reviews the issue of U.S. arms sales to Pakistan. It provides background details regarding recent major weapons transactions between the United States and Pakistan, as well as the rationale given for such sales...

  16. U.S. Arms Sales to Pakistan

    National Research Council Canada - National Science Library

    Grimmett, Richard F

    2007-01-01

    This report briefly reviews the issue of U.S. arms sales to Pakistan. It provides background details regarding recent major weapons transactions between the United States and Pakistan, as well as the rationale given for such sales...

  17. Arming and firing system for DISTANT RUNNER

    International Nuclear Information System (INIS)

    Skenandore, L.H.; Johnson, J.P.

    1982-01-01

    Sandia A and F systems Division 1132 provided arming and firing support for the DISTANT RUNNER Test Program at White Sands Missile Range. This report describes the field support and the firing system that was used

  18. The Prototype Automated Research Management System (ARMS)

    National Research Council Canada - National Science Library

    Prekop, Paul

    2004-01-01

    Automated Research Management System (ARMS) is a knowledge management application designed to address many of the knowledge management problems identified by SmartWays and FASSP's Knowledge Management Review...

  19. Radiation Pattern of Chair Armed Microstrip Antenna

    Science.gov (United States)

    Mishra, Rabindra Kishore; Sahu, Kumar Satyabrat

    2016-12-01

    This work analyzes planar antenna conformable to chair arm shaped surfaces for WLAN application. Closed form expressions for its radiation pattern are developed and validated using measurements on prototype and commercial EM code at 2.4 GHz.

  20. Inverse kinematics of OWI-535 robotic arm

    OpenAIRE

    DEBENEC, PRIMOŽ

    2015-01-01

    The thesis aims to calculate the inverse kinematics for the OWI-535 robotic arm. The calculation of the inverse kinematics determines the joint parameters that provide the right pose of the end effector. The pose consists of the position and orientation, however, we will focus only on the second one. Due to arm limitations, we have created our own type of the calculation of the inverse kinematics. At first we have derived it only theoretically, and then we have transferred the derivation into...

  1. Animals and the law of armed conflict

    OpenAIRE

    Roscini, M.

    2017-01-01

    The main purposes of this article are to assess whether the existing rules of the law of armed conflict provide adequate protection to animals and to highlight the fault lines in the law. The article distinguishes the general provisions of the law of armed conflict, i.e. those that were not adopted with specific regard to animals but the application of which might restrict the killing and injuring of animals, from the provisions that specifically provide protection to animals. The analysis es...

  2. Hysteresis of targeting civilians in armed conflicts

    OpenAIRE

    Uih Ran Lee

    2015-01-01

    This article explores warring groups’ intentional targeting behavior against civilians, a strictly prohibited war strategy by international norms. Using dynamic panel regressions run on a comprehensive dataset of contemporary warfare which covers 22 years (1989-2010), I find that warring actors, both sovereign states and formally organized armed groups, behave systematically in terms of civilian targeting when they are involved in prolonged armed conflict (15-22 years). Warring actors’ lethal...

  3. Student measurement of blood pressure using a simulator arm compared with a live subject's arm.

    Science.gov (United States)

    Lee, Jennifer J; Sobieraj, Diana M; Kuti, Effie L

    2010-06-15

    To compare accuracy of blood pressure measurements using a live subject and a simulator arm, and to determine students' preferences regarding measurement. This was a crossover study comparing blood pressure measurements from a live subject and a simulator arm. Students completed an anonymous survey instrument defining opinions on ease of measurement. Fifty-seven students completed blood pressure measurements on live subjects while 72 students completed blood pressure measurements using the simulator arm. There were no significant systematic differences between the 2 measurement techniques. Systolic blood pressure measurements from a live subject arm were less likely to be within 4 mm Hg compared with measurements of a simulator arm. Diastolic blood pressure measurements were not significantly different between the 2 techniques. Accuracy of student measurement of blood pressure using a simulator arm was similar to the accuracy with a live subject. There was no difference in students' preferences regarding measurement techniques.

  4. ARM assembly language with hardware experiments

    CERN Document Server

    Elahi, Ata

    2015-01-01

    This book provides a hands-on approach to learning ARM assembly language with the use of a TI microcontroller. The book starts with an introduction to computer architecture and then discusses number systems and digital logic. The text covers ARM Assembly Language, ARM Cortex Architecture and its components, and Hardware Experiments using TILM3S1968. Written for those interested in learning embedded programming using an ARM Microcontroller. ·         Introduces number systems and signal transmission methods   ·         Reviews logic gates, registers, multiplexers, decoders and memory   ·         Provides an overview and examples of ARM instruction set   ·         Uses using Keil development tools for writing and debugging ARM assembly language Programs   ·         Hardware experiments using a Mbed NXP LPC1768 microcontroller; including General Purpose Input/Output (GPIO) configuration, real time clock configuration, binary input to 7-segment display, creating ...

  5. The spiral arms of the Milky Way: The relative location of each different arm tracer within a typical spiral arm width

    International Nuclear Information System (INIS)

    Vallée, Jacques P.

    2014-01-01

    From the Sun's location in the Galactic disk, different arm tracers (CO, H I, hot dust, etc.) have been employed to locate a tangent to each spiral arm. Using all various and different observed spiral arm tracers (as published elsewhere), we embark on a new goal, namely the statistical analysis of these published data (data mining) to statistically compute the mean location of each spiral arm tracer. We show for a typical arm cross-cut, a separation of 400 pc between the mid-arm and the dust lane (at the inner edge of the arm, toward the Galactic center). Are some arms major and others minor? Separating arms into two sets, as suggested by some, we find the same arm widths between the two sets. Our interpretation is that we live in a multiple (four-arm) spiral (logarithmic) pattern (around a pitch angle of 12°) for the stars and gas in the Milky Way, with a sizable interarm separation (around 3 kpc) at the Sun's location and the same arm width for each arm (near 400 pc from mid-arm to dust lane).

  6. The spiral arms of the Milky Way: The relative location of each different arm tracer within a typical spiral arm width

    Energy Technology Data Exchange (ETDEWEB)

    Vallée, Jacques P., E-mail: jacques.vallee@nrc-cnrc.gc.ca [National Research Council Canada, National Science Infrastructure portfolio, Herzberg Astronomy and Astrophysics, 5071 West Saanich Road, Victoria, B.C., V9E 2E7 (Canada)

    2014-07-01

    From the Sun's location in the Galactic disk, different arm tracers (CO, H I, hot dust, etc.) have been employed to locate a tangent to each spiral arm. Using all various and different observed spiral arm tracers (as published elsewhere), we embark on a new goal, namely the statistical analysis of these published data (data mining) to statistically compute the mean location of each spiral arm tracer. We show for a typical arm cross-cut, a separation of 400 pc between the mid-arm and the dust lane (at the inner edge of the arm, toward the Galactic center). Are some arms major and others minor? Separating arms into two sets, as suggested by some, we find the same arm widths between the two sets. Our interpretation is that we live in a multiple (four-arm) spiral (logarithmic) pattern (around a pitch angle of 12°) for the stars and gas in the Milky Way, with a sizable interarm separation (around 3 kpc) at the Sun's location and the same arm width for each arm (near 400 pc from mid-arm to dust lane).

  7. Chimeric HCMV/HSV-1 and Δγ134.5 oncolytic herpes simplex virus elicit immune mediated antigliomal effect and antitumor memory

    Directory of Open Access Journals (Sweden)

    Mohammed G. Ghonime

    2018-02-01

    Full Text Available Malignant gliomas are the most common primary brain tumor and are characterized by rapid and highly invasive growth. Because of their poor prognosis, new therapeutic strategies are needed. Oncolytic virotherapy (OV is a promising strategy for treating cancer that incorporates both direct viral replication mediated and immune mediated mechanisms to kill tumor cells. C134 is a next generation Δγ134.5 oHSV-1 with improved intratumoral viral replication. It remains safe in the CNS environment by inducing early IFN signaling which restricts its replication in non-malignant cells. We sought to identify how C134 performed in an immunocompetent tumor model that restricts its replication advantage over first generation viruses. To achieve this we identified tumors that have intact IFN signaling responses that restrict C134 and first generation virus replication similarly. Our results show that both viruses elicit a T cell mediated anti-tumor effect and improved animal survival but that subtle difference exist between the viruses effect on median survival despite equivalent in vivo viral replication. To further investigate this we examined the anti-tumor activity in immunodeficient mice and in syngeneic models with re-challenge. These studies show that the T cell response is integral to C134 replication independent anti-tumor response and that OV therapy elicits a durable and circulating anti-tumor memory. The studies also show that repeated intratumoral administration can extend both OV anti-tumor effects and induce durable anti-tumor memory that is superior to tumor antigen exposure alone.

  8. Pediatric medulloblastoma xenografts including molecular subgroup 3 and CD133+ and CD15+ cells are sensitive to killing by oncolytic herpes simplex viruses.

    Science.gov (United States)

    Friedman, Gregory K; Moore, Blake P; Nan, Li; Kelly, Virginia M; Etminan, Tina; Langford, Catherine P; Xu, Hui; Han, Xiaosi; Markert, James M; Beierle, Elizabeth A; Gillespie, G Yancey

    2016-02-01

    Childhood medulloblastoma is associated with significant morbidity and mortality that is compounded by neurotoxicity for the developing brain caused by current therapies, including surgery, craniospinal radiation, and chemotherapy. Innate therapeutic resistance of some aggressive pediatric medulloblastoma has been attributed to a subpopulation of cells, termed cancer-initiating cells or cancer stemlike cells (CSCs), marked by the surface protein CD133 or CD15. Brain tumors characteristically contain areas of pathophysiologic hypoxia, which has been shown to drive the CSC phenotype leading to heightened invasiveness, angiogenesis, and metastasis. Novel therapies that target medulloblastoma CSCs are needed to improve outcomes and decrease toxicity. We hypothesized that oncolytic engineered herpes simplex virus (oHSV) therapy could effectively infect and kill pediatric medulloblastoma cells, including CSCs marked by CD133 or CD15. Using 4 human pediatric medulloblastoma xenografts, including 3 molecular subgroup 3 tumors, which portend worse patient outcomes, we determined the expression of CD133, CD15, and the primary HSV-1 entry molecule nectin-1 (CD111) by fluorescence activated cell sorting (FACS) analysis. Infectability and cytotoxicity of clinically relevant oHSVs (G207 and M002) were determined in vitro and in vivo by FACS, immunofluorescent staining, cytotoxicity assays, and murine survival studies. We demonstrate that hypoxia increased the CD133+ cell fraction, while having the opposite effect on CD15 expression. We established that all 4 xenografts, including the CSCs, expressed CD111 and were highly sensitive to killing by G207 or M002. Pediatric medulloblastoma, including Group 3 tumors, may be an excellent target for oHSV virotherapy, and a clinical trial in medulloblastoma is warranted. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. 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.

  10. ARM Airborne Carbon Measurements (ARM-ACME) and ARM-ACME 2.5 Final Campaign Reports

    Energy Technology Data Exchange (ETDEWEB)

    Biraud, S. C. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Tom, M. S. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Sweeney, C. [NOAA Earth Systems Research Lab., Boulder, CO (United States)

    2016-01-01

    We report on a 5-year multi-institution and multi-agency airborne study of atmospheric composition and carbon cycling at the Atmospheric Radiation Measurement (ARM) Climate Research Facility’s Southern Great Plains (SGP) site, with scientific objectives that are central to the carbon-cycle and radiative-forcing goals of the U.S. Global Change Research Program and the North American Carbon Program (NACP). The goal of these measurements is to improve understanding of 1) the carbon exchange of the Atmospheric Radiation Measurement (ARM) SGP region; 2) how CO2 and associated water and energy fluxes influence radiative-forcing, convective processes, and CO2 concentrations over the ARM SGP region, and 3) how greenhouse gases are transported on continental scales.

  11. Ganciclovir uptake in human mammary carcinoma cells expressing herpes simplex virus thymidine kinase

    International Nuclear Information System (INIS)

    Haberkorn, Uwe; Khazaie, Khashayarsha; Morr, Iris; Altmann, Annette; Mueller, Markus; Kaick, Gerhard van

    1998-01-01

    Assessment of suicide enzyme activity would have considerable impact on the planning and the individualization of suicide gene therapy of malignant tumors. This may be done by determining the pharmacokinetics of specific substrates. We generated ganciclovir (GCV)-sensitive human mammary carcinoma cell lines after transfection with a retroviral vector bearing the herpes simplex virus thymidine kinase (HSV-tk) gene. Thereafter, uptake measurements and HPLC analyses were performed up to 48 h in an HSV-tk-expressing cell line and in a wild-type cell line using tritiated GCV. HSV-tk-expressing cells showed higher GCV uptake and phosphorylation than control cells, whereas in wild-type MCF7 cells no phosphorylated GCV was detected. In bystander experiments the total GCV uptake was related to the amount of HSV-tk-expressing cells. Furthermore, the uptake of GCV correlated closely with the growth inhibition (r=0.92). Therefore, the accumulation of specific substrates may serve as an indicator of the HSV-tk activity and of therapy outcome. Inhibition and competition experiments demonstrated slow transport of GCV by the nucleoside carriers. The slow uptake and low affinity to HSV-tk indicate that GCV is not an ideal substrate for the nucleoside transport systems or for HSV-tk. This may be the limiting factor for therapy success, necessitating the search for better substrates of HSV-tk

  12. Monitoring of herpes simplex virus thymidine kinase enzyme activity using positron emission tomography

    NARCIS (Netherlands)

    Hospers, GAP; Calogero, Anna; van Waarde, A; Doze, P; Vaalburg, W; Mulder, NH; de Vries, EFJ

    2000-01-01

    9-[(1-[F-18]Fluoro-3-hydroxy-2-propoxy)methyl]guanine ([F-18]FHPG) wasevaluated as a tracer for noninvasive positron emission tomography (PET) imaging of herpes simplex virus type 1 thymidine kinase (HSV-tk) gene expression. C6 rat glioma cells with and without the HSV-tk gene were incubated with

  13. Elimination of the truncated message from the herpes simplex virus thymidine kinase suicide gene

    NARCIS (Netherlands)

    Chalmers, D; Ferrand, C; Apperley, JF; Melo, JV; Ebeling, S; Newton, [No Value; Duperrier, A; Hagenbeek, A; Garrett, E; Tiberghien, P; Garin, M

    Introduction of the Herpes simplex virus thymidine kinase (HSV-tk) gene into target cells renders them susceptible to killing by ganciclovir (GCV). We are studying the use of HSV-tk-transduced T lymphocytes in the context of hematopoietic stem cell transplantation. We have previously shown, in vitro

  14. Organization of octopus arm movements: a model system for studying the control of flexible arms.

    Science.gov (United States)

    Gutfreund, Y; Flash, T; Yarom, Y; Fiorito, G; Segev, I; Hochner, B

    1996-11-15

    Octopus arm movements provide an extreme example of controlled movements of a flexible arm with virtually unlimited degrees of freedom. This study aims to identify general principles in the organization of these movements. Video records of the movements of Octopus vulgaris performing the task of reaching toward a target were studied. The octopus extends its arm toward the target by a wave-like propagation of a bend that travels from the base of the arm toward the tip. Similar bend propagation is seen in other octopus arm movements, such as locomotion and searching. The kinematics (position and velocity) of the midpoint of the bend in three-dimensional space were extracted using the direct linear transformation algorithm. This showed that the bend tends to move within a single linear plane in a simple, slightly curved path connecting the center of the animal's body with the target location. Approximately 70% of the reaching movements demonstrated a stereotyped tangential velocity profile. An invariant profile was observed when movements were normalized for velocity and distance. Two arms, extended together in the same behavioral context, demonstrated identical velocity profiles. The stereotyped features of the movements were also observed in spontaneous arm extensions (not toward an external target). The simple and stereotypic appearance of the bend trajectory suggests that the position of the bend in space and time is the controlled variable. We propose that this strategy reduces the immense redundancy of the octopus arm movements and hence simplifies motor control.

  15. Armed guards on vessels : insurance and liability

    Directory of Open Access Journals (Sweden)

    Mišo Mudrić

    2011-12-01

    Full Text Available The Paper examines the insurance and liability issues resulting from the use of armed guards on board vessels. The study begins with an overview of the available data on key economic fi gures representing the projected overall annual costs of modern piracy. The focus is then shifted to the issue of public versus private security, where possible dangers of private-based security options are discussed in general. After explaining why the Somalia region deserves a closer attention when compared to other pirate-infested waters, a brief summary of the international effort to combat piracy threat is presented, followed by a structured overview of the use of private maritime security options in the maritime sector in general. One security option is the use of armed guards on board vessels. This option is explored both from the political (the acceptance by stakeholders and legal standpoint (legal issues arising from the use of armed guards. An important remedy for the shipping companies/ operators threatened by the piracy hazard is the existence of affordable and effective (specialized marine insurance. A study of available piracy insurance policies is presented, followed by an analysis of case law and other legal issues arising from piracy attacks, which could prove important when considering the legal implications of armed guards employment. Finally, a simplifi ed economic analysis of available security options is presented, followed by the final assessment of benefi ts derived from the use of armed guards.

  16. Stellar complexes in spiral arms of galaxies

    Science.gov (United States)

    Efremov, Yu. N.

    The history of the introduction and development of the star complexes conception is briefly described. These large groups of stars were picked out and named as such ones in our Galaxy with argumentation and evidence for their physical unity (using the Cepheid variables the distances and ages of which are easy determined from their periods); anyway earlier the complexes were noted along the spiral arms of the Andromeda galaxy, but were not recognized as a new kind of star group. The chains of complexes along the spiral arms are observed quite rarely; their origin is explained by magneto- gravitational or purely gravitational instability developing along the arm. It is not clear why these chains are quite a rare phenomenon - and more so why sometimes the regular chain of complexes are observed in one arm only. Probably intergalactic magnetic field participated in formation of such chains. Apart from the complexes located along the arms, there are isolated giant complexes known (up to 700 pc in diameter) which look like super-gigantic but rather rarefied globular clusters. Until now only two of these formations are studied, in NGC 6946 and M51.

