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Sample records for adenoviral vector-based strategies

  1. An Adenoviral Vector Based Vaccine for Rhodococcus equi.

    Carla Giles

    Full Text Available Rhodococcus equi is a respiratory pathogen which primarily infects foals and is endemic on farms around the world with 50% mortality and 80% morbidity in affected foals. Unless detected early and treated appropriately the disease can be fatal. Currently, there is no vaccine available to prevent this disease. For decades researchers have endeavoured to develop an effective vaccine to no avail. In this study a novel human adenoviral vector vaccine for R. equi was developed and tested in the mouse model. This vaccine generated a strong antibody and cytokine response and clearance of R. equi was demonstrated following challenge. These results show that this vaccine could potentially be developed further for use as a vaccine to prevent R. equi disease in foals.

  2. Adenoviral vector immunity: its implications and circumvention strategies.

    Ahi, Yadvinder S; Bangari, Dinesh S; Mittal, Suresh K

    2011-08-01

    Adenoviral (Ad) vectors have emerged as a promising gene delivery platform for a variety of therapeutic and vaccine purposes during last two decades. However, the presence of preexisting Ad immunity and the rapid development of Ad vector immunity still pose significant challenges to the clinical use of these vectors. Innate inflammatory response following Ad vector administration may lead to systemic toxicity, drastically limit vector transduction efficiency and significantly abbreviate the duration of transgene expression. Currently, a number of approaches are being extensively pursued to overcome these drawbacks by strategies that target either the host or the Ad vector. In addition, significant progress has been made in the development of novel Ad vectors based on less prevalent human Ad serotypes and nonhuman Ad. This review provides an update on our current understanding of immune responses to Ad vectors and delineates various approaches for eluding Ad vector immunity. Approaches targeting the host and those targeting the vector are discussed in light of their promises and limitations.

  3. Prophylactic and therapeutic adenoviral vector-based multivirus-specific T-cell immunotherapy for transplant patients

    Vijayendra Dasari

    2016-01-01

    Full Text Available Viral infections including cytomegalovirus, Epstein-Barr virus, adenovirus, and BK virus are a common and predictable problem in transplant recipients. While cellular immune therapies have been successfully used to tackle infectious complications in transplant recipients, manufacturing immunotherapies to address the multitude of possible pathogens can be technically challenging and labor-intensive. Here we describe a novel adenoviral antigen presentation platform (Ad-MvP as a tool for rapid generation of multivirus-specific T-cells in a single step. Ad-MvP encodes 32 CD8+ T-cell epitopes from cytomegalovirus, Epstein-Barr virus, adenovirus, and BK virus as a contiguous polyepitope. We demonstrate that Ad-MvP vector can be successfully used for rapid in vitro expansion of multivirus-specific T-cells from transplant recipients and in vivo priming of antiviral T-cell immunity. Most importantly, using an in vivo murine model of Epstein-Barr virus-induced lymphoma, we also show that adoptive immunotherapy with Ad-MvP expanded autologous and allogeneic multivirus-specific T-cells is highly effective in controlling Epstein-Barr virus tumor outgrowth and improving overall survival. We propose that Ad-MvP has wide ranging therapeutic applications in greatly facilitating in vivo priming of antiviral T-cells, the generation of third-party T-cell banks as “off-the-shelf” therapeutics as well as autologous T-cell therapies for transplant patients.