  17. ARM Airborne Carbon Measurements VI (ARM-ACME VI) Field Campaign Report

    Energy Technology Data Exchange (ETDEWEB)

    Biraud, Sebastien [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2017-05-01

    From October 1, 2015 through September 30, 2016, AAF deployed a Cessna 206 aircraft over the Southern Great Plains, collecting observations of trace gas mixing ratios over the ARM/SGP Central Facility. The aircraft payload included two Atmospheric Observing Systems (AOS Inc.) analyzers for continuous measurements of CO2, and a 12-flask sampler for analysis of carbon cycle gases (CO2, CO, CH4, N2O, 13CO2). The aircraft payload also includes solar/infrared radiation measurements. This research (supported by DOE ARM and TES programs) builds upon previous ARM-ACME missions. The goal of these measurements is to improve understanding of: (a) the carbon exchange of the ARM region; (b) how CO2 and associated water and energy fluxes influence radiative forcing, convective processes, and CO2 concentrations over the ARM region, and (c) how greenhouse gases are transported on continental scales.

  18. Fractures of the humerus during arm wrestling

    Directory of Open Access Journals (Sweden)

    Bumbaširević Marko Ž.

    2014-01-01

    Full Text Available Background/Aim. Humeral shaft fractures may occur as a result of arm wrestling. The aim of this study was to present our treatment of humerus fracture sustained during arm wrestling. Methods. A total of six patients, aged 22 to 48, were treated at our department form January 2008 to January 2010 with open reduction and internal fixation and with hanging arm casts. A review of all the relevant literature on the subject was also presented. Results. In all the cases, the fractures healed and function returned to normal. No patient had any neural or vascular compromise. Conclusion. Closed and operative treatments were equally successful in all reported cases. [Projekat Ministarstva nauke Republike Srbije, br. 175-095

  19. Spiral arms, comets and terrestrial catastrophism

    International Nuclear Information System (INIS)

    Clube, S.V.M.; Napier, W.M.

    1982-01-01

    A review is presented of an hypothesis of terrestrial catastrophism in which comets grow in molecular clouds and are captured by the Sun as it passes through the spiral arms of the Galaxy. Assuming that comets are a major supplier of the Earth-crossing (Appollo) asteroid population, the latter fluctuates correspondingly and leads to episodes of terrestrial bombardment. Changes in the rotational momentum of core and mantle, generated by impacts, lead to episodes of magnetic field reversal and tectonic activity, while surface phenomena lead to ice-ages and mass extinctions. An episodic geophysical history with an interstellar connection is thus implied. If comets in spiral arms are necessary intermediaries in the process of star formation, the theory also has implications relating to early solar system history and galactic chemistry. These aspects are briefly discussed with special reference to the nature of spiral arms. (author)

  20. Systems Approach to Arms Control Verification

    Energy Technology Data Exchange (ETDEWEB)

    Allen, K; Neimeyer, I; Listner, C; Stein, G; Chen, C; Dreicer, M

    2015-05-15

    Using the decades of experience of developing concepts and technologies for verifying bilateral and multilateral arms control agreements, a broad conceptual systems approach is being developed that takes into account varying levels of information and risk. The IAEA has already demonstrated the applicability of a systems approach by implementing safeguards at the State level, with acquisition path analysis as the key element. In order to test whether such an approach could also be implemented for arms control verification, an exercise was conducted in November 2014 at the JRC ITU Ispra. Based on the scenario of a hypothetical treaty between two model nuclear weapons states aimed at capping their nuclear arsenals at existing levels, the goal of this exercise was to explore how to use acquisition path analysis in an arms control context. Our contribution will present the scenario, objectives and results of this exercise, and attempt to define future workshops aimed at further developing verification measures that will deter or detect treaty violations.

  1. CHARACTERIZING SPIRAL ARM AND INTERARM STAR FORMATION

    Energy Technology Data Exchange (ETDEWEB)

    Kreckel, K.; Schinnerer, E.; Meidt, S. [Max Planck Institut für Astronomie, Königstuhl 17, D-69117 Heidelberg (Germany); Blanc, G. A. [Departamento de Astronomía, Universidad de Chile, Camino del Observatorio 1515, Las Condes, Santiago (Chile); Groves, B. [Research School of Astronomy and Astrophysics, Australian National University, Canberra, ACT 2611 (Australia); Adamo, A. [Department of Astronomy, The Oskar Klein Centre, Stockholm University, AlbaNova University Centre, SE-106 91 Stockholm (Sweden); Hughes, A., E-mail: kreckel@mpia.de [CNRS, IRAP, 9 Av. du Colonel Roche, BP 44346, F-31028 Toulouse cedex 4 (France)

    2016-08-20

    Interarm star formation contributes significantly to a galaxy’s star formation budget and provides an opportunity to study stellar birthplaces unperturbed by spiral arm dynamics. Using optical integral field spectroscopy of the nearby galaxy NGC 628 with VLT/MUSE, we construct H α maps including detailed corrections for dust extinction and stellar absorption to identify 391 H ii regions at 35 pc resolution over 12 kpc{sup 2}. Using tracers sensitive to the underlying gravitational potential, we associate H ii regions with either arm (271) or interarm (120) environments. Using our full spectral coverage of each region, we find that most physical properties (luminosity, size, metallicity, ionization parameter) of H ii regions are independent of environment. We calculate the fraction of H α luminosity due to the background of diffuse ionized gas (DIG) contaminating each H ii region, and find the DIG surface brightness to be higher within H ii regions than in the surroundings, and slightly higher within arm H ii regions. Use of the temperature-sensitive [S ii]/H α line ratio instead of the H α surface brightness to identify the boundaries of H ii regions does not change this result. Using the dust attenuation as a tracer of the gas, we find depletion times consistent with previous work (2 × 10{sup 9} yr) with no differences between the arm and interarm, but this is very sensitive to the DIG correction. Unlike molecular clouds, which can be dynamically affected by the galactic environment, we see fairly consistent properties of H ii regions in both arm and interarm environments. This suggests either a difference in star formation and feedback in arms or a decoupling of dense star-forming clumps from the more extended surrounding molecular gas.

  2. Gender Integration and the Swedish Armed Forces

    DEFF Research Database (Denmark)

    Gustafsson, Daniel Marcus Sunil

    This paper discusses different gender aspects of the Swedish Armed Forces with specific references to sexual harassment and prostitution. By using the concept of Hegemonic Masculinity, sexual harassment of the women in the Swedish Armed Forces is explained in terms of a need of the men within...... the organisation to reinforce the notion of women as inferior and subordinate to men, whereby the external hegemony is believed to be restored. Likewise, male Swedish peacekeepers’ demand for prostitution during international peacekeeping missions is explained in terms of a need to confirm manhood and as homo...

  3. Two-Armed, Mobile, Sensate Research Robot

    Science.gov (United States)

    Engelberger, J. F.; Roberts, W. Nelson; Ryan, David J.; Silverthorne, Andrew

    2004-01-01

    The Anthropomorphic Robotic Testbed (ART) is an experimental prototype of a partly anthropomorphic, humanoid-size, mobile robot. The basic ART design concept provides for a combination of two-armed coordination, tactility, stereoscopic vision, mobility with navigation and avoidance of obstacles, and natural-language communication, so that the ART could emulate humans in many activities. The ART could be developed into a variety of highly capable robotic assistants for general or specific applications. There is especially great potential for the development of ART-based robots as substitutes for live-in health-care aides for home-bound persons who are aged, infirm, or physically handicapped; these robots could greatly reduce the cost of home health care and extend the term of independent living. The ART is a fully autonomous and untethered system. It includes a mobile base on which is mounted an extensible torso topped by a head, shoulders, and two arms. All subsystems of the ART are powered by a rechargeable, removable battery pack. The mobile base is a differentially- driven, nonholonomic vehicle capable of a speed >1 m/s and can handle a payload >100 kg. The base can be controlled manually, in forward/backward and/or simultaneous rotational motion, by use of a joystick. Alternatively, the motion of the base can be controlled autonomously by an onboard navigational computer. By retraction or extension of the torso, the head height of the ART can be adjusted from 5 ft (1.5 m) to 6 1/2 ft (2 m), so that the arms can reach either the floor or high shelves, or some ceilings. The arms are symmetrical. Each arm (including the wrist) has a total of six rotary axes like those of the human shoulder, elbow, and wrist joints. The arms are actuated by electric motors in combination with brakes and gas-spring assists on the shoulder and elbow joints. The arms are operated under closed-loop digital control. A receptacle for an end effector is mounted on the tip of the wrist and

  4. MPL-net at ARM Sites

    Science.gov (United States)

    Spinhirne, J. D.; Welton, E. J.; Campbell, J. R.; Berkoff, T. A.; Starr, David OC. (Technical Monitor)

    2002-01-01

    The NASA MPL-net project goal is consistent data products of the vertical distribution of clouds and aerosol from globally distributed lidar observation sites. The four ARM micro pulse lidars are a basis of the network to consist of over twelve sites. The science objective is ground truth for global satellite retrievals and accurate vertical distribution information in combination with surface radiation measurements for aerosol and cloud models. The project involves improvement in instruments and data processing and cooperation with ARM and other partners.

  5. Neurobiology: motor control of flexible octopus arms.

    Science.gov (United States)

    Sumbre, Germán; Fiorito, Graziano; Flash, Tamar; Hochner, Binyamin

    2005-02-10

    Animals with rigid skeletons can rely on several mechanisms to simplify motor control--for example, they have skeletal joints that reduce the number of variables and degrees of freedom that need to be controlled. Here we show that when the octopus uses one of its long and highly flexible arms to transfer an object from one place to another, it employs a vertebrate-like strategy, temporarily reconfiguring its arm into a stiffened, articulated, quasi-jointed structure. This indicates that an articulated limb may provide an optimal solution for achieving precise, point-to-point movements.

  6. Arms Control, Disarmament, and Peace Newsletters.

    Science.gov (United States)

    Atkins, Stephen

    1986-01-01

    Considers the research value of four types of newsletters on arms control, disarmament, and peace: direct-action, informational, scholarly, and single-issue. An annotated list of 58 newsletters includes those considered most significant of their type and recommended for library collections. (EM)

  7. STRUCTURED MOLECULAR GAS REVEALS GALACTIC SPIRAL ARMS

    Energy Technology Data Exchange (ETDEWEB)

    Sawada, Tsuyoshi [Joint ALMA Office, Alonso de Cordova 3107, Vitacura, Santiago 763-0355 (Chile); Hasegawa, Tetsuo [NAOJ Chile Observatory, Joaquin Montero 3000 Oficina 702, Vitacura, Santiago 763-0409 (Chile); Koda, Jin, E-mail: sawada.tsuyoshi@nao.ac.jp [Department of Physics and Astronomy, Stony Brook University, Stony Brook, NY 11794-3800 (United States)

    2012-11-01

    We explore the development of structures in molecular gas in the Milky Way by applying the analysis of the brightness distribution function and the brightness distribution index (BDI) in the archival data from the Boston University-Five College Radio Astronomy Observatory {sup 13}CO J = 1-0 Galactic Ring Survey. The BDI measures the fractional contribution of spatially confined bright molecular emission over faint emission extended over large areas. This relative quantity is largely independent of the amount of molecular gas and of any conventional, pre-conceived structures, such as cores, clumps, or giant molecular clouds. The structured molecular gas traced by higher BDI is located continuously along the spiral arms in the Milky Way in the longitude-velocity diagram. This clearly indicates that molecular gas changes its structure as it flows through the spiral arms. Although the high-BDI gas generally coincides with H II regions, there is also some high-BDI gas with no/little signature of ongoing star formation. These results support a possible evolutionary sequence in which unstructured, diffuse gas transforms itself into a structured state on encountering the spiral arms, followed by star formation and an eventual return to the unstructured state after the spiral arm passage.

  8. Colleges Grapple with the "Behavioral Broken Arm"

    Science.gov (United States)

    Hoover, Eric

    2008-01-01

    After the fatal shootings at Virginia Tech last April, colleges went shopping for hardware. They bought sirens, mass-messaging systems, surveillance cameras, and door locks. Some colleges armed their police departments for the first time. Others added assault rifles to their arsenals. "Active shooter" drills happened everywhere. As administrators…

  9. Neurosurgical robotic arm drilling navigation system.

    Science.gov (United States)

    Lin, Chung-Chih; Lin, Hsin-Cheng; Lee, Wen-Yo; Lee, Shih-Tseng; Wu, Chieh-Tsai

    2017-09-01

    The aim of this work was to develop a neurosurgical robotic arm drilling navigation system that provides assistance throughout the complete bone drilling process. The system comprised neurosurgical robotic arm navigation combining robotic and surgical navigation, 3D medical imaging based surgical planning that could identify lesion location and plan the surgical path on 3D images, and automatic bone drilling control that would stop drilling when the bone was to be drilled-through. Three kinds of experiment were designed. The average positioning error deduced from 3D images of the robotic arm was 0.502 ± 0.069 mm. The correlation between automatically and manually planned paths was 0.975. The average distance error between automatically planned paths and risky zones was 0.279 ± 0.401 mm. The drilling auto-stopping algorithm had 0.00% unstopped cases (26.32% in control group 1) and 70.53% non-drilled-through cases (8.42% and 4.21% in control groups 1 and 2). The system may be useful for neurosurgical robotic arm drilling navigation. Copyright © 2016 John Wiley & Sons, Ltd.

  10. ATLAS software stack on ARM64

    CERN Document Server

    Smith, Joshua Wyatt; The ATLAS collaboration

    2016-01-01

    The ATLAS experiment explores new hardware and software platforms that, in the future, may be more suited to its data intensive workloads. One such alternative hardware platform is the ARM architecture, which is designed to be extremely power efficient and is found in most smartphones and tablets. CERN openlab recently installed a small cluster of ARM 64-bit evaluation prototype servers. Each server is based on a single-socket ARM 64-bit system on a chip, with 32 Cortex-A57 cores. In total, each server has 128 GB RAM connected with four fast memory channels. This paper reports on the port of the ATLAS software stack onto these new prototype ARM64 servers. This included building the "external" packages that the ATLAS software relies on. Patches were needed to introduce this new architecture into the build as well as patches that correct for platform specific code that caused failures on non-x86 architectures. These patches were applied such that porting to further platforms will need no or only very little adj...

  11. 49 CFR 236.702 - Arm, semaphore.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Arm, semaphore. 236.702 Section 236.702 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION..., semaphore. The part of a semaphore signal displaying an aspect. It consists of a blade fastened to a...

  12. 'Great power' intervention in African armed conflicts

    DEFF Research Database (Denmark)

    Olsen, Gorm Rye

    2015-01-01

    This paper asks why the United States (US), China and the European Union (EU) have intervened in a number of armed conflicts in Africa in the twenty-first century. Scrutiny and comparison of the motivations and interests of the three non-African actors in intervening in African crises are assumed...

  13. Endpoints of arm movements to visual targets

    NARCIS (Netherlands)

    van den Dobbelsteen, John; Brenner, Eli; Smeets, Jeroen B J

    2001-01-01

    Reaching out for objects with an unseen arm involves using both visual and kinesthetic information. Neither visual nor kinesthetic information is perfect. Each is subject to both constant and variable errors. To evaluate how such errors influence performance in natural goal-directed movements, we

  14. Light duty utility arm software requirements specification

    International Nuclear Information System (INIS)

    Kiebel, G.R.

    1995-01-01

    This document defines the software requirements for the integrated control and data acquisition system of the Light Duty Utility Arm (LDUA) System. It is intended to be used to guide the design of the application software, to be a basis for assessing the application software design, and to establish what is to be tested in the finished application software product

  15. Light Duty Utility Arm Software Test Plan

    International Nuclear Information System (INIS)

    Kiebel, G.R.

    1995-01-01

    This plan describes how validation testing of the software will be implemented for the integrated control and data acquisition system of the Light Duty Utility Arm System (LDUA). The purpose of LDUA software validation testing is to demonstrate and document that the LDUA software meets its software requirements specification

  16. Instructional Technology in the Armed Forces.

    Science.gov (United States)

    Hitchens, Howard B., Jr.

    Broad areas of communications media used in technical training in specific occupational skills within the armed forces are examined in the first part of this report. These areas include: traditional audiovisual media, television, the techniques of programed instruction and instructional systems development, and the use of computers. In the second…

  17. Light duty utility arm startup plan

    International Nuclear Information System (INIS)

    Barnes, G.A.

    1998-01-01

    This plan details the methods and procedures necessary to ensure a safe transition in the operation of the Light Duty Utility Arm (LDUA) System. The steps identified here outline the work scope and identify responsibilities to complete startup, and turnover of the LDUA to Characterization Project Operations (CPO)

  18. Parallelogram mechanisms for mine manipulator arms

    Energy Technology Data Exchange (ETDEWEB)

    Yoncheva, N

    1983-01-01

    Kinematic equations are written for the mechanism of a manipulator arm which is used as the operational element of a basic machine and is shaped like a parallelogram. The drive is accomplished using a hydraulic cylinder. A transfer functions method is used to acquire kinematic equations of the final shifts and equations for determining accelerations.

  19. The lure of disarmament and arms reduction

    International Nuclear Information System (INIS)

    Paris, H.

    2011-01-01

    Nuclear disarmament and arms reduction do not have the same aims. Confusing their definitions means misunderstanding the logic which currently drives the power calculations of yesterday's Great Powers, and their associated approaches to the new strategic actor: China. The author knows the subject well from personal experience. (author)

  20. The HDAC Inhibitors Scriptaid and LBH589 Combined with the Oncolytic Virus Delta24-RGD Exert Enhanced Anti-Tumor Efficacy in Patient-Derived Glioblastoma Cells.

    Directory of Open Access Journals (Sweden)

    Lotte M E Berghauser Pont

    Full Text Available A phase I/II trial for glioblastoma with the oncolytic adenovirus Delta24-RGD was recently completed. Delta24-RGD conditionally replicates in cells with a disrupted retinoblastoma-pathway and enters cells via αvβ3/5 integrins. Glioblastomas are differentially sensitive to Delta24-RGD. HDAC inhibitors (HDACi affect integrins and share common cell death pathways with Delta24-RGD. We studied the combination treatment effects of HDACi and Delta24-RGD in patient-derived glioblastoma stem-like cells (GSC, and we determined the most effective HDACi.SAHA, Valproic Acid, Scriptaid, MS275 and LBH589 were combined with Delta24-RGD in fourteen distinct GSCs. Synergy was determined by Chou Talalay method. Viral infection and replication were assessed using luciferase and GFP encoding vectors and hexon-titration assays. Coxsackie adenovirus receptor and αvβ3 integrin levels were determined by flow cytometry. Oncolysis and mechanisms of cell death were studied by viability, caspase-3/7, LDH and LC3B/p62, phospho-p70S6K. Toxicity was studied on normal human astrocytes. MGMT promotor methylation status, TCGA classification, Rb-pathway and integrin gene expression levels were assessed as markers of responsiveness.Scriptaid and LBH589 acted synergistically with Delta24-RGD in approximately 50% of the GSCs. Both drugs moderately increased αvβ3 integrin levels and viral infection in responding but not in non-responding GSCs. LBH589 moderately increased late viral gene expression, however, virus titration revealed diminished viral progeny production by both HDACi, Scriptaid augmented caspase-3/7 activity, LC3B conversion, p62 and phospho-p70S6K consumption, as well as LDH levels. LBH589 increased LDH and phospho-p70S6K consumption. Responsiveness correlated with expression of various Rb-pathway genes and integrins. Combination treatments induced limited toxicity to human astrocytes.LBH589 and Scriptaid combined with Delta24-RGD revealed synergistic anti

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

    International Nuclear Information System (INIS)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    David C Gaston

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

  3. 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

  4. European Union's Arms Control Regime and Arms Exports to China: Background and Legal Analysis

    National Research Council Canada - National Science Library

    Grimmett, Richard F; Papademetriou, Theresa

    2005-01-01

    In recent months, discussions have been held within the European Union (EU) on the question of lifting the embargo on arms exports to the People's Republic of China that was imposed on China on June 27, 1989...

  5. How does a planet excite multiple spiral arms?

    Science.gov (United States)

    Bae, Jaehan; Zhu, Zhaohuan

    2018-01-01

    Protoplanetary disk simulations show that a single planet excites multiple spiral arms in the background disk, potentially supported by the multi-armed spirals revealed with recent high-resolution observations in some disks. The existence of multiple spiral arms is of importance in many aspects. It is empirically found that the arm-to-arm separation increases as a function of the planetary mass, so one can use the morphology of observed spiral arms to infer the mass of unseen planets. In addition, a spiral arm opens a radial gap as it steepens into a shock, so when a planet excites multiple spiral arms it can open multiple gaps in the disk. Despite the important implications, however, the formation mechanism of multiple spiral arms has not been fully understood by far.In this talk, we explain how a planet excites multiple spiral arms. The gravitational potential of a planet can be decomposed into a Fourier series, a sum of individual azimuthal modes having different azimuthal wavenumbers. Using a linear wave theory, we first demonstrate that appropriate sets of Fourier decomposed waves can be in phase, raising a possibility that constructive interference among the waves can produce coherent structures - spiral arms. More than one spiral arm can form since such constructive interference can occur at different positions in the disk for different sets of waves. We then verify this hypothesis using a suite of two-dimensional hydrodynamic simulations. Finally, we present non-linear behavior in the formation of multiple spiral arms.

  6. Rosoboroneksport: Arms Sales and the Structure of Russian Defense Industry

    National Research Council Canada - National Science Library

    Blank, Stephen J

    2007-01-01

    .... Arms sales thus have become the main source of its revenue until the present and will play a key role in Russia's ongoing attempt to regenerate its armed forces while winning friends and influence abroad...

  7. Feasibility Analysis of an All Volunteer Armed Force in Turkey

    National Research Council Canada - National Science Library

    Alanc, Ozgun U

    2007-01-01

    .... Accordingly, this project report provides a Draft versus All Volunteer Forces (AVF) analysis for the Turkish Armed Forces, by evaluating the feasibility and the desirability of an AVF for the Turkish Armed Forces...

  8. 77 FR 42707 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-07-20

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-35] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... Force (DAY) [[Page 42709

  9. Limited consensus around ARM information protection practices1

    African Journals Online (AJOL)

    KATUU, Shadrack

    surrounding Information Protection (IP) has been ... compares IP and ARM information protection through .... decision-making methodology used to help ... and differing requirements of institutions into account. ARM literature is prescriptive with.

  10. ARM Enhanced Shortwave Experiment (ARESE) Solar Radiation Data

    Data.gov (United States)

    National Aeronautics and Space Administration — The ARM Enhanced Shortwave Experiment (ARESE) was conducted at the Department of Energy's ARM Southern Great Plains (SGP) Central Facility between September 22, 1995...

  11. Kinematic decomposition and classification of octopus arm movements

    OpenAIRE

    Zelman, Ido; Titon, Myriam; Yekutieli, Yoram; Hanassy, Shlomi; Hochner, Binyamin; Flash, Tamar

    2013-01-01

    The octopus arm is a muscular hydrostat and due to its deformable and highly flexible structure it is capable of a rich repertoire of motor behaviors. Its motor control system uses planning principles and control strategies unique to muscular hydrostats. We previously reconstructed a data set of octopus arm movements from records of natural movements using a sequence of 3D curves describing the virtual backbone of arm configurations. Here we describe a novel representation of octopus arm move...

  12. Simulation of Octopus Arm Based on Coupled CPGs

    OpenAIRE

    Juan Tian; Qiang Lu

    2015-01-01

    The octopus arm has attracted many researchers’ interests and became a research hot spot because of its amazing features. Several dynamic models inspired by an octopus arm are presented to realize the structure with a large number of degrees of freedom. The octopus arm is made of a soft material introducing high-dimensionality, nonlinearity, and elasticity, which makes the octopus arm difficult to control. In this paper, three coupled central pattern generators (CPGs) are built and a 2-dimens...

  13. ATLAS software stack on ARM64

    CERN Document Server

    AUTHOR|(INSPIRE)INSPIRE-00529764; The ATLAS collaboration; Stewart, Graeme; Seuster, Rolf; Quadt, Arnulf

    2017-01-01

    This paper reports on the port of the ATLAS software stack onto new prototype ARM64 servers. This included building the “external” packages that the ATLAS software relies on. Patches were needed to introduce this new architecture into the build as well as patches that correct for platform specific code that caused failures on non-x86 architectures. These patches were applied such that porting to further platforms will need no or only very little adjustments. A few additional modifications were needed to account for the different operating system, Ubuntu instead of Scientific Linux 6 / CentOS7. Selected results from the validation of the physics outputs on these ARM 64-bit servers will be shown. CPU, memory and IO intensive benchmarks using ATLAS specific environment and infrastructure have been performed, with a particular emphasis on the performance vs. energy consumption.

  14. ATLAS software stack on ARM64

    Science.gov (United States)

    Smith, Joshua Wyatt; Stewart, Graeme A.; Seuster, Rolf; Quadt, Arnulf; ATLAS Collaboration

    2017-10-01

    This paper reports on the port of the ATLAS software stack onto new prototype ARM64 servers. This included building the “external” packages that the ATLAS software relies on. Patches were needed to introduce this new architecture into the build as well as patches that correct for platform specific code that caused failures on non-x86 architectures. These patches were applied such that porting to further platforms will need no or only very little adjustments. A few additional modifications were needed to account for the different operating system, Ubuntu instead of Scientific Linux 6 / CentOS7. Selected results from the validation of the physics outputs on these ARM 64-bit servers will be shown. CPU, memory and IO intensive benchmarks using ATLAS specific environment and infrastructure have been performed, with a particular emphasis on the performance vs. energy consumption.

  15. China and nuclear arms limitation agreements

    International Nuclear Information System (INIS)

    Roberts, E.V.

    1980-01-01

    The Chinese attitudes from 1949 to 1980 towards nuclear arms limitation are divided into four distinct periods: 1949-1956, 1957-1963, 1964-1972 and 1973-1980. During 1949-1956, China held the view that an atom bomb or nuclear weapons are not decisive for the outcome of any war. It is the people who decide the outcome of a war. The period 1957-1963, after Soviet refusal to transfer nuclear technology, is marked by the development of the nuclear programme which led to the explosion of a nuclear device in 1964. China continued to build nuclear capability during 1964-1972. Mao died in 1976 and the relations with the U.S.A. were normalised in 1979. Taking an anti-Soviet stance China now takes the view that any nuclear arms agreement with Soviet Union is futile and describes SALT II agreement as an absolute farce. (M.G.B.)

  16. MAGIC: Marine ARM GPCI Investigation of Clouds

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, ER; Wiscombe, WJ; Albrecht, BA; Bland, GL; Flagg, CN; Klein, SA; Kollias, P; Mace, G; Reynolds, RM; Schwartz, SE; Siebesma, AP; Teixeira, J; Wood, R; Zhang, M

    2012-10-03

    The second Atmospheric Radiation Measurement (ARM) Mobile Facility (AMF2) will be deployed aboard the Horizon Lines cargo container ship merchant vessel (M/V) Spirit for MAGIC, the Marine ARM GPCI1 Investigation of Clouds. The Spirit will traverse the route between Los Angeles, California, and Honolulu, Hawaii, from October 2012 through September 2013 (except for a few months in the middle of this time period when the ship will be in dry dock). During this field campaign, AMF2 will observe and characterize the properties of clouds and precipitation, aerosols, and atmospheric radiation; standard meteorological and oceanographic variables; and atmospheric structure. There will also be two intensive observational periods (IOPs), one in January 2013 and one in July 2013, during which more detailed measurements of the atmospheric structure will be made.

  17. Special Gripper for a Robotic Arm

    Directory of Open Access Journals (Sweden)

    Miguel Angel SELLES

    2012-12-01

    Full Text Available New structures for gripping objects in robotic manipulation processes are oriented to the new arrangement of mechanical structures using new materials and processing technologies and innovative procedures for the implementation of contact gripping element links to an object with a high degree of adaptively of applications together with the ability to alter the structure of grip and limiting the intensity of the contact stiffness variation of snap elements custody and pliability. The application of elastomeric materials and surface finishes is important. This paper presents both a new gripper design for robot arms but also the search of the selected materials to make an experimental evaluation of technical parameters that are used to assess their application potential and suitability for the targeted applications. Also the results and conclusions for gripper testing in manipulation operations with two different robot arms are presented.

  18. Robot-Arm Dynamic Control by Computer

    Science.gov (United States)

    Bejczy, Antal K.; Tarn, Tzyh J.; Chen, Yilong J.

    1987-01-01

    Feedforward and feedback schemes linearize responses to control inputs. Method for control of robot arm based on computed nonlinear feedback and state tranformations to linearize system and decouple robot end-effector motions along each of cartesian axes augmented with optimal scheme for correction of errors in workspace. Major new feature of control method is: optimal error-correction loop directly operates on task level and not on joint-servocontrol level.

  19. Diversity in the Danish Armed Forces

    DEFF Research Database (Denmark)

    Schaub Jr, Gary John; Pradhan-Blach, Flemming; Larsen, Esben Salling

    The Danish Armed Forces face the functional imperative of becoming a smaller, professional expeditionary force and the societal imperative of including women and ethnic minorities. It currently lags behind its NATO partners in gender and ethnic diversity. Lessons to be learned from NATO members...... and realistic goals, systematically developing recruitment, development, and retention policies, and the superiority of an all-volunteer force over conscription in fulfilling this societal imperative....

  20. Gorbachev’s Arms Control Strategy.

    Science.gov (United States)

    1987-01-22

    on- site inspection for verifying nuclear tests as well as for dismantling missiles on Soviet territory. Clearlv Gorbachev wants an arms , -4- control...bring its seismological test equipment to what he called the "holy of holies", the area adjoining the Soviet proving ground near Semipalatinsk to offer...prenotification and observation of military exercises including on- site inspection on Soviet territory. But on the big issues--- nuclear testing , strategic weapons

  1. Memories of the armed struggle in Argentina

    Directory of Open Access Journals (Sweden)

    Laura Margarita Pasquali

    2013-06-01

    Full Text Available This article presents and develops some of the edges on working of the guerrilla that emerge in the memories of the former militants of the armed organizations in Argentina. Beginig from this journey we will have access to the registration that one has presently on it, which will allows us to establish part of the subjective environment of the moment, the main characters consideration of the activism and their significance in the general context of the militancy.

  2. Rock Moved by Mars Lander Arm

    Science.gov (United States)

    2008-01-01

    The robotic arm on NASA's Phoenix Mars Lander slid a rock out of the way during the mission's 117th Martian day (Sept. 22, 2008) to gain access to soil that had been underneath the rock.The lander's Surface Stereo Imager took the two images for this stereo view later the same day, showing the rock, called 'Headless,' after the arm pushed it about 40 centimeters (16 inches) from its previous location. 'The rock ended up exactly where we intended it to,' said Matt Robinson of NASA's Jet Propulsion Laboratory, robotic arm flight software lead for the Phoenix team. The arm had enlarged the trench near Headless two days earlier in preparation for sliding the rock into the trench. The trench was dug to about 3 centimeters (1.2 inches) deep. The ground surface between the rock's prior position and the lip of the trench had a slope of about 3 degrees downward toward the trench. Headless is about the size and shape of a VHS videotape. The Phoenix science team sought to move the rock in order to study the soil and the depth to subsurface ice underneath where the rock had been. This image was taken at about 12:30 p.m., local solar time on Mars. The view is to the north northeast of the lander. The Phoenix Mission is led by the University of Arizona, Tucson, on behalf of NASA. Project management of the mission is by JPL, Pasadena, Calif. Spacecraft development was by Lockheed Martin Space Systems, Denver.

  3. Financial Ratio Analysis using ARMS Data

    OpenAIRE

    Ahrendsen, Bruce L.; Katchova, Ani L.

    2012-01-01

    The purpose of this research is to evaluate the financial performance measures calculated and reported by Economic Resource Service (ERS) from ARMS data. The evaluation includes the calculation method and the underlying assumptions used in obtaining the reported values. The financial measures calculated and reported are compared with those recommended by the Farm Financial Standards Council (FFSC). The underlying assumptions are identified by analyzing the software code used in calculating th...

  4. Putting the Glare of Publicity on International Arms Sales.

    Science.gov (United States)

    Hartman, William

    1992-01-01

    Reports on a United Nations committee recommendation that the Security Council establish a universal register of arms. Suggests that such a register would limit the destabilizing influence of major arms sales on developing nations. Argues that visibility of arms sales may help reduce their number. (DK)

  5. 49 CFR 236.810 - Spectacle, semaphore arm.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Spectacle, semaphore arm. 236.810 Section 236.810 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Spectacle, semaphore arm. That part of a semaphore arm which holds the roundels and to which the blade is...

  6. Continuum robot arms inspired by cephalopods

    Science.gov (United States)

    Walker, Ian D.; Dawson, Darren M.; Flash, Tamar; Grasso, Frank W.; Hanlon, Roger T.; Hochner, Binyamin; Kier, William M.; Pagano, Christopher C.; Rahn, Christopher D.; Zhang, Qiming M.

    2005-05-01

    In this paper, we describe our recent results in the development of a new class of soft, continuous backbone ("continuum") robot manipulators. Our work is strongly motivated by the dexterous appendages found in cephalopods, particularly the arms and suckers of octopus, and the arms and tentacles of squid. Our ongoing investigation of these animals reveals interesting and unexpected functional aspects of their structure and behavior. The arrangement and dynamic operation of muscles and connective tissue observed in the arms of a variety of octopus species motivate the underlying design approach for our soft manipulators. These artificial manipulators feature biomimetic actuators, including artificial muscles based on both electro-active polymers (EAP) and pneumatic (McKibben) muscles. They feature a "clean" continuous backbone design, redundant degrees of freedom, and exhibit significant compliance that provides novel operational capacities during environmental interaction and object manipulation. The unusual compliance and redundant degrees of freedom provide strong potential for application to delicate tasks in cluttered and/or unstructured environments. Our aim is to endow these compliant robotic mechanisms with the diverse and dexterous grasping behavior observed in octopuses. To this end, we are conducting fundamental research into the manipulation tactics, sensory biology, and neural control of octopuses. This work in turn leads to novel approaches to motion planning and operator interfaces for the robots. The paper describes the above efforts, along with the results of our development of a series of continuum tentacle-like robots, demonstrating the unique abilities of biologically-inspired design.

  7. Arms control agency faces uncertain future

    International Nuclear Information System (INIS)

    Ember, L.