  4. Tropism-Modification Strategies for Targeted Gene Delivery Using Adenoviral Vectors

    Andrew H. Baker

    2010-10-01

    Full Text Available Achieving high efficiency, targeted gene delivery with adenoviral vectors is a long-standing goal in the field of clinical gene therapy. To achieve this, platform vectors must combine efficient retargeting strategies with detargeting modifications to ablate native receptor binding (i.e. CAR/integrins/heparan sulfate proteoglycans and “bridging” interactions. “Bridging” interactions refer to coagulation factor binding, namely coagulation factor X (FX, which bridges hepatocyte transduction in vivo through engagement with surface expressed heparan sulfate proteoglycans (HSPGs. These interactions can contribute to the off-target sequestration of Ad5 in the liver and its characteristic dose-limiting hepatotoxicity, thereby significantly limiting the in vivo targeting efficiency and clinical potential of Ad5-based therapeutics. To date, various approaches to retargeting adenoviruses (Ad have been described. These include genetic modification strategies to incorporate peptide ligands (within fiber knob domain, fiber shaft, penton base, pIX or hexon, pseudotyping of capsid proteins to include whole fiber substitutions or fiber knob chimeras, pseudotyping with non-human Ad species or with capsid proteins derived from other viral families, hexon hypervariable region (HVR substitutions and adapter-based conjugation/crosslinking of scFv, growth factors or monoclonal antibodies directed against surface-expressed target antigens. In order to maximize retargeting, strategies which permit detargeting from undesirable interactions between the Ad capsid and components of the circulatory system (e.g. coagulation factors, erythrocytes, pre-existing neutralizing antibodies, can be employed simultaneously. Detargeting can be achieved by genetic ablation of native receptor-binding determinants, ablation of “bridging interactions” such as those which occur between the hexon of Ad5 and coagulation factor X (FX, or alternatively, through the use of polymer

  5. A new virtual-flux-vector based droop control strategy for parallel connected inverters in microgrids

    Hu, Jiefeng; Zhu, Jianguo; Qu, Yanqing

    2013-01-01

    Voltage and frequency droop method is commonly used in microgrids to achieve proper autonomous power sharing without rely on intercommunication systems. This paper proposes a new control strategy for parallel connected inverters in microgrid applications by drooping the flux instead of the invert...

  6. VectorBase

    U.S. Department of Health & Human Services — VectorBase is a Bioinformatics Resource Center for invertebrate vectors. It is one of four Bioinformatics Resource Centers funded by NIAID to provide web-based...

  7. Genetically engineering adenoviral vectors for gene therapy.

    Coughlan, Lynda

    2014-01-01

    Adenoviral (Ad) vectors are commonly used for various gene therapy applications. Significant advances in the genetic engineering of Ad vectors in recent years has highlighted their potential for the treatment of metastatic disease. There are several methods to genetically modify the Ad genome to incorporate retargeting peptides which will redirect the natural tropism of the viruses, including homologous recombination in bacteria or yeast. However, homologous recombination in yeast is highly efficient and can be achieved without the need for extensive cloning strategies. In addition, the method does not rely on the presence of unique restriction sites within the Ad genome and the reagents required for this method are widely available and inexpensive. Large plasmids containing the entire adenoviral genome (~36 kbp) can be modified within Saccharomyces cerevisiae yeast and genomes easily rescued in Escherichia coli hosts for analysis or amplification. A method for two-step homologous recombination in yeast is described in this chapter.

  8. Presumed Acute Adenoviral Dacryoadenitis Associated with ...

    of serum adenoviral antibodies IgM and presence of inclusion bodies in conjunctival smear. Epidemic keratoconjunctivitis is caused by adenovirus serovars. 8, 19, and 37.[7] Serological typing and polymerase chain reaction for adenoviral were not available in smear in both eyes. A computerized tomography scan of.

  9. Ex vivo adenoviral vector-mediated neurotrophin gene transfer to olfactory ensheathing glia : effects on rubrospinal tract regeneration, lesion size, and functional recovery after implantation in the injured rat spinal cord

    Ruitenberg, Marc J; Plant, Giles W; Hamers, Frank P T; Wortel, Joke; Blits, Bas; Dijkhuizen, Paul A; Gispen, Willem Hendrik; Boer, Gerard J; Verhaagen, J.

    2003-01-01

    The present study uniquely combines olfactory ensheathing glia (OEG) implantation with ex vivo adenoviral (AdV) vector-based neurotrophin gene therapy in an attempt to enhance regeneration after cervical spinal cord injury. Primary OEG were transduced with AdV vectors encoding rat brain-derived

  10. Circumventing antivector immunity: potential use of nonhuman adenoviral vectors.

    Lopez-Gordo, Estrella; Podgorski, Iva I; Downes, Nicholas; Alemany, Ramon

    2014-04-01

    Adenoviruses are efficient gene delivery vectors based on their ability to transduce a wide variety of cell types and drive high-level transient transgene expression. While there have been advances in modifying human adenoviral (HAdV) vectors to increase their safety profile, there are still pitfalls that need to be further addressed. Preexisting humoral and cellular immunity against common HAdV serotypes limits the efficacy of gene transfer and duration of transgene expression. As an alternative, nonhuman AdV (NHAdV) vectors can circumvent neutralizing antibodies against HAdVs in immunized mice and monkeys and in human sera, suggesting that NHAdV vectors could circumvent preexisting humoral immunity against HAdVs in a clinical setting. Consequently, there has been an increased interest in developing NHAdV vectors for gene delivery in humans. In this review, we outline the recent advances and limitations of HAdV vectors for gene therapy and describe examples of NHAdV vectors focusing on their immunogenicity, tropism, and potential as effective gene therapy vehicles.

  11. Genetic Passive Immunization with Adenoviral Vector Expressing Chimeric Nanobody-Fc Molecules as Therapy for Genital Infection Caused by Mycoplasma hominis.

    Daria A Burmistrova

    Full Text Available Developing pathogen-specific recombinant antibody fragments (especially nanobodies is a very promising strategy for the treatment of infectious disease. Nanobodies have great potential for gene therapy application due to their single-gene nature. Historically, Mycoplasma hominis has not been considered pathogenic bacteria due to the lack of acute infection and partially due to multiple studies demonstrating high frequency of isolation of M. hominis samples from asymptomatic patients. However, recent studies on the role of latent M. hominis infection in oncologic transformation, especially prostate cancer, and reports that M. hominis infects Trichomonas and confers antibiotic resistance to Trichomonas, have generated new interest in this field. In the present study we have generated specific nanobody against M. hominis (aMh, for which the identified target is the ABC-transporter substrate-binding protein. aMh exhibits specific antibacterial action against M. hominis. In an attempt to improve the therapeutic properties, we have developed the adenoviral vector-based gene therapy approach for passive immunization with nanobodies against M. hominis. For better penetration into the mucous layer of the genital tract, we fused aMh with the Fc-fragment of IgG. Application of this comprehensive approach with a single systemic administration of recombinant adenovirus expressing aMh-Fc demonstrated both prophylactic and therapeutic effects in a mouse model of genital M. hominis infection.

  12. High stability vector-based direct power control for DFIG-based wind turbine

    Zhu, Rongwu; Chen, Zhe; Wu, Xiaojie

    2015-01-01

    This paper proposes an improved vector-based direct power control (DPC) strategy for the doubly-fed induction generator (DFIG)-based wind energy conversion system. Based on the small signal model, the proposed DPC improves the stability of the DFIG, and avoids the DFIG operating in the marginal...

  13. Modification of liposomal concentration in liposome/adenoviral complexes allows significant protection of adenoviral vectors from neutralising antibody, in vitro.

    Steel, Jason C; Cavanagh, Heather M A; Burton, Mark A; Dingwall, Daniel J; Kalle, Wouter H J

    2005-06-01

    Adenoviral vectors have been commonly used in gene therapy protocols, however the success of their use is often limited by the induction of host immunity to the vector. Following exposure to the adenoviral vector, adenoviral-specific neutralising antibodies are produced which limits further administration. This study examines the efficacy of complexing liposomes to adenovirus for the protection of the adenovirus from neutralising antibodies in an in vitro setting. Dimethyldioctadecylammonium bromide (DDAB)-dioleoyl-l-phosphatidylethanolamine (DOPE) liposomes were bound at varying concentrations to adenovirus to form AL complexes and tested these complexes' ability to prevent adenoviral neutralisation. It is shown that by increasing the concentration of liposomes in the adenoviral-liposome (AL) complexes we can increase the level of immuno-shielding afforded the adenovirus. It is also shown that the increase in liposomal concentration may lead to drawbacks such as increased cytotoxicity and reductions in expression levels.

  14. Endothelial Cell-Targeted Adenoviral Vector for Suppressing Breast Malignancies

    Huang, Shuang

    2004-01-01

    .... Our proposal is designed to develop an endothelial cell-targeted adenoviral vector and to use the targeted vector to express high levels of anticancer therapeutic genes in the sites of angiogenenic...