    1993-01-01

    National security cognoscenti are busy sifting tea leaves trying to puzzle out the fate of arms control and nonproliferation policy in the new Administration. Of special concern to these policy gurus is the future of the semiautonomous Arms Control and Disarmament Agency (ACDA). ACDA's existence as a separate entity on the executive branch's organization chart is precarious. The agency has never functioned as intended since Congress created it in 1961. Its stock over the decades has ebbed and flowed, paralleling the prominence and clout of its director. And except for a few notable successes--the conclusion of the chemical weapons treaty being one--the agency's authority has plummeted in the past 14 years. Today, almost every interested party agrees that something has to be done, that the agency cannot continue as it now functions. Several recent studies have called for its rejuvenation. Still other studies have suggested that ACDA be dismantled, and those activities relevant to national security in a post-Cold War environment be shifted to and integrated into the State Department. Observers expect ACDA to evolve into an agency whose primary focus is on problems of proliferation. In a world in which tighter export controls on dual-use technologies, restraint on arms transfers, and economic assistance conditional on a recipients's security behavior will be the norm for security and stability, a role for ACDA as the U.S.'s nonproliferation nanny is not a bad one

  8. Monitoring and Controlling an Underwater Robotic Arm

    Science.gov (United States)

    Haas, John; Todd, Brian Keith; Woodcock, Larry; Robinson, Fred M.

    2009-01-01

    The SSRMS Module 1 software is part of a system for monitoring an adaptive, closed-loop control of the motions of a robotic arm in NASA s Neutral Buoyancy Laboratory, where buoyancy in a pool of water is used to simulate the weightlessness of outer space. This software is so named because the robot arm is a replica of the Space Shuttle Remote Manipulator System (SSRMS). This software is distributed, running on remote joint processors (RJPs), each of which is mounted in a hydraulic actuator comprising the joint of the robotic arm and communicating with a poolside processor denoted the Direct Control Rack (DCR). Each RJP executes the feedback joint-motion control algorithm for its joint and communicates with the DCR. The DCR receives joint-angular-velocity commands either locally from an operator or remotely from computers that simulate the flight like SSRMS and perform coordinated motion calculations based on hand-controller inputs. The received commands are checked for validity before they are transmitted to the RJPs. The DCR software generates a display of the statuses of the RJPs for the DCR operator and can shut down the hydraulic pump when excessive joint-angle error or failure of a RJP is detected.

  9. The Perseus arm in the anticenter direction

    Science.gov (United States)

    Monguió, M.; Grosbøl, P.; Figueras, F.

    2015-05-01

    The stellar overdensity due to the Perseus arm has been detected in the anticenter direction through individual field stars. For that purpose, a Str&{uml;o}mgren photometric survey covering 16° ^2 was developed with the Wide Field Camera at the Isaac Newton Telescope. This photometry allowed us to compute individual physical parameters for these stars using a new method based on atmospheric models and evolutionary tracks. The analysis of the surface density as a function of distance for intermediate young stars in this survey allowed us to detect an overdensity at 1.6±0.2 kpc from the Sun, that can be associated with the Perseus arm, with a surface density amplitude of ˜14%. The significance of the detection is above 4σ for all the cases. The fit for the radial scale length of the Galactic disk provided values in the range [2.9,3.5] kpc for the population of the B4-A1 stars. We also analyzed the interstellar visual absorption distribution, and its variation as a function of distance is coherent with a dust layer before the Perseus arm location.

  10. Galactic spiral arms formed by central explosions

    International Nuclear Information System (INIS)

    Havnes, O.

    1978-01-01

    Calculations have been made of spiral arm formation due to central explosions in a nucleus surrounded by a disc containing most of the galactic mass with the purpose of obtaining estimates on lifetimes of arms and the requirements on the energy involved in the process. The ejected gas is taken to be a few percent, or less, of the central nucleus and is ejected with velocities of the order of 1000 km s -1 . The gas, considered to be in forms of blobs, moves under the gravitational force from the disc and the nucleus and the drag force by the gas in the disc. The orbits of the blobs evolve towards the circular orbits of the disc due to this drag force and the velocities in the arms will therefore, after some time, approach those of a normal rotation curve. A relatively open structure will last 8 years. Stable ring structures with longer lifetimes may be formed by some explosions. With an energy of approximately 5 x 10 57 erg in the initial gas-blob motion and a duration of the explosion of approximately 10 7 years, the energy output in such explosions has to be > 10 43 erg s -1 . (Auth.)

  11. Nonparetic arm force does not overinhibit the paretic arm in chronic poststroke hemiparesis.

    Science.gov (United States)

    Dimyan, Michael A; Perez, Monica A; Auh, Sungyoung; Tarula, Erick; Wilson, Matthew; Cohen, Leonardo G

    2014-05-01

    To determine whether nonparetic arm force overinhibits the paretic arm in patients with chronic unilateral poststroke hemiparesis. Case-control neurophysiological and behavioral study of patients with chronic stroke. Research institution. Eighty-six referred patients were screened to enroll 9 participants (N=9) with a >6 month history of 1 unilateral ischemic infarct that resulted in arm hemiparesis with residual ability to produce 1Nm of wrist flexion torque and without contraindication to transcranial magnetic stimulation. Eight age- and handedness-matched healthy volunteers without neurologic diagnosis were studied for comparison. Not applicable. Change in interhemispheric inhibition targeting the ipsilesional primary motor cortex (M1) during nonparetic arm force. We hypothesized that interhemispheric inhibition would increase more in healthy controls than in patients with hemiparesis. Healthy age-matched controls had significantly greater increases in inhibition from their active to resting M1 than patients with stroke from their active contralesional to resting ipsilesional M1 in the same scenario (20%±7% vs -1%±4%, F1,12=6.61, P=.025). Patients with greater increases in contralesional to ipsilesional inhibition were better performers on the 9-hole peg test of paretic arm function. Our findings reveal that producing force with the nonparetic arm does not necessarily overinhibit the paretic arm. Though our study is limited in generalizability by the small sample size, we found that greater active contralesional to resting ipsilesional M1 inhibition was related with better recovery in this subset of patients with chronic poststroke. Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  12. Design of a multi-arm randomized clinical trial with no control arm.

    Science.gov (United States)

    Magaret, Amalia; Angus, Derek C; Adhikari, Neill K J; Banura, Patrick; Kissoon, Niranjan; Lawler, James V; Jacob, Shevin T

    2016-01-01

    Clinical trial designs that include multiple treatments are currently limited to those that perform pairwise comparisons of each investigational treatment to a single control. However, there are settings, such as the recent Ebola outbreak, in which no treatment has been demonstrated to be effective; and therefore, no standard of care exists which would serve as an appropriate control. For illustrative purposes, we focused on the care of patients presenting in austere settings with critically ill 'sepsis-like' syndromes. Our approach involves a novel algorithm for comparing mortality among arms without requiring a single fixed control. The algorithm allows poorly-performing arms to be dropped during interim analyses. Consequently, the study may be completed earlier than planned. We used simulation to determine operating characteristics for the trial and to estimate the required sample size. We present a potential study design targeting a minimal effect size of a 23% relative reduction in mortality between any pair of arms. Using estimated power and spurious significance rates from the simulated scenarios, we show that such a trial would require 2550 participants. Over a range of scenarios, our study has 80 to 99% power to select the optimal treatment. Using a fixed control design, if the control arm is least efficacious, 640 subjects would be enrolled into the least efficacious arm, while our algorithm would enroll between 170 and 430. This simulation method can be easily extended to other settings or other binary outcomes. Early dropping of arms is efficient and ethical when conducting clinical trials with multiple arms. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Bilateral movements increase sustained extensor force in the paretic arm.

    Science.gov (United States)

    Kang, Nyeonju; Cauraugh, James H

    2018-04-01

    Muscle weakness in the extensors poststroke is a common motor impairment. Unfortunately, research is unclear on whether bilateral movements increase extensor force production in the paretic arm. This study investigated sustained force production while stroke individuals maximally extended their wrist and fingers on their paretic arm. Specifically, we determined isometric force production in three conditions: (a) unilateral paretic arm, (b) unilateral nonparetic arm, and (c) bilateral (both arms executing the same movement simultaneously). Seventeen chronic stroke patients produced isometric sustained force by executing wrist and fingers extension in unilateral and bilateral contraction conditions. Mean force, force variability (coefficient of variation), and signal-to-noise ratio were calculated for each contraction condition. Analysis of two-way (Arm × Type of Condition: 2 × 2; Paretic or Nonparetic Arm × Unilateral or Bilateral Conditions) within-subjects ANOVAs revealed that the bilateral condition increased sustained force in the paretic arm, but reduced sustained force in the nonparetic arm. Further, although the paretic arm exhibited more force variability and less signal-to-noise ratio than the nonparetic arm during a unilateral condition, there were no differences when participants simultaneously executed isometric contractions with both arms. Our unique findings indicate that bilateral contractions transiently increased extensor force in the paretic arm. Implications for Rehabilitation Bilateral movements increased isometric wrsit extensor force in paretic arms and redcued force in nonparetic arms versus unilateral movements. Both paretic and nonparetic arms produced similar force variability and signal-to-noise ratio during bilateral movements. Increased sustained force in the paretic arm during the bilateral condition indicates that rehabilitation protocols based on bilateral movements may be beneficial for functional recovery.

  14. Supporting the President's Arms Control and Nonproliferation Agenda: Transparency and Verification for Nuclear Arms Reductions

    International Nuclear Information System (INIS)

    Doyle, James E.; Meek, Elizabeth

    2009-01-01

    The President's arms control and nonproliferation agenda is still evolving and the details of initiatives supporting it remain undefined. This means that DOE, NNSA, NA-20, NA-24 and the national laboratories can help define the agenda, and the policies and the initiatives to support it. This will require effective internal and interagency coordination. The arms control and nonproliferation agenda is broad and includes the path-breaking goal of creating conditions for the elimination of nuclear weapons. Responsibility for various elements of the agenda will be widely scattered across the interagency. Therefore an interagency mapping exercise should be performed to identify the key points of engagement within NNSA and other agencies for creating effective policy coordination mechanisms. These can include informal networks, working groups, coordinating committees, interagency task forces, etc. It will be important for NA-20 and NA-24 to get a seat at the table and a functional role in many of these coordinating bodies. The arms control and nonproliferation agenda comprises both mature and developing policy initiatives. The more mature elements such as CTBT ratification and a follow-on strategic nuclear arms treaty with Russia have defined milestones. However, recent press reports indicate that even the START follow-on strategic arms pact that is planned to be complete by the end of 2009 may take significantly longer and be more expansive in scope. The Russians called for proposals to count non-deployed as well as deployed warheads. Other elements of the agenda such as FMCT, future bilateral nuclear arms reductions following a START follow-on treaty, nuclear posture changes, preparations for an international nuclear security summit, strengthened international safeguards and multilateral verification are in much earlier stages of development. For this reason any survey of arms control capabilities within the USG should be structured to address potential needs across the

  15. Effects of age, sex and arm on the precision of arm position sense—left-arm superiority in healthy right-handers

    OpenAIRE

    Schmidt, Lena; Depper, Lena; Kerkhoff, Georg

    2013-01-01

    Position sense is an important proprioceptive ability. Disorders of arm position sense (APS) often occur after unilateral stroke, and are associated with a negative functional outcome. In the present study we assessed horizontal APS by measuring angular deviations from a visually defined target separately for each arm in a large group of healthy subjects. We analyzed the accuracy and instability of horizontal APS as a function of age, sex and arm. Subjects were required to specify verbally th...

  16. Spiral-arm instability: giant clump formation via fragmentation of a galactic spiral arm

    Science.gov (United States)

    Inoue, Shigeki; Yoshida, Naoki

    2018-03-01

    Fragmentation of a spiral arm is thought to drive the formation of giant clumps in galaxies. Using linear perturbation analysis for self-gravitating spiral arms, we derive an instability parameter and define the conditions for clump formation. We extend our analysis to multicomponent systems that consist of gas and stars in an external potential. We then perform numerical simulations of isolated disc galaxies with isothermal gas, and compare the results with the prediction of our analytic model. Our model describes accurately the evolution of the spiral arms in our simulations, even when spiral arms dynamically interact with one another. We show that most of the giant clumps formed in the simulated disc galaxies satisfy the instability condition. The clump masses predicted by our model are in agreement with the simulation results, but the growth time-scale of unstable perturbations is overestimated by a factor of a few. We also apply our instability analysis to derive scaling relations of clump properties. The expected scaling relation between the clump size, velocity dispersion, and circular velocity is slightly different from that given by the Toomre instability analyses, but neither is inconsistent with currently available observations. We argue that the spiral-arm instability is a viable formation mechanism of giant clumps in gas-rich disc galaxies.

  17. Control of octopus arm extension by a peripheral motor program.

    Science.gov (United States)

    Sumbre, G; Gutfreund, Y; Fiorito, G; Flash, T; Hochner, B

    2001-09-07

    For goal-directed arm movements, the nervous system generates a sequence of motor commands that bring the arm toward the target. Control of the octopus arm is especially complex because the arm can be moved in any direction, with a virtually infinite number of degrees of freedom. Here we show that arm extensions can be evoked mechanically or electrically in arms whose connection with the brain has been severed. These extensions show kinematic features that are almost identical to normal behavior, suggesting that the basic motor program for voluntary movement is embedded within the neural circuitry of the arm itself. Such peripheral motor programs represent considerable simplification in the motor control of this highly redundant appendage.

  18. Visual Display of 5p-arm and 3p-arm miRNA Expression with a Mobile Application.

    Science.gov (United States)

    Pan, Chao-Yu; Kuo, Wei-Ting; Chiu, Chien-Yuan; Lin, Wen-Chang

    2017-01-01

    MicroRNAs (miRNAs) play important roles in human cancers. In previous studies, we have demonstrated that both 5p-arm and 3p-arm of mature miRNAs could be expressed from the same precursor and we further interrogated the 5p-arm and 3p-arm miRNA expression with a comprehensive arm feature annotation list. To assist biologists to visualize the differential 5p-arm and 3p-arm miRNA expression patterns, we utilized a user-friendly mobile App to display. The Cancer Genome Atlas (TCGA) miRNA-Seq expression information. We have collected over 4,500 miRNA-Seq datasets from 15 TCGA cancer types and further processed them with the 5p-arm and 3p-arm annotation analysis pipeline. In order to be displayed with the RNA-Seq Viewer App, annotated 5p-arm and 3p-arm miRNA expression information and miRNA gene loci information were converted into SQLite tables. In this distinct application, for any given miRNA gene, 5p-arm miRNA is illustrated on the top of chromosome ideogram and 3p-arm miRNA is illustrated on the bottom of chromosome ideogram. Users can then easily interrogate the differentially 5p-arm/3p-arm expressed miRNAs with their mobile devices. This study demonstrates the feasibility and utility of RNA-Seq Viewer App in addition to mRNA-Seq data visualization.

  19. Visual Display of 5p-arm and 3p-arm miRNA Expression with a Mobile Application

    Directory of Open Access Journals (Sweden)

    Chao-Yu Pan

    2017-01-01

    Full Text Available MicroRNAs (miRNAs play important roles in human cancers. In previous studies, we have demonstrated that both 5p-arm and 3p-arm of mature miRNAs could be expressed from the same precursor and we further interrogated the 5p-arm and 3p-arm miRNA expression with a comprehensive arm feature annotation list. To assist biologists to visualize the differential 5p-arm and 3p-arm miRNA expression patterns, we utilized a user-friendly mobile App to display. The Cancer Genome Atlas (TCGA miRNA-Seq expression information. We have collected over 4,500 miRNA-Seq datasets from 15 TCGA cancer types and further processed them with the 5p-arm and 3p-arm annotation analysis pipeline. In order to be displayed with the RNA-Seq Viewer App, annotated 5p-arm and 3p-arm miRNA expression information and miRNA gene loci information were converted into SQLite tables. In this distinct application, for any given miRNA gene, 5p-arm miRNA is illustrated on the top of chromosome ideogram and 3p-arm miRNA is illustrated on the bottom of chromosome ideogram. Users can then easily interrogate the differentially 5p-arm/3p-arm expressed miRNAs with their mobile devices. This study demonstrates the feasibility and utility of RNA-Seq Viewer App in addition to mRNA-Seq data visualization.

  20. Optimizing Armed Forces Capabilities for Hybrid Warfare – New Challenge for Slovak Armed Forces

    Directory of Open Access Journals (Sweden)

    Peter PINDJÁK

    2015-09-01

    Full Text Available The paper deals with the optimization of military capabilities of the Slovak Armed Forces for conducting operations in a hybrid conflict, which represents one of the possible scenarios of irregular warfare. Whereas in the regular warfare adversaries intend to eliminate the centers of gravity of each other, most often command and control structures, in irregular conflicts, the center of gravity shifts towards the will and cognitive perception of the target population. Hybrid warfare comprises a thoroughly planned combination of conventional military approaches and kinetic operations with subversive, irregular activities, including information and cyber operations. These efforts are often accompanied by intensified activities of intelligence services, special operation forces, and even mercenary and other paramilitary groups. The development of irregular warfare capabilities within the Slovak Armed Forces will require a progressive transformation process that may turn the armed forces into a modern and adaptable element of power, capable of deployment in national and international crisis management operations.