  15. Targeted cancer gene therapy : the flexibility of adenoviral gene therapy vectors

    Rots, MG; Curiel, DT; Gerritsen, WR; Haisma, HJ

    2003-01-01

    Recombinant adenoviral vectors are promising reagents for therapeutic interventions in humans, including gene therapy for biologically complex diseases like cancer and cardiovascular diseases. In this regard, the major advantage of adenoviral vectors is their superior in vivo gene transfer

  16. Reactivation of presumed adenoviral keratitis after laser in situ keratomileusis.

    Safak, Nilgün; Bilgihan, Kamil; Gürelik, Gökhan; Ozdek, Sengül; Hasanreisoğlu, Berati

    2002-04-01

    We report a patient with reactivation of presumed adenoviral keratoconjunctivitis after laser in situ keratomileusis (LASIK) to correct high myopia. The preoperative refraction was -13.00 diopters (D) in the right eye and -14.00 D in the left eye, and the best corrected visual acuity was 20/20 in both eyes. On the first postoperative day, mild conjunctival hyperemia and multiple subepithelial infiltrations localized in the flap zone consistent with adenoviral keratoconjunctivitis were seen. After prompt treatment, the lesions resolved. As a consequence, LASIK successfully corrected the high myopia. Adenoviral keratoconjunctivitis can be reactivated after LASIK, unlike after photorefractive keratectomy, despite the absence of symptomatic and clinical findings before the procedure.

  17. Adenoviral vectors as genome editing tools : repairing defective DMD alleles

    Maggio, Ignazio

    2016-01-01

    Adenoviral vectors (AdVs) constitute powerful gene delivery vehicles. However, so far, their potential for genome editing has not been extensively investigated. By tailoring AdVs as carriers of designer nucleases and donor DNA sequences, the research presented in this thesis expands the utility of

  18. Efficient Vector-Based Forwarding for Underwater Sensor Networks

    Peng Xie

    2010-01-01

    Full Text Available Underwater Sensor Networks (UWSNs are significantly different from terrestrial sensor networks in the following aspects: low bandwidth, high latency, node mobility, high error probability, and 3-dimensional space. These new features bring many challenges to the network protocol design of UWSNs. In this paper, we tackle one fundamental problem in UWSNs: robust, scalable, and energy efficient routing. We propose vector-based forwarding (VBF, a geographic routing protocol. In VBF, the forwarding path is guided by a vector from the source to the target, no state information is required on the sensor nodes, and only a small fraction of the nodes is involved in routing. To improve the robustness, packets are forwarded in redundant and interleaved paths. Further, a localized and distributed self-adaptation algorithm allows the nodes to reduce energy consumption by discarding redundant packets. VBF performs well in dense networks. For sparse networks, we propose a hop-by-hop vector-based forwarding (HH-VBF protocol, which adapts the vector-based approach at every hop. We evaluate the performance of VBF and HH-VBF through extensive simulations. The simulation results show that VBF achieves high packet delivery ratio and energy efficiency in dense networks and HH-VBF has high packet delivery ratio even in sparse networks.

  19. Novel recombinant alphaviral and adenoviral vectors for cancer immunotherapy.

    Osada, Takuya; Morse, Michael A; Hobeika, Amy; Lyerly, H Kim

    2012-06-01

    Although cellular immunotherapy based on autolgous dendritic cells (DCs) targeting antigens expressed by metastatic cancer has demonstrated clinical efficacy, the logistical challenges in generating an individualized cell product create an imperative to develop alternatives to DC-based cancer vaccines. Particularly attractive alternatives include in situ delivery of antigen and activation signals to resident antigen-presenting cells (APCs), which can be achieved by novel fusion molecules targeting the mannose receptor and by recombinant viral vectors expressing the antigen of interest and capable of infecting DCs. A particular challenge in the use of viral vectors is the well-appreciated clinical obstacles to their efficacy, specifically vector-specific neutralizing immune responses. Because heterologous prime and boost strategies have been demonstrated to be particularly potent, we developed two novel recombinant vectors based on alphaviral replicon particles and a next-generation adenovirus encoding an antigen commonly overexpressed in many human cancers, carcinoembryonic antigen (CEA). The rationale for developing these vectors, their unique characteristics, the preclinical studies and early clinical experience with each, and opportunities to enhance their effectiveness will be reviewed. The potential of each of these potent recombinant vectors to efficiently generate clinically active anti-tumor immune response alone, or in combination, will be discussed. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. Adenoviral Gene Delivery to Primary Human Cutaneous Cells and Burn Wounds

    Hirsch, Tobias; von Peter, Sebastian; Dubin, Grzegorz; Mittler, Dominik; Jacobsen, Frank; Lehnhardt, Markus; Eriksson, Elof; Steinau, Hans-Ulrich; Steinstraesser, Lars

    2006-01-01

    The adenoviral transfer of therapeutic genes into epidermal and dermal cells is an interesting approach to treat skin diseases and to promote wound healing. The aim of this study was to assess the in vitro and in vivo transfection efficacy in skin and burn wounds after adenoviral gene delivery. Primary keratinocytes (HKC), fibroblasts (HFB), and HaCaT cells were transfected using different concentrations of an adenoviral construct (eGFP). Transfection efficiency and cytotoxicity was determine...

  1. Molecular epidemiology of adenoviral keratoconjunctivitis in Saudi Arabia.

    Tabbara, Khalid F; Omar, Nazri; Hammouda, Ehab; Akanuma, Masataka; Ohguchi, Takeshi; Ariga, Toshihide; Tagawa, Yoshitsugu; Kitaichi, Nobuyoshi; Ishida, Susumu; Aoki, Koki; Ishiko, Hiroaki; Ohno, Shigeaki

    2010-10-24

    Adenoviral keratoconjunctivitis is a major cause of ocular morbidity and may lead to visual loss. Adenovirus types 8, 19, and 37 may cause epidemic keratoconjunctivitis. The main objective of this study was to determine the types of adenoviruses causing keratoconjunctivitis in Saudi Arabia. We conducted a non-interventional observational clinical study. Seventy three eyes from 65 patients who presented to The Eye Center in Riyadh, Saudi Arabia with clinical features of acute adenoviral keratoconjunctivitis were included. Each patient underwent complete clinical examination and features such as membranous reaction, conjunctival hemorrhage, subepithelial corneal infiltrates, and preauricular lymph node enlargement were recorded. Conjunctival swabs were obtained from patients with presumed acute viral conjunctivitis. Immunochromatography (IC) and restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) were performed on the conjunctival swabs obtained from each eye. Serotype identification was performed using direct sequencing technique. Forty-nine (67.1%) were adenovirus type 8, 8 (11.0%) were adenovirus type 3, 6 (8.2%) type 37, 5 (6.8%) were adenovirus type 4, and 2 (2.3%) type 19. The remaining 5 were types 14, 19, and 22. The prevalence of membranous conjunctivitis was highest (83%) among eyes with adenovirus type 37 while subepithelial corneal opacities were most commonly seen among eyes with adenovirus type 8 (47%). Immunochromatography tests were positive for adenovirus in 48 (65.7%) out of 73 eyes. This study determined the types of adenoviruses causing keratoconjunctivitis at one center in Saudi Arabia. Direct sequencing techniques is an efficient, accurate, and rapid means of diagnosing adenoviral keratoconjunctivitis. The most common causes of adenoviral keratoconjunctivitis in Saudi Arabia were adenovirus types 8, 3, and 37. Membranous conjunctivitis and subepithelial opacities had the highest frequency of adenovirus types 37 and 8

  2. Matrix-Vector Based Fast Fourier Transformations on SDR Architectures

    Y. He

    2008-05-01

    Full Text Available Today Discrete Fourier Transforms (DFTs are applied in various radio standards based on OFDM (Orthogonal Frequency Division Multiplex. It is important to gain a fast computational speed for the DFT, which is usually achieved by using specialized Fast Fourier Transform (FFT engines. However, in face of the Software Defined Radio (SDR development, more general (parallel processor architectures are often desirable, which are not tailored to FFT computations. Therefore, alternative approaches are required to reduce the complexity of the DFT. Starting from a matrix-vector based description of the FFT idea, we will present different factorizations of the DFT matrix, which allow a reduction of the complexity that lies between the original DFT and the minimum FFT complexity. The computational complexities of these factorizations and their suitability for implementation on different processor architectures are investigated.