  1. Association between intramuscular fat in the arm following arm training and INSIG2

    DEFF Research Database (Denmark)

    Popadic Gacesa, J Z; Secher, N H; Momcilovic, M

    2014-01-01

    ) ; mean ± standard deviation) carried out a 12-week two-arm elbow extensor training (10 maximal extensions with 1 min recovery between bouts) five times per day, five times per week. For 17 volunteers, upper arm muscle and adipose tissue [subcutaneous (SCAT) and intramuscular (IMAT)] volumes were.......0 ± 0.9%; GC/CC: %IMAT 0.6 ± 0.5% (P > 0.05). However, in the year following the training, accumulation of upper arm IMAT was twice as large in participants homozygous for the G allele (GG: Δ%IMAT +2.5 ± 0.8%; GC/CC: Δ%IMAT +1.1 ± 0.7%; P 

  2. Planet-driven Spiral Arms in Protoplanetary Disks. II. Implications

    Science.gov (United States)

    Bae, Jaehan; Zhu, Zhaohuan

    2018-06-01

    We examine whether various characteristics of planet-driven spiral arms can be used to constrain the masses of unseen planets and their positions within their disks. By carrying out two-dimensional hydrodynamic simulations varying planet mass and disk gas temperature, we find that a larger number of spiral arms form with a smaller planet mass and a lower disk temperature. A planet excites two or more spiral arms interior to its orbit for a range of disk temperatures characterized by the disk aspect ratio 0.04≤slant {(h/r)}p≤slant 0.15, whereas exterior to a planet’s orbit multiple spiral arms can form only in cold disks with {(h/r)}p≲ 0.06. Constraining the planet mass with the pitch angle of spiral arms requires accurate disk temperature measurements that might be challenging even with ALMA. However, the property that the pitch angle of planet-driven spiral arms decreases away from the planet can be a powerful diagnostic to determine whether the planet is located interior or exterior to the observed spirals. The arm-to-arm separations increase as a function of planet mass, consistent with previous studies; however, the exact slope depends on disk temperature as well as the radial location where the arm-to-arm separations are measured. We apply these diagnostics to the spiral arms seen in MWC 758 and Elias 2–27. As shown in Bae et al., planet-driven spiral arms can create concentric rings and gaps, which can produce a more dominant observable signature than spiral arms under certain circumstances. We discuss the observability of planet-driven spiral arms versus rings and gaps.

  3. Arm and neck pain in ultrasonographers.

    Science.gov (United States)

    Claes, Frank; Berger, Jan; Stassijns, Gaëtane

    2015-03-01

    The aim of this study was to evaluate the prevalence of upper-body-quadrant pain among ultrasonographers and to evaluate the association between individual ergonomics, musculoskeletal disorders, and occurrence of neck pain. A hundred and ten (N = 110) Belgian and Dutch male and female hospital ultrasonographers were consecutively enrolled in the study. Data on work-related ergonomic and musculoskeletal disorders were collected with an electronic inquiry, including questions regarding ergonomics (position of the screen, high-low table, and ergonomic chair), symptoms (neck pain, upper-limb pain), and work-related factors (consecutive working hours a day, average working hours a week). Subjects with the screen on their left had significantly more neck pain (odds ratio [OR] = 3.6, p = .0286). Depending on the workspace, high-low tables increased the chance of developing neck pain (OR = 12.9, p = .0246). A screen at eye level caused less neck pain (OR = .22, p = .0610). Employees with a fixed working space were less susceptible to arm pain (OR = 0.13, p = .0058). The prevalence of arm pain was significantly higher for the vascular department compared to radiology, urology, and gynecology departments (OR = 9.2, p = .0278). Regarding prevention of upper-limb pain in ultrasonograph, more attention should be paid to the work environment and more specialty to the ultrasound workstation layout. Primary ergonomic prevention could provide a painless work situation for the ultrasonographer. Further research on the ergonomic conditions of ultrasonography is necessary to develop ergonomic solutions in the work environment that will help to alleviate neck and arm pain. © 2014, Human Factors and Ergonomics Society.

  4. Limitation and reduction of conventional arms

    International Nuclear Information System (INIS)

    Chervov, N.

    1989-01-01

    We are living at a time when war between East and West---not only nuclear but also conventional war--- is totally senseless. It cannot solve any problem---political, economic, or other. From the military point of view, war between East and West is madness. Calculations show that after 20 days of conventional warfare Europe could become another Hiroshima. Therefore we must work out forms of long-term cooperation. Before it is too late, we must radically reduce our military potentials and rethink our military doctrines. The reduction by 500,000 men is for the USSR no simple solution. But that step may become a model for further actions by East and West. The West's proposal that armed forces should be reduced to the level of 95 percent of NATO's armed forces is not a solution. Both sides---the Warsaw Treaty Organization and NATO---must be deprived of the capacity to launch a sudden attack; they must be deprived of their attack potential. The USSR initiative shows the true way toward that goal. What is happening in connection with our decision is not always correctly interpreted in the West, and so I should like to draw attention to some distinctive features of the Soviet armed forces reductions and, first of all, their scale (equivalent to the Bundeswehr of the Federal Republic of Germany). With respect to Europe, Soviet troops are to be reduced in the German Democratic Republic, Czechoslovakia, Hungary, Poland, and the European part of the Soviet Union---a total of 240,000 men, 10,000 tanks, 9,500 artillery systems, and 800 combat aircraft

  5. Nuclear disarmament or survival of nuclear arms?

    International Nuclear Information System (INIS)

    Stroot, J.P.

    1997-01-01

    START II has not yet been ratified by the US or Russian parliaments. Doubts may be raised over whether it will ever be. In the best case there will be more than 20,000 nuclear warheads in the arsenals of these two countries by the year 2003. All five nuclear states consider that nuclear weapons are an essential component of their national defense. It might sound childish but, the whole story is is so often childish: the five powers refuse to break their nuclear toys. They take even all possible measures to maintain and improve them and to ensure the survivability of their arsenals. To prepare for the next arms race..

  6. Well ARMed and FiRM

    DEFF Research Database (Denmark)

    Rasmussen, Kourosh Marjani; Zenios, Stavros A.

    2007-01-01

    of mortgage loans of a homeowner and apply it to data from the Danish market. Even in the presence of mortgage origination costs it is shown that most risk averse homeowners will do well to consider a diversified portfolio of both fixed (FRM) and adjustable (ARM) rate mortgages. This is particularly so if one...... or the homeowner's situation warrants it. And while, traditionally, a single mortgage loan would serve borrower needs, today it appears that a portfolio of loans may satisfy much better the mortgage needs of the individual and his or her appetite for risk. In this paper we develop a model for the diversification...

  7. HS06 Benchmark for an ARM Server

    Science.gov (United States)

    Kluth, Stefan

    2014-06-01

    We benchmarked an ARM cortex-A9 based server system with a four-core CPU running at 1.1 GHz. The system used Ubuntu 12.04 as operating system and the HEPSPEC 2006 (HS06) benchmarking suite was compiled natively with gcc-4.4 on the system. The benchmark was run for various settings of the relevant gcc compiler options. We did not find significant influence from the compiler options on the benchmark result. The final HS06 benchmark result is 10.4.

  8. An Approach to Naval Arms Control

    Science.gov (United States)

    1989-07-01

    commentary pro and con on the control of SLCM’s has 9 I: been uttered by people not known to be expert on maritime strategy and the roles of navies in crisis ... transcultural misunderstanding is indeed deep and widespread (e.g., witness the surprise on the part of America’s leading television pundits that China’s...force on behalf of (U.S definition of) international order in situations short of war; 0 alliance cohesion; 37 i * crisis , arms race, and political

  9. ARM CLASIC ER2 CRS/EDOP

    Energy Technology Data Exchange (ETDEWEB)

    Gerald Heymsfield

    2010-12-20

    Data was taken with the NASA ER-2 aircraft with the Cloud Radar System and other instruments in conjunction with the DOE ARM CLASIC field campaign. The flights were near the SGP site in north Central Oklahoma and targeted small developing convection. The CRS is a 94 GHz nadir pointing Doppler radar. Also on board the ER-2 was the Cloud Physics Lidar (CPL). Seven science flights were conducted but the weather conditions did not cooperate in that there was neither developing convection, or there was heavy rain.

  10. The extended arm of health professionals?

    DEFF Research Database (Denmark)

    Norlyk, Annelise; Martinsen, Bente

    2013-01-01

    responsibility for both the patient's well-being and for the patient's compliance with the daily regimen. Relatives were caught in a conflicting double role. They were the extended arm of the health professionals but also the caring, supporting partner. A tension arose between relatives' desire to help....... Due to the early discharge and the increasing demands on patients for self-care, patients' relatives seem to play a pivotal role in fast-track programmes. However, research is limited into how patients' close relatives are affected by and involved in the postoperative recovery process. Design...

  11. Keeping the lid on nuclear arms

    International Nuclear Information System (INIS)

    Milhollin, G.; Weeks, J.

    1991-01-01

    In November 1990 Brazil and Argentina agreed not to produce nuclear weapons and to allow mutual inspections of their secret nuclear sites. This exciting move towards nuclear arms control may form the basis of a model of international inspection which other countries may seek to follow. However, neither country will yet unconditionally accept the verification scale proposed by the International Atomic Energy Agency (IAEA). The IAEA seeks to ensure that civilian nuclear materials are not diverted for military use. Military authorities in both countries oppose the plan. It is anticipated that existing difficulties will be overcome. (UK)

  12. HS06 benchmark for an ARM server

    International Nuclear Information System (INIS)

    Kluth, Stefan

    2014-01-01

    We benchmarked an ARM cortex-A9 based server system with a four-core CPU running at 1.1 GHz. The system used Ubuntu 12.04 as operating system and the HEPSPEC 2006 (HS06) benchmarking suite was compiled natively with gcc-4.4 on the system. The benchmark was run for various settings of the relevant gcc compiler options. We did not find significant influence from the compiler options on the benchmark result. The final HS06 benchmark result is 10.4.

  13. ARM assembly language fundamentals and techniques

    CERN Document Server

    Hohl, William

    2009-01-01

    Written by the director of ARM's worldwide academic program, this volume gives computer science professionals and students an edge, regardless of their preferred coding language. For those with some basic background in digital logic and high-level programming, the book examines code relevant to hardware and peripherals found on today's microcontrollers and looks at situations all programmers will eventually encounter. The book's carefully chosen examples teach easily transferrable skills that will help readers optimize routines and significantly streamline coding, especially in the embedded sp

  14. Kootenay Lake Fertilization Experiment, Year 15 (North Arm) and Year 3 (South Arm) (2006) Report

    Energy Technology Data Exchange (ETDEWEB)

    Schindler, E.U.; Sebastian, D.; Andrusak, G.F. [Fish and Wildlife Science and Allocation, Ministry of Environment, Province of British Columbia

    2009-07-01

    This report summarizes results from the fifteenth year (2006) of nutrient additions to the North Arm of Kootenay Lake and three years of nutrient additions to the South Arm. Experimental fertilization of the lake has been conducted using an adaptive management approach in an effort to restore lake productivity lost as a result of nutrient uptake in upstream reservoirs. The primary objective of the experiment is to restore kokanee (Oncorhynchus nerka) populations, which are the main food source for Gerrard rainbow trout (Oncorhynchus mykiss) and bull trout (Salvelinus confluentus). The quantity of agricultural grade liquid fertilizer (10-34-0, ammonium polyphosphate and 28-0-0, urea ammonium nitrate) added to the North Arm in 2006 was 44.7 tonnes of P and 248.4 tonnes of N. The total fertilizer load added to the South Arm was 257 tonnes of nitrogen; no P was added. Kootenay Lake has an area of 395 km{sup 2}, a maximum depth of 150 m, a mean depth of 94 m, and a water renewal time of approximately two years. Kootenay Lake is a monomictic lake, generally mixing from late fall to early spring and stratifying during the summer. Surface water temperatures generally exceed 20 C for only a few weeks in July. Results of oxygen profiles were similar to previous years with the lake being well oxygenated from the surface to the bottom depths at all stations. Similar to past years, Secchi disc measurements at all stations in 2006 indicate a typical seasonal pattern of decreasing depths associated with the spring phytoplankton bloom, followed by increasing depths as the bloom gradually decreases by the late summer and fall. Total phosphorus (TP) ranged from 2-7 {micro}g/L and tended to decrease as summer advanced. Over the sampling season dissolved inorganic nitrogen (DIN) concentrations decreased, with the decline corresponding to nitrate (the dominant component of DIN) being utilized by phytoplankton during summer stratification. Owing to the importance of epilimnetic nitrate

  15. A dual function fusion protein of Herpes simplex virus type 1 thymidine kinase and firefly luciferase for noninvasive in vivo imaging of gene therapy in malignant glioma.

    Science.gov (United States)

    Söling, Ariane; Theiss, Christian; Jungmichel, Stephanie; Rainov, Nikolai G

    2004-08-04

    BACKGROUND: Suicide gene therapy employing the prodrug activating system Herpes simplex virus type 1 thymidine kinase (HSV-TK)/ ganciclovir (GCV) has proven to be effective in killing experimental brain tumors. In contrast, glioma patients treated with HSV-TK/ GCV did not show significant treatment benefit, most likely due to insufficient transgene delivery to tumor cells. Therefore, this study aimed at developing a strategy for real-time noninvasive in vivo monitoring of the activity of a therapeutic gene in brain tumor cells. METHODS: The HSV-TK gene was fused to the firefly luciferase (Luc) gene and the fusion construct HSV-TK-Luc was expressed in U87MG human malignant glioma cells. Nude mice with subcutaneous gliomas stably expressing HSV-TK-Luc were subjected to GCV treatment and tumor response to therapy was monitored in vivo by serial bioluminescence imaging. Bioluminescent signals over time were compared with tumor volumes determined by caliper. RESULTS: Transient and stable expression of the HSV-TK-Luc fusion protein in U87MG glioma cells demonstrated close correlation of both enzyme activities. Serial optical imaging of tumor bearing mice detected in all cases GCV induced death of tumor cells expressing the fusion protein and proved that bioluminescence can be reliably used for repetitive and noninvasive quantification of HSV-TK/ GCV mediated cell kill in vivo. CONCLUSION: This approach may represent a valuable tool for the in vivo evaluation of gene therapy strategies for treatment of malignant disease.

  16. Arm-to-arm variation when evaluating neuromuscular block: an analysis of the precision and the bias and agreement between arms when using mechanomyography or acceleromyography

    DEFF Research Database (Denmark)

    Claudius, C; Skovgaard, L T; Viby-Mogensen, J

    2010-01-01

    Studies comparing acceleromyography and mechanomyography indicate that the two methods cannot be used interchangeably. However, it is uncertain to what extent differences in precision between the methods and the naturally occurring arm-to-arm variation have influenced the results of these studies...

  17. Robust coordinated control of a dual-arm space robot

    Science.gov (United States)

    Shi, Lingling; Kayastha, Sharmila; Katupitiya, Jay

    2017-09-01

    Dual-arm space robots are more capable of implementing complex space tasks compared with single arm space robots. However, the dynamic coupling between the arms and the base will have a serious impact on the spacecraft attitude and the hand motion of each arm. Instead of considering one arm as the mission arm and the other as the balance arm, in this work two arms of the space robot perform as mission arms aimed at accomplishing secure capture of a floating target. The paper investigates coordinated control of the base's attitude and the arms' motion in the task space in the presence of system uncertainties. Two types of controllers, i.e. a Sliding Mode Controller (SMC) and a nonlinear Model Predictive Controller (MPC) are verified and compared with a conventional Computed-Torque Controller (CTC) through numerical simulations in terms of control accuracy and system robustness. Both controllers eliminate the need to linearly parameterize the dynamic equations. The MPC has been shown to achieve performance with higher accuracy than CTC and SMC in the absence of system uncertainties under the condition that they consume comparable energy. When the system uncertainties are included, SMC and CTC present advantageous robustness than MPC. Specifically, in a case where system inertia increases, SMC delivers higher accuracy than CTC and costs the least amount of energy.

  18. CHARACTERISTICS OF SPIRAL ARMS IN LATE-TYPE GALAXIES

    International Nuclear Information System (INIS)

    Honig, Z. N.; Reid, M. J.

    2015-01-01

    We have measured the positions of large numbers of H II regions in four nearly face-on, late-type, spiral galaxies: NGC 628 (M74), NGC 1232, NGC 3184, and NGC 5194 (M51). Fitting log-periodic spiral models to segments of each arm yields local estimates of spiral pitch angle and arm width. While pitch angles vary considerably along individual arms, among arms within a galaxy, and among galaxies, we find no systematic trend with galactocentric distance. We estimate the widths of the arm segments from the scatter in the distances of the H II regions from the spiral model. All major arms in these galaxies show spiral arm width increasing with distance from the galactic center, similar to the trend seen in the Milky Way. However, in the outermost parts of the galaxies, where massive star formation declines, some arms reverse this trend and narrow. We find that spiral arms often appear to be composed of segments of ∼5 kpc length, which join to form kinks and abrupt changes in pitch angle and arm width; these characteristics are consistent with properties seen in the large N-body simulations of D'Onghia et al. and others

  19. Electromechanical and robot-assisted arm training for improving activities of daily living, arm function, and arm muscle strength after stroke.

    Science.gov (United States)

    Mehrholz, Jan; Pohl, Marcus; Platz, Thomas; Kugler, Joachim; Elsner, Bernhard

    2015-11-07

    Electromechanical and robot-assisted arm training devices are used in rehabilitation, and may help to improve arm function after stroke. To assess the effectiveness of electromechanical and robot-assisted arm training for improving activities of daily living, arm function, and arm muscle strength in people after stroke. We also assessed the acceptability and safety of the therapy. We searched the Cochrane Stroke Group's Trials Register (last searched February 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2015, Issue 3), MEDLINE (1950 to March 2015), EMBASE (1980 to March 2015), CINAHL (1982 to March 2015), AMED (1985 to March 2015), SPORTDiscus (1949 to March 2015), PEDro (searched April 2015), Compendex (1972 to March 2015), and Inspec (1969 to March 2015). We also handsearched relevant conference proceedings, searched trials and research registers, checked reference lists, and contacted trialists, experts, and researchers in our field, as well as manufacturers of commercial devices. Randomised controlled trials comparing electromechanical and robot-assisted arm training for recovery of arm function with other rehabilitation or placebo interventions, or no treatment, for people after stroke. Two review authors independently selected trials for inclusion, assessed trial quality and risk of bias, and extracted data. We contacted trialists for additional information. We analysed the results as standardised mean differences (SMDs) for continuous variables and risk differences (RDs) for dichotomous variables. We included 34 trials (involving 1160 participants) in this update of our review. Electromechanical and robot-assisted arm training improved activities of daily living scores (SMD 0.37, 95% confidence interval (CI) 0.11 to 0.64, P = 0.005, I² = 62%), arm function (SMD 0.35, 95% CI 0.18 to 0.51, P arm muscle strength (SMD 0.36, 95% CI 0.01 to 0.70, P = 0.04, I² = 72%), but the quality of the evidence was low to very low

  20. ARM Climate Research Facility Annual Report 2004

    Energy Technology Data Exchange (ETDEWEB)

    Voyles, J.

    2004-12-31

    Like a rock that slowly wears away beneath the pressure of a waterfall, planet earth?s climate is almost imperceptibly changing. Glaciers are getting smaller, droughts are lasting longer, and extreme weather events like fires, floods, and tornadoes are occurring with greater frequency. Why? Part of the answer is clouds and the amount of solar radiation they reflect or absorb. These two factors clouds and radiative transfer represent the greatest source of error and uncertainty in the current generation of general circulation models used for climate research and simulation. The U.S. Global Change Research Act of 1990 established an interagency program within the Executive Office of the President to coordinate U.S. agency-sponsored scientific research designed to monitor, understand, and predict changes in the global environment. To address the need for new research on clouds and radiation, the U.S. Department of Energy (DOE) established the Atmospheric Radiation Measurement (ARM) Program. As part of the DOE?s overall Climate Change Science Program, a primary objective of the ARM Program is improved scientific understanding of the fundamental physics related to interactions between clouds and radiative feedback processes in the atmosphere.

  1. The politics of arms control treaty ratification

    International Nuclear Information System (INIS)

    Krepon, M.; Caldwell, D.

    1991-01-01

    This book presents a critical examination of executive-congressional relations and the domestic politics of arms control treaty ratification within the United States during the twentieth century. The staring point of this study is the hypothesis that the politics of treaty ratification can be as important as the negotiations leading up to agreements. Benefits to international peace and security sought in years of painstaking diplomatic effort can be lost without Senate consent, as was the case with the Treaty of Versailles and the second treaty arising from the Strategic Arms Limitation Talks (SALT II). The authors of the case studies were requested to present first a brief, historical introduction to the case indicating why the case was important, the background concerning the origins of the treaty, and the treaty's major provisions. The purpose of the introduction to the case was not to provide a complete picture of the negotiating record but to set the stage for a more in-depth discussion of the events that followed after the treaty was signed. The authors address five substantive areas: the international political context of the treaty, the domestic political context, the role of the president, executive-congressional relations, and public opinion and the role of interest groups. The questions and issues concerning each of these areas are briefly summarized

  2. An Articulated Inspection Arm for fusion purposes

    International Nuclear Information System (INIS)

    Villedieu, E.; Bruno, V.; Pastor, P.; Gargiulo, L.; Song, Y.T.; Cheng, Y.; Feng, H.; Liu, C.; Shi, S.S.

    2016-01-01

    Highlights: • Requirements for in vacuum tokamak inspection are presented. • Development of a prototype of the Articulated Inspection Arm is described. • The upgrade of the prototype to convert it into a fully operational device is detailed. • Future applications of inspection robots in the new fusion reactors is discussed. - Abstract: Fusion Tokamaks are complex machines which require special conditions for their operation, in particular, high vacuum inside the vessel and high temperature of the vessel walls. During plasma phases, the first wall components are highly stressed and a control is necessary in case of doubt about their condition. To be able to make safely such an inspection in a short period of time is a great advantage. The Articulated Inspection Arm (AIA) developed by the CEA provides the capability for fast inspections of the first wall overall surface keeping the vacuum and temperature conditions of the vessel. The robot prototype was validated in Tore Supra in 2008. In the frame of a joint laboratory, CEA/IRFM and ASIPP have decided to upgrade the existing AIA prototype to use it routinely in the EAST and WEST tokamaks. The robot has followed an important upgrade program in 2013 and 2014. The document presents the various upgrades made on the mechanics, the sensors, the electronics, the control station and the integration adaptation for the operation on EAST. From the AIA experience, thoughts for future inspection robots are given.

  3. An Articulated Inspection Arm for fusion purposes

    Energy Technology Data Exchange (ETDEWEB)

    Villedieu, E., E-mail: eric.villedieu@cea.fr [CEA-IRFM, 13108 Saint Paul lez Durance (France); Bruno, V.; Pastor, P.; Gargiulo, L. [CEA-IRFM, 13108 Saint Paul lez Durance (France); Song, Y.T.; Cheng, Y.; Feng, H. [Institute of Plasma Physics, Chinese Academy of Sciences, Hefei (China); Liu, C. [CEA-IRFM, 13108 Saint Paul lez Durance (France); Institute of Plasma Physics, Chinese Academy of Sciences, Hefei (China); Shi, S.S. [Institute of Plasma Physics, Chinese Academy of Sciences, Hefei (China)

    2016-11-01

    Highlights: • Requirements for in vacuum tokamak inspection are presented. • Development of a prototype of the Articulated Inspection Arm is described. • The upgrade of the prototype to convert it into a fully operational device is detailed. • Future applications of inspection robots in the new fusion reactors is discussed. - Abstract: Fusion Tokamaks are complex machines which require special conditions for their operation, in particular, high vacuum inside the vessel and high temperature of the vessel walls. During plasma phases, the first wall components are highly stressed and a control is necessary in case of doubt about their condition. To be able to make safely such an inspection in a short period of time is a great advantage. The Articulated Inspection Arm (AIA) developed by the CEA provides the capability for fast inspections of the first wall overall surface keeping the vacuum and temperature conditions of the vessel. The robot prototype was validated in Tore Supra in 2008. In the frame of a joint laboratory, CEA/IRFM and ASIPP have decided to upgrade the existing AIA prototype to use it routinely in the EAST and WEST tokamaks. The robot has followed an important upgrade program in 2013 and 2014. The document presents the various upgrades made on the mechanics, the sensors, the electronics, the control station and the integration adaptation for the operation on EAST. From the AIA experience, thoughts for future inspection robots are given.

  4. The Phoenix Mars Lander Robotic Arm

    Science.gov (United States)

    Bonitz, Robert; Shiraishi, Lori; Robinson, Matthew; Carsten, Joseph; Volpe, Richard; Trebi-Ollennu, Ashitey; Arvidson, Raymond E.; Chu, P. C.; Wilson, J. J.; Davis, K. R.

    2009-01-01

    The Phoenix Mars Lander Robotic Arm (RA) has operated for over 150 sols since the Lander touched down on the north polar region of Mars on May 25, 2008. During its mission it has dug numerous trenches in the Martian regolith, acquired samples of Martian dry and icy soil, and delivered them to the Thermal Evolved Gas Analyzer (TEGA) and the Microscopy, Electrochemistry, and Conductivity Analyzer (MECA). The RA inserted the Thermal and Electrical Conductivity Probe (TECP) into the Martian regolith and positioned it at various heights above the surface for relative humidity measurements. The RA was used to point the Robotic Arm Camera to take images of the surface, trenches, samples within the scoop, and other objects of scientific interest within its workspace. Data from the RA sensors during trenching, scraping, and trench cave-in experiments have been used to infer mechanical properties of the Martian soil. This paper describes the design and operations of the RA as a critical component of the Phoenix Mars Lander necessary to achieve the scientific goals of the mission.

  5. Computing Arm Movements with a Monkey Brainet.

    Science.gov (United States)

    Ramakrishnan, Arjun; Ifft, Peter J; Pais-Vieira, Miguel; Byun, Yoon Woo; Zhuang, Katie Z; Lebedev, Mikhail A; Nicolelis, Miguel A L

    2015-07-09

    Traditionally, brain-machine interfaces (BMIs) extract motor commands from a single brain to control the movements of artificial devices. Here, we introduce a Brainet that utilizes very-large-scale brain activity (VLSBA) from two (B2) or three (B3) nonhuman primates to engage in a common motor behaviour. A B2 generated 2D movements of an avatar arm where each monkey contributed equally to X and Y coordinates; or one monkey fully controlled the X-coordinate and the other controlled the Y-coordinate. A B3 produced arm movements in 3D space, while each monkey generated movements in 2D subspaces (X-Y, Y-Z, or X-Z). With long-term training we observed increased coordination of behavior, increased correlations in neuronal activity between different brains, and modifications to neuronal representation of the motor plan. Overall, performance of the Brainet improved owing to collective monkey behaviour. These results suggest that primate brains can be integrated into a Brainet, which self-adapts to achieve a common motor goal.

  6. Europe, arms control and American security

    International Nuclear Information System (INIS)

    Burns, W.F.

    1992-01-01

    What has come to be called the Revolution of 1989 has swept away longstanding political and economic arrangements in Eastern Europe. Perhaps more important, it has also called into question the fundamental underpinnings of European security created during the nonpeace that followed World War II. In June 1990, the Warsaw Treaty Organization abandoned the notion that NATO was the ideological enemy. At the same time, NATO ministers agreed at Tunberry, Scotland, to consider defining the Atlantic Alliance as more of a partner of the Soviet Union than as an enemy. The Washington summit of May 1990 between president Mikhail Gorbachev and president George Bush further highlighted the recent changes in the Soviet Union and its former satellites. Issues going to the heart of the viability of the Soviet Union and the communist system of political and economic organization competed with German reunification as central themes. Arms control issues, particularly as they pertain in European military stability, became contingent and dependent on the development of a broader political and economic framework for a new Europe. Whether this framework is viable remains an open question as Gorbachev's role is challenged more and more within the Soviet Union. This paper deals with European arms control issues from the point of view of the United States and its own security interests. The United States involved its security inextricably with that of Western Europe as a conscious decision in the turmoil following World War II

  7. Mid-upper-arm-circumference and mid-upper-arm circumference z-score

    DEFF Research Database (Denmark)

    Rasmussen, J; Andersen, A; Fisker, A B

    2012-01-01

    Mid-upper-arm circumference (MUAC) is a simple method of assessing nutritional status in children above 6 months of age. In 2007 World Health Organization (WHO) introduced a MUAC z-score for children above 3 months of age. We evaluated whether MUAC or MUAC z-score had the best ability to identify...

  8. Robots testing robots: ALAN-Arm, a humanoid arm for the testing of robotic rehabilitation systems.

    Science.gov (United States)

    Brookes, Jack; Kuznecovs, Maksims; Kanakis, Menelaos; Grigals, Arturs; Narvidas, Mazvydas; Gallagher, Justin; Levesley, Martin

    2017-07-01

    Robotics is increasing in popularity as a method of providing rich, personalized and cost-effective physiotherapy to individuals with some degree of upper limb paralysis, such as those who have suffered a stroke. These robotic rehabilitation systems are often high powered, and exoskeletal systems can attach to the person in a restrictive manner. Therefore, ensuring the mechanical safety of these devices before they come in contact with individuals is a priority. Additionally, rehabilitation systems may use novel sensor systems to measure current arm position. Used to capture and assess patient movements, these first need to be verified for accuracy by an external system. We present the ALAN-Arm, a humanoid robotic arm designed to be used for both accuracy benchmarking and safety testing of robotic rehabilitation systems. The system can be attached to a rehabilitation device and then replay generated or human movement trajectories, as well as autonomously play rehabilitation games or activities. Tests of the ALAN-Arm indicated it could recreate the path of a generated slow movement path with a maximum error of 14.2mm (mean = 5.8mm) and perform cyclic movements up to 0.6Hz with low gain (<1.5dB). Replaying human data trajectories showed the ability to largely preserve human movement characteristics with slightly higher path length and lower normalised jerk.

  9. Poly(glycolide multi-arm star polymers: Improved solubility via limited arm length

    Directory of Open Access Journals (Sweden)

    Florian K. Wolf

    2010-06-01

    Full Text Available Due to the low solubility of poly(glycolic acid (PGA, its use is generally limited to the synthesis of random copolyesters with other hydroxy acids, such as lactic acid, or to applications that permit direct processing from the polymer melt. Insolubility is generally observed for PGA when the degree of polymerization exceeds 20. Here we present a strategy that allows the preparation of PGA-based multi-arm structures which significantly exceed the molecular weight of processable oligomeric linear PGA (<1000 g/mol. This was achieved by the use of a multifunctional hyperbranched polyglycerol (PG macroinitiator and the tin(II-2-ethylhexanoate catalyzed ring-opening polymerization of glycolide in the melt. With this strategy it is possible to combine high molecular weight with good molecular weight control (up to 16,000 g/mol, PDI = 1.4–1.7, resulting in PGA multi-arm star block copolymers containing more than 90 wt % GA. The successful linkage of PGA arms and PG core via this core first/grafting from strategy was confirmed by detailed NMR and SEC characterization. Various PG/glycolide ratios were employed to vary the length of the PGA arms. Besides fluorinated solvents, the materials were soluble in DMF and DMSO up to an average arm length of 12 glycolic acid units. Reduction in the Tg and the melting temperature compared to the homopolymer PGA should lead to simplified processing conditions. The findings contribute to broadening the range of biomedical applications of PGA.

  10. The globalization of the arms industry: The next proliferation challenge

    Energy Technology Data Exchange (ETDEWEB)

    Bitzinger, R.A.

    1994-12-31

    The globalization of the arms industry entails a significant shift away from traditional, single-country patterns of weapons production toward internationalization of the development, production, and marketing of arms. While wholly indigenous armaments production may be on the decline, multinational arms production - through collaboration on individual weapon systems and increasingly via interfirm linkages across the international arms industry - appears actually to be expanding. In several instances, in fact, multinational armaments production is increasingly supplementing or even supplanting indigenous or autonomous weapons production or arms imports. The emergence of an increasingly transnational defense technology and industrial base is fundamentally affecting the shape and content of much of the global arms trade. This changing defense market, in turn, will have a profound impact on a number of national security issues concerning the Western industrialized nations. 3 figs., 2 tabs.

  11. ARM Operations and Engineering Procedure Mobile Facility Site Startup

    Energy Technology Data Exchange (ETDEWEB)

    Voyles, Jimmy W

    2015-05-01

    This procedure exists to define the key milestones, necessary steps, and process rules required to commission and operate an Atmospheric Radiation Measurement (ARM) Mobile Facility (AMF), with a specific focus toward on-time product delivery to the ARM Data Archive. The overall objective is to have the physical infrastructure, networking and communications, and instrument calibration, grooming, and alignment (CG&A) completed with data products available from the ARM Data Archive by the Operational Start Date milestone.

  12. The Role of Ethics in International Arms Transfers

    Science.gov (United States)

    2016-06-01

    i THE ROLE OF ETHICS IN INTERNATIONAL ARMS TRANSFERS BY MAJOR ROB ARNETT A THESIS PRESENTED TO THE FACULTY OF THE SCHOOL OF...War’s Ends” provided the intellectual spark to explore the topic of ethics in international arms sales. Additionally, Dr. Murphy was kind enough to... ethics in American arms transfer policy to determine whether the Just War tradition’s jus ad bellum framework can help policymakers through a complex

  13. Participation in Armed Forces, National, and International Sports Activities

    Science.gov (United States)

    1987-03-09

    American Games , Olympic Games , and other authorized national and international sports competitions (to include qualifying and preparatory events) as long...concerning the participation of Armed Forces personnel in Armed Forces, national, and international sports competitions ; establishes a Senior Military Sports ...program is to ensure that the U.S. Armed Forces are appropriately represented in national and international sports competitions . 3. The purpose of this

  14. A Unified Approach for Reporting ARM Measurement Uncertainties Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Campos, E [Argonne National Lab. (ANL), Argonne, IL (United States); Sisterson, Douglas [Argonne National Lab. (ANL), Argonne, IL (United States)

    2016-12-01

    The U.S. Department of Energy (DOE) Atmospheric Radiation Measurement (ARM) Climate Research Facility is observationally based, and quantifying the uncertainty of its measurements is critically important. With over 300 widely differing instruments providing over 2,500 datastreams, concise expression of measurement uncertainty is quite challenging. The ARM Facility currently provides data and supporting metadata (information about the data or data quality) to its users through a number of sources. Because the continued success of the ARM Facility depends on the known quality of its measurements, the Facility relies on instrument mentors and the ARM Data Quality Office (DQO) to ensure, assess, and report measurement quality. Therefore, an easily accessible, well-articulated estimate of ARM measurement uncertainty is needed. Note that some of the instrument observations require mathematical algorithms (retrievals) to convert a measured engineering variable into a useful geophysical measurement. While those types of retrieval measurements are identified, this study does not address particular methods for retrieval uncertainty. As well, the ARM Facility also provides engineered data products, or value-added products (VAPs), based on multiple instrument measurements. This study does not include uncertainty estimates for those data products. We propose here that a total measurement uncertainty should be calculated as a function of the instrument uncertainty (calibration factors), the field uncertainty (environmental factors), and the retrieval uncertainty (algorithm factors). The study will not expand on methods for computing these uncertainties. Instead, it will focus on the practical identification, characterization, and inventory of the measurement uncertainties already available in the ARM community through the ARM instrument mentors and their ARM instrument handbooks. As a result, this study will address the first steps towards reporting ARM measurement uncertainty

  15. Naval trends in ASEAN: is there a new arms race?

    OpenAIRE

    Jones, Frank Curtis

    1995-01-01

    Global military spending is decreasing. However this trend does not apply to some regions of the world, specifically Southeast Asia. This thesis describes the ongoing naval arms buildup in this region and examines why it is occurring when the rest of the world is decreasing military spending. Next, this thesis asks if this arms build-up is dangerous. Unlike many other arms races around the world, the Southeast Asian build-up is not particularly dangerous because of the parallel development of...