  3. Gene therapy for barrett's esophagus: adenoviral gene transfer in different intestinal models

    Marsman, Willem A.; Buskens, Christianne J.; Wesseling, John G.; van Lanschot, J. Jan B.; Bosma, Piter J.

    2005-01-01

    Adenoviral gene therapy could potentially be used for treatment of patients with a Barrett's esophagus. In order to study the feasibility of this approach it is important to study adenoviral intestinal transduction both in vitro and in vivo. In the present study, we used differentiating Caco-2

  4. Sidestream smoke exposure increases the susceptibility of airway epithelia to adenoviral infection.

    Priyanka Sharma

    Full Text Available Although significant epidemiological evidence indicates that cigarette smoke exposure increases the incidence and severity of viral infection, the molecular mechanisms behind the increased susceptibility of the respiratory tract to viral pathogens are unclear. Adenoviruses are non-enveloped DNA viruses and important causative agents of acute respiratory disease. The Coxsackievirus and adenovirus receptor (CAR is the primary receptor for many adenoviruses. We hypothesized that cigarette smoke exposure increases epithelial susceptibility to adenovirus infection by increasing the abundance of apical CAR.Cultured human airway epithelial cells (CaLu-3 were used as a model to investigate the effect of sidestream cigarette smoke (SSS, mainstream cigarette smoke (MSS, or control air exposure on the susceptibility of polarized respiratory epithelia to adenoviral infection. Using a Cultex air-liquid interface exposure system, we have discovered novel differences in epithelial susceptibility between SSS and MSS exposures. SSS exposure upregulates an eight-exon isoform of CAR and increases adenoviral entry from the apical surface whilst MSS exposure is similar to control air exposure. Additionally, the level of cellular glycogen synthase kinase 3β (GSK3β is downregulated by SSS exposure and treatment with a specific GSK3β inhibitor recapitulates the effects of SSS exposure on CAR expression and viral infection.This is the first time that SSS exposure has been shown to directly enhance the susceptibility of a polarized epithelium to infection by a common respiratory viral pathogen. This work provides a novel understanding of the impact of SSS on the burden of respiratory viral infections and may lead to new strategies to alter viral infections. Moreover, since GSK3β inhibitors are under intense clinical investigation as therapeutics for a diverse range of diseases, studies such as these might provide insight to extend the use of clinically relevant

  5. Efficient Gene Delivery to Pig Airway Epithelia and Submucosal Glands Using Helper-Dependent Adenoviral Vectors

    Huibi Cao

    2013-01-01

    Full Text Available Airway gene delivery is a promising strategy to treat patients with life-threatening lung diseases such as cystic fibrosis (CF. However, this strategy has to be evaluated in large animal preclinical studies in order to translate it to human applications. Because of anatomic and physiological similarities between the human and pig lungs, we utilized pig as a large animal model to examine the safety and efficiency of airway gene delivery with helper-dependent adenoviral vectors. Helper-dependent vectors carrying human CFTR or reporter gene LacZ were aerosolized intratracheally into pigs under bronchoscopic guidance. We found that the LacZ reporter and hCFTR transgene products were efficiently expressed in lung airway epithelial cells. The transgene vectors with this delivery can also reach to submucosal glands. Moreover, the hCFTR transgene protein localized to the apical membrane of both ciliated and nonciliated epithelial cells, mirroring the location of wild-type CF transmembrane conductance regulator (CFTR. Aerosol delivery procedure was well tolerated by pigs without showing systemic toxicity based on the limited number of pigs tested. These results provide important insights into developing clinical strategies for human CF lung gene therapy.

  6. A Genetically Modified Adenoviral Vector with a Phage Display-Derived Peptide Incorporated into Fiber Fibritin Chimera Prolongs Survival in Experimental Glioma.

    Kim, Julius W; Kane, J Robert; Young, Jacob S; Chang, Alan L; Kanojia, Deepak; Morshed, Ramin A; Miska, Jason; Ahmed, Atique U; Balyasnikova, Irina V; Han, Yu; Zhang, Lingjiao; Curiel, David T; Lesniak, Maciej S

    2015-09-01

    The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic strategies with direct patient impact. Adenovirus-mediated virotherapy represents a potentially effective approach for glioma therapy. In this research, we generated a novel glioma-specific adenovirus by instituting more advanced genetic modifications that can maximize the efficiency and safety of therapeutic adenoviral vectors. In this regard, a glioma-specific targeted fiber was developed through the incorporation of previously published glioma-specific, phage-panned peptide (VWT peptide) on a fiber fibritin-based chimeric fiber, designated as "GliomaFF." We showed that the entry of this virus was highly restricted to glioma cells, supporting the specificity imparted by the phage-panned peptide. In addition, the stability of the targeting moiety presented by fiber fibritin structure permitted greatly enhanced infectivity. Furthermore, the replication of this virus was restricted in glioma cells by controlling expression of the E1 gene under the activity of the tumor-specific survivin promoter. Using this approach, we were able to explore the combinatorial efficacy of various adenoviral modifications that could amplify the specificity, infectivity, and exclusive replication of this therapeutic adenovirus in glioma. Finally, virotherapy with this modified virus resulted in up to 70% extended survival in an in vivo murine glioma model. These data demonstrate that this novel adenoviral vector is a safe and efficient treatment for this difficult malignancy.

  7. A simple and robust vector-based shRNA expression system used for RNA interference.

    Wang, Xue-jun; Li, Ying; Huang, Hai; Zhang, Xiu-juan; Xie, Pei-wen; Hu, Wei; Li, Dan-dan; Wang, Sheng-qi

    2013-01-01

    RNA interference (RNAi) mediated by small interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) has become a powerful genetic tool for conducting functional studies. Previously, vector-based shRNA-expression strategies capable of inducing RNAi in viable cells have been developed, however, these vector systems have some disadvantages, either because they were error-prone or cost prohibitive. In this report we described the development of a simple, robust shRNA expression system utilizing 1 long oligonucleotide or 2 short oligonucleotides for half the cost of conventional shRNA construction methods and with a >95% cloning success rate. The shRNA loop sequence and stem structure were also compared and carefully selected for better RNAi efficiency. Furthermore, an easier strategy was developed based on isocaudomers which permit rapid combination of the most efficient promoter-shRNA cassettes. Finally, using this method, the conservative target sites for hepatitis B virus (HBV) knockdown were systemically screened and HBV antigen expression shown to be successfully suppressed in the presence of connected multiple shRNAs both in vitro and in vivo. This novel design describes an inexpensive and effective way to clone and express single or multiple shRNAs from the same vector with the capacity for potent and effective silencing of target genes.

  8. A simple and robust vector-based shRNA expression system used for RNA interference.

    Xue-jun Wang

    Full Text Available BACKGROUND: RNA interference (RNAi mediated by small interfering RNAs (siRNAs or short hairpin RNAs (shRNAs has become a powerful genetic tool for conducting functional studies. Previously, vector-based shRNA-expression strategies capable of inducing RNAi in viable cells have been developed, however, these vector systems have some disadvantages, either because they were error-prone or cost prohibitive. RESULTS: In this report we described the development of a simple, robust shRNA expression system utilizing 1 long oligonucleotide or 2 short oligonucleotides for half the cost of conventional shRNA construction methods and with a >95% cloning success rate. The shRNA loop sequence and stem structure were also compared and carefully selected for better RNAi efficiency. Furthermore, an easier strategy was developed based on isocaudomers which permit rapid combination of the most efficient promoter-shRNA cassettes. Finally, using this method, the conservative target sites for hepatitis B virus (HBV knockdown were systemically screened and HBV antigen expression shown to be successfully suppressed in the presence of connected multiple shRNAs both in vitro and in vivo. CONCLUSION: This novel design describes an inexpensive and effective way to clone and express single or multiple shRNAs from the same vector with the capacity for potent and effective silencing of target genes.