  16. WORKSPACE DRAWING FROM A MANIPULATOR ARM WITH 6 DOF

    Directory of Open Access Journals (Sweden)

    NAIDIN Gigi

    2011-06-01

    Full Text Available Modelling and simulation is an important aspect in robotic field. Knowing of the workspace is very important to the operation of manipulators arm. This paper investigates operational performance of space manipulator arm destined for industrial manufacturing, by defining and analyzing their workspace and manipulability measure. The authors show that manipulator arm developing requires the consideration of more efficient dynamic models and use of dedicated processing techniques such as Autodesk-Inventor 9, MATLAB, WorkSpace software.

  17. SIPRI's new conceptual approach to arms control and disarmament

    International Nuclear Information System (INIS)

    Rotfeld, Adam Daniel

    2000-01-01

    The end of the cold war deprioritized arms control and disarmament, and progress in the field was no longer a measure of relations among the major powers. In that context, the future of arms control and disarmament was discussed at the Nobel Symposium in October 1999. Stockholm International Peace Research Institute (SIPRI) views arms control as an instrument for shaping a new inclusive and cooperative security order. The author questions whether arms control challenges today can and should be resolved in the institutions established and the procedures elaborated in the bipolar framework. (author)

  18. Transforming the Albanian Armed Forces, Overcoming the Challenges

    National Research Council Canada - National Science Library

    Cahani, Nazmi

    2009-01-01

    The Albanian Armed Forces (AAF) are currently undergoing an extensive defense reform process that consists of transformation of its strategic concept, doctrine, organizational structure, personnel management system, military...

  19. Information booklet on personal protective equipment: arm and hand protection

    International Nuclear Information System (INIS)

    1992-01-01

    Fire, heat, cold, electro-magnetic and ionising radiation, electricity, chemicals, impacts, cuts, abrasion, etc. are the common hazards for arms and hands at work. The gloves chosen for protection of the arm and hand should cover those parts adequately and the material of the gloves should be capable of offering protection against the specific hazard involved. Criteria for choosing arm and hand protection equipment will be based on their shape and part of the arm and hand protected. Guide lines for choosing such personal protection equipment for nuclear facilities are given. (M.K.V.). 3 annexures, 1 appendix

  20. Simulation of Octopus Arm Based on Coupled CPGs

    Directory of Open Access Journals (Sweden)

    Juan Tian

    2015-01-01

    Full Text Available The octopus arm has attracted many researchers’ interests and became a research hot spot because of its amazing features. Several dynamic models inspired by an octopus arm are presented to realize the structure with a large number of degrees of freedom. The octopus arm is made of a soft material introducing high-dimensionality, nonlinearity, and elasticity, which makes the octopus arm difficult to control. In this paper, three coupled central pattern generators (CPGs are built and a 2-dimensional dynamic model of the octopus arm is presented to explore possible strategies of the octopus movement control. And the CPGs’ signals treated as activation are added on the ventral, dorsal, and transversal sides, respectively. The effects of the octopus arm are discussed when the parameters of the CPGs are changed. Simulations show that the octopus arm movements are mainly determined by the shapes of three CPGs’ phase diagrams. Therefore, some locomotion modes are supposed to be embedded in the neuromuscular system of the octopus arm. And the octopus arm movements can be achieved by modulating the parameters of the CPGs. The results are beneficial for researchers to understand the octopus movement further.

  1. Manipulator arm for a nuclear reactor vessel inspection device

    International Nuclear Information System (INIS)

    1980-01-01

    A manipulator arm for a reactor vessel in-service inspection apparatus is adapted to transport a transducer array for ultrasonic examination of welds at any point in the vessel. The removal of the inspection device from the reactor vessel in an emergency presents a problem where a relatively long manipulator arm is used. This invention provides an improved arm with means for changing the normal orientation of the arm to a shorter one to permit safe removal of the inspection device from the reactor vessel. (author)

  2. Hot Galactic Arms Point To Vicious Cycle

    Science.gov (United States)

    2001-12-01

    NASA's Chandra X-ray Observatory has revealed the aftermath of a titanic explosion that wracked the elliptical galaxy known as NGC 4636. This eruption could be the latest episode in a cycle of violence that is triggered by gas falling into a central massive black hole. Chandra's images of NGC 4636 show spectacular symmetric arms, or arcs, of hot gas extending 25,000 light years into a huge cloud of multimillion-degree-Celsius gas that envelopes the galaxy. At a temperature of 10 million degrees, the arms are 30 percent hotter than the surrounding gas cloud. "The temperature jump, together with the symmetry and scale of the arms, suggests that we are observing the effects of a tremendous outburst that occurred in the center of the galaxy," said Christine Jones of the Harvard-Smithsonian Center for Astrophysics in Cambridge, Mass., lead author of a paper on these observations scheduled for publication in Astrophysical Journal Letters. "The energy of this explosion would be the equivalent of several hundred thousand supernovas." The arms appear to be the leading edges of a galaxy-sized shock wave that is racing outward at 700 kilometers per second, or 1.6 million miles per hour. At this speed, it would take 3 million years for the structures to attain their present size. Cavities detected in the hot gas cloud to the east and west of the center of the galaxy support the shockwave explanation. The authors suggest that the explosion is part of a majestic cosmic feedback process that keeps the galaxy in a state of turmoil. Over a period of a few million years, a hot gas cloud that envelops the stars in the galaxy cools and falls inward toward a central, massive black hole. The feeding of the black hole by the infalling material leads to an explosion that heats the hot gaseous envelope, starting the cycle anew. NGC 4636 NGC 4636 Background Subtracted This feedback cycle may explain one puzzling feature of the galaxy - the lack of a strong radio source of the type that is

  3. Phoenix Robotic Arm's Workspace After 90 Sols

    Science.gov (United States)

    2008-01-01

    During the first 90 Martian days, or sols, after its May 25, 2008, landing on an arctic plain of Mars, NASA's Phoenix Mars Lander dug several trenches in the workspace reachable with the lander's robotic arm. The lander's Surface Stereo Imager camera recorded this view of the workspace on Sol 90, early afternoon local Mars time (overnight Aug. 25 to Aug. 26, 2008). The shadow of the the camera itself, atop its mast, is just left of the center of the image and roughly a third of a meter (one foot) wide. The workspace is on the north side of the lander. The trench just to the right of center is called 'Neverland.' The Phoenix Mission is led by the University of Arizona, Tucson, on behalf of NASA. Project management of the mission is by NASA's Jet Propulsion Laboratory, Pasadena, Calif. Spacecraft development is by Lockheed Martin Space Systems, Denver.

  4. Tolerance at arm's length: the Dutch experience.

    Science.gov (United States)

    Schuijer, J

    1990-01-01

    With respect to pedophilia and the age of consent, the Netherlands warrants special attention. Although pedophilia is not as widely accepted in the Netherlands as sometimes is supposed, developments in the judicial practice showed a growing reservedness. These developments are a spin-off of related developments in Dutch society. The tolerance in the Dutch society has roots that go far back in history and is also a consequence of the way this society is structured. The social changes of the sixties and seventies resulted in a "tolerance at arm's length" for pedophiles, which proved to be deceptive when the Dutch government proposed to lower the age of consent in 1985. It resulted in a vehement public outcry. The prevailing sex laws have been the prime target of protagonists of pedophile emancipation. Around 1960, organized as a group, they started to undertake several activities. In the course of their existence, they came to redefine the issue of pedophilia as one of youth emancipation.

  5. Magnetic spiral arms in galaxy haloes

    Science.gov (United States)

    Henriksen, R. N.

    2017-08-01

    We seek the conditions for a steady mean field galactic dynamo. The parameter set is reduced to those appearing in the α2 and α/ω dynamo, namely velocity amplitudes, and the ratio of sub-scale helicity to diffusivity. The parameters can be allowed to vary on conical spirals. We analyse the mean field dynamo equations in terms of scale invariant logarithmic spiral modes and special exact solutions. Compatible scale invariant gravitational spiral arms are introduced and illustrated in an appendix, but the detailed dynamical interaction with the magnetic field is left for another work. As a result of planar magnetic spirals `lifting' into the halo, multiple sign changes in average rotation measures forming a regular pattern on each side of the galactic minor axis, are predicted. Such changes have recently been detected in the Continuum Halos in Nearby Galaxies-an EVLA Survey (CHANG-ES) survey.

  6. Testbed model and data assimilation for ARM

    International Nuclear Information System (INIS)

    Louis, J.F.

    1992-01-01

    The objectives of this contract are to further develop and test the ALFA (AER Local Forecast and Assimilation) model originally designed at AER for local weather prediction and apply it to three distinct but related purposes in connection with the Atmospheric Radiation Measurement (ARM) program: (a) to provide a testbed that simulates a global climate model in order to facilitate the development and testing of new cloud parametrizations and radiation models; (b) to assimilate the ARM data continuously at the scale of a climate model, using the adjoint method, thus providing the initial conditions and verification data for testing parameumtions; (c) to study the sensitivity of a radiation scheme to cloud parameters, again using the adjoint method, thus demonstrating the usefulness of the testbed model. The data assimilation will use a variational technique that minimizes the difference between the model results and the observation during the analysis period. The adjoint model is used to compute the gradient of a measure of the model errors with respect to nudging terms that are added to the equations to force the model output closer to the data. The radiation scheme that will be included in the basic ALFA model makes use of a gen two-stream approximation, and is designed for vertically inhonogeneous, multiple-scattering atmospheres. The sensitivity of this model to the definition of cloud parameters will be studied. The adjoint technique will also be used to compute the sensitivities. This project is designed to provide the Science Team members with the appropriate tools and modeling environment for proper testing and tuning of new radiation models and cloud parametrization schemes

  7. Nuclear arms race gearing for speedup

    International Nuclear Information System (INIS)

    Heylin, M.

    1981-01-01

    To probe the rationale behind the big buildup in US strategic arms that is presaged by the current enhanced R and D effort - and to explore the broader, more long-term role of science and technology in the nuclear arms race - C and EN in recent months spoke with a host of experts both within and outside the defense establishment. It is a topic of incredible complexity, high controversy, and of the highest stakes imaginable - the survival of civilization. This buildup will include over the next decade, apart from the MX, a new, highly accurate, submarine-launched ballistic missile and a fleet of very large submarines to carry it; an air-launched cruise missile; a new long-range bomber; a new intermediate-range missile and a new ground-launched cruise missile, both capable of hitting targets in the Soviet Union from proposed bases in Western Europe; and a new sea-launched cruise missile that can be fired from conventional submarines or other naval vessels. To spokesmen for, and members of, the defense establishment the US buildup is prudent, even minimal. According to them, it is needed to keep the US at least on a par with the growth of Soviet strategic might which was very substantial in the 1970's and which will carry over into the 1980's with further major gains. It also is needed to keep the lid on Soviet expansionism; and it is the best way to prevent a nuclear war. To critics, the proposed buildup is the height of lunacy. According to them, the US strategic arsenal is more than adequate today. And it can continue to serve its only legitimate purpose - to deter nuclear war, no matter how much the Soviets may choose to build up their nuclear forces - with a much-more-modest modernization program

  8. The Illusion of Owning a Third Arm

    Science.gov (United States)

    Ehrsson, H. Henrik

    2011-01-01

    Could it be possible that, in the not-so-distant future, we will be able to reshape the human body so as to have extra limbs? A third arm helping us out with the weekly shopping in the local grocery store, or an extra artificial limb assisting a paralysed person? Here we report a perceptual illusion in which a rubber right hand, placed beside the real hand in full view of the participant, is perceived as a supernumerary limb belonging to the participant's own body. This effect was supported by questionnaire data in conjunction with physiological evidence obtained from skin conductance responses when physically threatening either the rubber hand or the real one. In four well-controlled experiments, we demonstrate the minimal required conditions for the elicitation of this “supernumerary hand illusion”. In the fifth, and final experiment, we show that the illusion reported here is qualitatively different from the traditional rubber hand illusion as it is characterised by less disownership of the real hand and a stronger feeling of having two right hands. These results suggest that the artificial hand ‘borrows’ some of the multisensory processes that represent the real hand, leading to duplication of touch and ownership of two right arms. This work represents a major advance because it challenges the traditional view of the gross morphology of the human body as a fundamental constraint on what we can come to experience as our physical self, by showing that the body representation can easily be updated to incorporate an additional limb. PMID:21383847

  9. The illusion of owning a third arm.

    Directory of Open Access Journals (Sweden)

    Arvid Guterstam

    Full Text Available Could it be possible that, in the not-so-distant future, we will be able to reshape the human body so as to have extra limbs? A third arm helping us out with the weekly shopping in the local grocery store, or an extra artificial limb assisting a paralysed person? Here we report a perceptual illusion in which a rubber right hand, placed beside the real hand in full view of the participant, is perceived as a supernumerary limb belonging to the participant's own body. This effect was supported by questionnaire data in conjunction with physiological evidence obtained from skin conductance responses when physically threatening either the rubber hand or the real one. In four well-controlled experiments, we demonstrate the minimal required conditions for the elicitation of this "supernumerary hand illusion". In the fifth, and final experiment, we show that the illusion reported here is qualitatively different from the traditional rubber hand illusion as it is characterised by less disownership of the real hand and a stronger feeling of having two right hands. These results suggest that the artificial hand 'borrows' some of the multisensory processes that represent the real hand, leading to duplication of touch and ownership of two right arms. This work represents a major advance because it challenges the traditional view of the gross morphology of the human body as a fundamental constraint on what we can come to experience as our physical self, by showing that the body representation can easily be updated to incorporate an additional limb.

  10. Version of the galaxy spiral structure model with opposite-directed arms and inter-arm links

    Energy Technology Data Exchange (ETDEWEB)

    Dolidze, M V [AN Gruzinskoj SSR, Abastumani. Abastumanskaya Astrofizicheskaya Observatoriya

    1963-05-01

    An attempt is made to explain some peculiarities of the local spiral structure and large-scale distribution of HII regions in the Galaxy by coexistence of the trailing and leading arm systems of different power and development. The existence of opposite-directed arms and inter-arm links in the circular zone (5-15 kpc) is analysed from the point of view of different Galaxy models.

  11. Octopus-inspired multi-arm robotic swimming.

    Science.gov (United States)

    Sfakiotakis, M; Kazakidi, A; Tsakiris, D P

    2015-05-13

    The outstanding locomotor and manipulation characteristics of the octopus have recently inspired the development, by our group, of multi-functional robotic swimmers, featuring both manipulation and locomotion capabilities, which could be of significant engineering interest in underwater applications. During its little-studied arm-swimming behavior, as opposed to the better known jetting via the siphon, the animal appears to generate considerable propulsive thrust and rapid acceleration, predominantly employing movements of its arms. In this work, we capture the fundamental characteristics of the corresponding complex pattern of arm motion by a sculling profile, involving a fast power stroke and a slow recovery stroke. We investigate the propulsive capabilities of a multi-arm robotic system under various swimming gaits, namely patterns of arm coordination, which achieve the generation of forward, as well as backward, propulsion and turning. A lumped-element model of the robotic swimmer, which considers arm compliance and the interaction with the aquatic environment, was used to study the characteristics of these gaits, the effect of various kinematic parameters on propulsion, and the generation of complex trajectories. This investigation focuses on relatively high-stiffness arms. Experiments employing a compliant-body robotic prototype swimmer with eight compliant arms, all made of polyurethane, inside a water tank, successfully demonstrated this novel mode of underwater propulsion. Speeds of up to 0.26 body lengths per second (approximately 100 mm s(-1)), and propulsive forces of up to 3.5 N were achieved, with a non-dimensional cost of transport of 1.42 with all eight arms and of 0.9 with only two active arms. The experiments confirmed the computational results and verified the multi-arm maneuverability and simultaneous object grasping capability of such systems.

  12. Re-usable low density polyethylene arm glove for puerperal ...

    African Journals Online (AJOL)

    Objective: To design a long arm glove that can be used within a puerperal uterus to prevent the health-care worker contracting HIV from an infected patient. The designed long arm glove should be cheap (affordable) and readily available in low resource centres and must have proven sterility assurance and tensile strength ...

  13. Satellite data sets for the atmospheric radiation measurement (ARM) program

    Energy Technology Data Exchange (ETDEWEB)

    Shi, L.; Bernstein, R.L. [SeaSpace Corp., San Diego, CA (United States)

    1996-04-01

    This abstract describes the type of data obtained from satellite measurements in the Atmospheric Radiation Measurement (ARM) program. The data sets have been widely used by the ARM team to derive cloud-top altitude, cloud cover, snow and ice cover, surface temperature, water vapor, and wind, vertical profiles of temperature, and continuoous observations of weather needed to track and predict severe weather.

  14. A Review of the Effects of Armed Conflict on Children ...

    African Journals Online (AJOL)

    Among many countries that have experienced one form of conflict, this paper tried to review the experiences of children during armed conflict in Nepal, Columbia and Nigeria. The review also delved into the impact of armed conflict on health, nutrition and education of children and further, outlined some international ...

  15. Kinematic properties of supergiants in the Perseus spiral arm

    Energy Technology Data Exchange (ETDEWEB)

    Gerasimenko, T P [Ural' skij Gosudarstvennyj Univ., Sverdlovsk (USSR)

    1963-05-01

    Large-scale inhomogeneity of the velocity field in the Perseus spiral arm region is found on the basis of the analysis of spatial motions of supergiants. The inhomogeneity seems to be connected with both presence of large groups of young stars and systematic motions in the arm predicted by the density wave theory. Proper motions of 78 stars are presented.

  16. Prognostic significance of between-arm blood pressure differences.

    Science.gov (United States)

    Agarwal, Rajiv; Bunaye, Zerihun; Bekele, Dagim M

    2008-03-01

    Blood pressure (BP) recordings often differ between arms, but the extent to which these differences are reproducible and whether the differences have prognostic importance is unknown. We enrolled 421 consecutive patients from a medicine and a renal clinic at a veterans' hospital. Three BP recordings were obtained in each arm using an oscillometric device in a sequential manner and repeated in 1 week. Patients were followed for all-cause mortality arm had 5.1-mm Hg higher systolic BP that attenuated by approximately 2.2 mm Hg a week later. Systolic BP dropped 6.9 mm Hg over 1 week and by an additional 5.3 mm Hg in patients with chronic kidney disease. Accounting for the visit and arm effect improved the reproducibility of the BP measurements. The intraclass correlation coefficient was 0.74, which improved to 0.88 after accounting for visit and 0.93 after accounting for arm. The crude mortality rate was 6.33 per 100 patient-years. Every 10-mm Hg difference in systolic BP between the arms conferred a mortality hazard of 1.24 (95% CI: 1.01 to 1.52) after adjusting for average systolic BP and chronic kidney disease. BP differences between arms are reproducible and carry prognostic information. Patients should have evaluation of BP in both arms at the screening visit.

  17. Why and how the EU should act on armed drones

    DEFF Research Database (Denmark)

    Martins, Bruno Oliveira; Backhaus, Benedikt

    2015-01-01

    This article systematizes the reasons that demand EU action on the issue of armed drones. It argues that a clear positioning of Brussels is required due to consistency with former practices in similar events and fundamental vectors of EU foreign and security policy, as well as legal and strategic...... position itself in the international debate on the regulation of armed drones....

  18. Systematic medical data collection of intentional injuries during armed conflicts

    DEFF Research Database (Denmark)

    Helweg-Larsen, Karin; Abdel-Jabbar Al-Qadi, Ashraf Hasan; Al-Jabriri, Jalal

    2004-01-01

    A study was undertaken on implementing medical data collection as a tool to assess the relative number and character of intentional injuries before and during an armed conflict.......A study was undertaken on implementing medical data collection as a tool to assess the relative number and character of intentional injuries before and during an armed conflict....

  19. The Accountability of Armed Groups under Human Rights Law

    NARCIS (Netherlands)

    Fortin, K.M.A.

    2015-01-01

    The starting point for this NWOI funded Ph.D. research is the observation that although UN accountability mechanisms are increasingly holding armed groups ‘accountable’ under human rights law, the legal basis for the responsibility of armed groups under human rights law remains controversial

  20. Kinematic feedback control laws for generating natural arm movements

    International Nuclear Information System (INIS)

    Kim, Donghyun; Jang, Cheongjae; Park, Frank C

    2014-01-01

    We propose a stochastic optimal feedback control law for generating natural robot arm motions. Our approach, inspired by the minimum variance principle of Harris and Wolpert (1998 Nature 394 780–4) and the optimal feedback control principles put forth by Todorov and Jordan (2002 Nature Neurosci. 5 1226–35) for explaining human movements, differs in two crucial respects: (i) the endpoint variance is minimized in joint space rather than Cartesian hand space, and (ii) we ignore the dynamics and instead consider only the second-order differential kinematics. The feedback control law generating the motions can be straightforwardly obtained by backward integration of a set of ordinary differential equations; these equations are obtained exactly, without any linear–quadratic approximations. The only parameters to be determined a priori are the variance scale factors, and for both the two-DOF planar arm and the seven-DOF spatial arm, a table of values is constructed based on the given initial and final arm configurations; these values are determined via an optimal fitting procedure, and consistent with existing findings about neuromuscular motor noise levels of human arm muscles. Experiments conducted with a two-link planar arm and a seven-DOF spatial arm verify that the trajectories generated by our feedback control law closely resemble human arm motions, in the sense of producing nearly straight-line hand trajectories, having bell-shaped velocity profiles, and satisfying Fitts Law. (paper)

  1. Brain-Machine Interface Enables Bimanual Arm Movements in Monkeys

    Science.gov (United States)

    Ifft, Peter J.; Shokur, Solaiman; Li, Zheng; Lebedev, Mikhail A.; Nicolelis, Miguel A. L.

    2014-01-01

    Brain-machine interfaces (BMIs) are artificial systems that aim to restore sensation and movement to severely paralyzed patients. However, previous BMIs enabled only single arm functionality, and control of bimanual movements was a major challenge. Here, we developed and tested a bimanual BMI that enabled rhesus monkeys to control two avatar arms simultaneously. The bimanual BMI was based on the extracellular activity of 374–497 neurons recorded from several frontal and parietal cortical areas of both cerebral hemispheres. Cortical activity was transformed into movements of the two arms with a decoding algorithm called a 5th order unscented Kalman filter (UKF). The UKF is well-suited for BMI decoding because it accounts for both characteristics of reaching movements and their representation by cortical neurons. The UKF was trained either during a manual task performed with two joysticks or by having the monkeys passively observe the movements of avatar arms. Most cortical neurons changed their modulation patterns when both arms were engaged simultaneously. Representing the two arms jointly in a single UKF decoder resulted in improved decoding performance compared with using separate decoders for each arm. As the animals’ performance in bimanual BMI control improved over time, we observed widespread plasticity in frontal and parietal cortical areas. Neuronal representation of the avatar and reach targets was enhanced with learning, whereas pairwise correlations between neurons initially increased and then decreased. These results suggest that cortical networks may assimilate the two avatar arms through BMI control. PMID:24197735

  2. 78 FR 46579 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-08-01

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-30] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...: FMS case YAD-$22M-16Jan10. (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None...

  3. 76 FR 17111 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-03-28

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-10] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  4. 78 FR 62590 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-10-22

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-43] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None (vii) Sensitivity of...

  5. 76 FR 37071 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-06-24

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-03] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  6. 75 FR 60424 - 36(b)(1) Arms Sales Notifications

    Science.gov (United States)

    2010-09-30

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-28 and 10-30] 36(b)(1) Arms Sales Notifications AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of two section 36(b)(1) arms sales notifications to...

  7. 78 FR 78939 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-12-27

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-68] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...-$98M (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: N/A (vii) Sensitivity of...

  8. 76 FR 37075 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-06-24

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-77] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  9. 76 FR 43659 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-07-21

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-28] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  10. 78 FR 78941 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-12-27

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-70] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... any: FMS Case GAC--$82M--12Mar10 (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid...

  11. 76 FR 27026 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-05-10

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-13] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, Department of Defense. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  12. 76 FR 37078 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-06-24

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-68] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  13. 77 FR 42709 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-07-20

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-24] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... Cases, if any: None (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None (vii...

  14. 77 FR 60384 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-10-03

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-54] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This is...

  15. 76 FR 43662 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-07-21

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-15] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...) Military Department: Navy (AAR) (v) Prior Related Cases, if any: None (vi) Sales Commission, Fee, etc...

  16. 75 FR 61440 - 36(b)(1) Arms Sales Notifications

    Science.gov (United States)

    2010-10-05

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-47, 10-48, and 10-51] 36(b)(1) Arms Sales Notifications AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of three section 36(b)(1) arms sales notifications...

  17. 77 FR 37884 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-06-25

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-19] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... Department: Navy (LAN). (v) Prior Related Cases, if any: None. (vi) Sales Commission, Fee, etc., Paid...

  18. 76 FR 72686 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-11-25

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-47] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This..., if any: FMS Case FAL-$73M-6Apr11 (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed To Be...

  19. 75 FR 29998 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-05-28

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal No. 10-22] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification to fulfill the...

  20. 76 FR 29212 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-05-20

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-75] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, Department of Defense. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  1. 78 FR 26324 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-05-06

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-20] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... Gasoline). (v) Prior Related Cases, if any: Numerous cases dating back to 1995. (vi) Sales Commission, Fee...

  2. 75 FR 48646 - 36(b)(1) Arms Sales Notifications

    Science.gov (United States)

    2010-08-11

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-27, 10-31 and 10-41] 36(b)(1) Arms Sales Notifications AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of three section 36(b)(1) arms sales notifications...

  3. 75 FR 23247 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-05-03

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal No. 10-08] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification to fulfill the...

  4. 76 FR 60461 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-09-29

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-27] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... any: FMS Case JAH-$402 million-11Dec91. FMS Case ZUF-$375 million-22Dec08. (vi) Sales Commission, Fee...

  5. 78 FR 76114 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-12-16

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-66] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None (vii) Sensitivity of Technology...

  6. 77 FR 42711 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-07-20

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-20] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This..., Amd 3). (v) Prior Related Cases, if any: FMS case ULJ-$46M-15Jan10. (vi) Sales Commission, Fee, etc...

  7. 75 FR 27314 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-05-14

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal No. 10-19] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification to fulfill the...

  8. 75 FR 11865 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-03-12

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal No. 10-12] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification to fulfill the...

  9. 78 FR 76112 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-12-16

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-63] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... case LAJ-$22M--8Mar07 FMS case GAU-$45M--25Jul08 FMS case LAL-$293M--5Jan09 (vi) Sales Commission, Fee...

  10. 78 FR 42051 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-07-15

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-26] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... any: None (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None (vii...

  11. 75 FR 76418 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-12-08

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-65] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  12. 75 FR 76415 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-12-08

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-72] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, Department of Defense. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  13. 78 FR 32632 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-05-31

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-28] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...-31Dec06. FMS case NZU-$93 million-19Aug10. (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to...

  14. 75 FR 74011 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-11-30

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-24] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  15. 78 FR 26326 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-05-06

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-09] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...-20Feb08. (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None. (vii) Sensitivity of...

  16. 78 FR 62600 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-10-22

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-47] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...: None (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed To Be Paid: None (vii) Sensitivity of...

  17. 75 FR 76412 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-12-08

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-69] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, Department of Defense. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  18. 77 FR 60391 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-10-03

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-32] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This is...

  19. 76 FR 60455 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-09-29

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-71] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... support. (iv) Military Department: Army (UJT). (v) Prior Related Cases, if any: None. (vi) Sales...

  20. 75 FR 74014 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-11-30

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-49] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  1. 76 FR 27022 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-05-10

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-12] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, Department of Defense. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  2. 77 FR 60387 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-10-03

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-26] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This is...

  3. 77 FR 51780 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-08-27

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-42] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... support. (iv) Military Department: Air Force (QAZ). (v) Prior Related Cases, if any: None. (vi) Sales...

  4. 78 FR 26328 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-05-06

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-06] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...) Prior Related Cases, if any: FMS case QAA-$301M-3Dec08. (vi) Sales Commission, Fee, etc., Paid, Offered...

  5. 77 FR 70151 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-11-23

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-56] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...: Army (UAK). (v) Prior Related Cases, if any: None. (vi) Sales Commission, Fee, etc., Paid, Offered, or...

  6. 77 FR 13564 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-03-07

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-53] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This..., if any: None (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None (vii...

  7. 78 FR 62588 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-10-22

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-53] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None (vii) Sensitivity of Technology...

  8. 77 FR 12037 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-02-28

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-11] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... support. (iv) Military Department: Navy (SAF). (v) Prior Related Cases, if any: None. (vi) Sales...

  9. 76 FR 60459 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-09-29

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-19] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...-$280 million-29Nov07. (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None. (vii...

  10. 75 FR 76408 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-12-08

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-73] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, Department of Defense. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  11. 75 FR 41820 - 36(b)(1) Arms Sales Notifications

    Science.gov (United States)

    2010-07-19

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-05, 10-11, 10-18, 10-21 and 10-29] 36(b)(1) Arms Sales Notifications AGENCY: Defense Security Cooperation Agency, DoD. ACTION...) arms sales notifications to fulfill the requirements of section 155 of Public Law 104-164, dated 21...

  12. 77 FR 46417 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-08-03

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-39] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...: USA (UAF) (v) Prior Related Cases, if any: FMS case UAD-$95M-23Jan12 (vi) Sales Commission, Fee, etc...

  13. 76 FR 60467 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-09-29

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-34] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...: a Foreign Military Sales Order II (FMSO II) to provide funds for blanket order requisitions, under...

  14. 78 FR 69073 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-11-18

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-59] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...) Military Department: Air Force (QAH) (v) Prior Related Cases: None (vi) Sales Commission, Fee, etc., Paid...

  15. 78 FR 54242 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-09-03

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-38] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...--$54.3M--5May04 FMS case QZX--$62.4M--24Dec03 FMS case CCZ--$48.4M--12Aug02 [[Page 54244

  16. The European Union and armed drones: framing the debate

    DEFF Research Database (Denmark)

    Martins, Bruno Oliveira

    2015-01-01

    Armed drones are an issue extremely relevant for the EU. The recent emergence of targeted killings as a common counter-terrorism technique, the existence of several EU member states using armed and surveillance drones in military scenarios, the presence of member states troops in areas where armed...... drones have been active, the US use of European-originated intelligence to execute targeted killings, and the broader status of international law, are developments that illustrate the importance of the topic. Yet, the EU still does not have an official position on armed drones. In 2014 the European...... Parliament recognized that this is problematic, adopting a Resolution that expressed “grave concern over the use of armed drones outside the international legal framework” and that urged the EU to “develop an appropriate policy response at both European and global level”. This Forum answers to the European...

  17. A Unified Approach for Reporting ARM Measurement Uncertainties Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Campos, E [Argonne National Laboratory; Sisterson, DL [Argonne National Laboratory

    2015-10-01

    The Atmospheric Radiation Measurement (ARM) Climate Research Facility is observationally based, and quantifying the uncertainty of its measurements is critically important. With over 300 widely differing instruments providing over 2,500 datastreams, concise expression of measurement uncertainty is quite challenging. The ARM Facility currently provides data and supporting metadata (information about the data or data quality) to its users through a number of sources. Because the continued success of the ARM Facility depends on the known quality of its measurements, the Facility relies on instrument mentors and the ARM Data Quality Office (DQO) to ensure, assess, and report measurement quality. Therefore, an easily-accessible, well-articulated estimate of ARM measurement uncertainty is needed.

  18. A software radio platform based on ARM and FPGA

    Directory of Open Access Journals (Sweden)

    Yang Xin.

    2016-01-01

    Full Text Available The rapid rise in computational performance offered by computer systems has greatly increased the number of practical software radio applications. A scheme presented in this paper is a software radio platform based on ARM and FPGA. FPGA works as the coprocessor together with the ARM, which serves as the core processor. ARM is used for digital signal processing and real-time data transmission, and FPGA is used for synchronous timing control and serial-parallel conversion. A SPI driver for real-time data transmission between ARM and FPGA under ARM-Linux system is provided. By adopting modular design, the software radio platform is capable of implementing wireless communication functions and satisfies the requirements of real-time signal processing platform for high security and broad applicability.

  19. Effects of age, sex and arm on the precision of arm position sense-left-arm superiority in healthy right-handers.

    Science.gov (United States)

    Schmidt, Lena; Depper, Lena; Kerkhoff, Georg

    2013-01-01

    Position sense is an important proprioceptive ability. Disorders of arm position sense (APS) often occur after unilateral stroke, and are associated with a negative functional outcome. In the present study we assessed horizontal APS by measuring angular deviations from a visually defined target separately for each arm in a large group of healthy subjects. We analyzed the accuracy and instability of horizontal APS as a function of age, sex and arm. Subjects were required to specify verbally the position of their unseen arm on a 0-90° circuit by comparing the current position with the target position indicated by a LED lamp, while the arm was passively moved by the examiner. Eighty-seven healthy subjects participated in the study, ranging from 20 to 77 years, subdivided into three age groups. The results revealed that APS was not a function of age or sex, but was significantly better in the non-dominant (left) arm in absolute errors (AE) but not in constant errors (CE) across all age groups of right-handed healthy subjects. This indicates a right-hemisphere superiority for left APS in right-handers and neatly fits to the more frequent and more severe left-sided body-related deficits in patients with unilateral stroke (i.e. impaired APS in left spatial neglect, somatoparaphrenia) or in individuals with abnormalities of the right cerebral hemisphere. These clinical issues will be discussed.

  20. Changes in arm-hand function and arm-hand skill performance in patients after stroke during and after rehabilitation.

    Science.gov (United States)

    Franck, Johan Anton; Smeets, Rob Johannes Elise Marie; Seelen, Henk Alexander Maria

    2017-01-01

    Arm-hand rehabilitation programs applied in stroke rehabilitation frequently target specific populations and thus are less applicable in heterogeneous patient populations. Besides, changes in arm-hand function (AHF) and arm-hand skill performance (AHSP) during and after a specific and well-described rehabilitation treatment are often not well evaluated. This single-armed prospective cohort study featured three subgroups of stroke patients with either a severely, moderately or mildly impaired AHF. Rehabilitation treatment consisted of a Concise_Arm_and_hand_ Rehabilitation_Approach_in_Stroke (CARAS). Measurements at function and activity level were performed at admission, clinical discharge, 3, 6, 9 and 12 months after clinical discharge. Eighty-nine stroke patients (M/F:63/23; mean age:57.6yr (+/-10.6); post-stroke time:29.8 days (+/-20.1)) participated. All patients improved on AHF and arm-hand capacity during and after rehabilitation, except on grip strength in the severely affected subgroup. Largest gains occurred in patients with a moderately affected AHF. As to self-perceived AHSP, on average, all subgroups improved over time. A small percentage of patients declined regarding self-perceived AHSP post-rehabilitation. A majority of stroke patients across the whole arm-hand impairment severity spectrum significantly improved on AHF, arm-hand capacity and self-perceived AHSP. These were maintained up to one year post-rehabilitation. Results may serve as a control condition in future studies.