  9. Targeted Adenoviral Vector Demonstrates Enhanced Efficacy for In Vivo Gene Therapy of Uterine Leiomyoma.

    Abdelaziz, Mohamed; Sherif, Lotfy; ElKhiary, Mostafa; Nair, Sanjeeta; Shalaby, Shahinaz; Mohamed, Sara; Eziba, Noura; El-Lakany, Mohamed; Curiel, David; Ismail, Nahed; Diamond, Michael P; Al-Hendy, Ayman

    2016-04-01

    Gene therapy is a potentially effective non-surgical approach for the treatment of uterine leiomyoma. We demonstrated that targeted adenovirus vector, Ad-SSTR-RGD-TK/GCV, was highly effective in selectively inducing apoptosis and inhibiting proliferation of human leiomyoma cells in vitro while sparing normal myometrial cells. An in-vivo study, to compare efficacy and safety of modified adenovirus vector Ad-SSTR-RGD-TK/GCV versus untargeted vector for treatment of leiomyoma. Female nude mice were implanted with rat leiomyoma cells subcutaneously. Then mice were randomized into three groups. Group 1 received Ad-LacZ (marker gene), Group 2 received untargeted Ad-TK, and Group 3 received the targeted Ad-SSTR-RGD-TK. Tumors were measured weekly for 4 weeks. Then mice were sacrificed and tissue samples were collected. Evaluation of markers of apoptosis, proliferation, extracellular matrix, and angiogenesis was performed using Western Blot & Immunohistochemistry. Statistical analysis was done using ANOVA. Dissemination of adenovirus was assessed by PCR. In comparison with the untargeted vector, the targeted adenoviral vector significantly shrank leiomyoma size (P leiomyoma lesions with both targeted and untargeted adenovirus. Targeted adenovirus, effectively reduces tumor size in leiomyoma without dissemination to other organs. Further evaluation of this localized targeted strategy for gene therapy is needed in appropriate preclinical humanoid animal models in preparation for a future pilot human trial. © The Author(s) 2016.

  10. Adenoviral gene delivery to primary human cutaneous cells and burn wounds.

    Hirsch, Tobias; von Peter, Sebastian; Dubin, Grzegorz; Mittler, Dominik; Jacobsen, Frank; Lehnhardt, Markus; Eriksson, Elof; Steinau, Hans-Ulrich; Steinstraesser, Lars

    2006-01-01

    The adenoviral transfer of therapeutic genes into epidermal and dermal cells is an interesting approach to treat skin diseases and to promote wound healing. The aim of this study was to assess the in vitro and in vivo transfection efficacy in skin and burn wounds after adenoviral gene delivery. Primary keratinocytes (HKC), fibroblasts (HFB), and HaCaT cells were transfected using different concentrations of an adenoviral construct (eGFP). Transfection efficiency and cytotoxicity was determined up to 30 days. Expression was quantified by FACS analysis and fluorimeter. Cytotoxicity was measured using the trypan blue exclusion method. 45 male Sprague Dawley rats received 2x10(8) pfu of Ad5-CMV-LacZ or carrier control intradermally into either superficial partial thickness scald burn or unburned skin. Animals were euthanized after 48 h, 7 or 14 days posttreatment. Transgene expression was assessed using immunohistochemistry and bioluminescent assays. The highest transfection rate was observed 48 h posttransfection: 79% for HKC, 70% for HFB, and 48% for HaCaT. The eGFP expression was detectable in all groups over 30 days (P>0.05). Cytotoxic effects of the adenoviral vector were observed for HFB after 10 days and HaCaT after 30 days. Reporter gene expression in vivo was significantly higher in burned skin compared with unburned skin (P=0,004). Gene expression decreases from 2 to 7 days with no significant expression after 14 days. This study demonstrates that effective adenoviral-mediated gene transfer of epidermal primary cells and cell-lines is feasible. Ex vivo gene transfer in epithelial cells might have promise for the use in severely burned patients who receive autologous keratinocyte sheets. Transient cutaneous gene delivery in burn wounds using adenoviral vectors causes significant concentrations in the wound tissue for at least 1 week. Based on these findings, we hypothesize that transient cutaneous adenoviral gene delivery of wound healing promoting factors has

  11. Development of Novel Adenoviral Vectors to Overcome Challenges Observed With HAdV-5–based Constructs

    Alonso-Padilla, Julio; Papp, Tibor; Kaján, Győző L; Benkő, Mária; Havenga, Menzo; Lemckert, Angelique; Harrach, Balázs; Baker, Andrew H

    2016-01-01

    Recombinant vectors based on human adenovirus serotype 5 (HAdV-5) have been extensively studied in preclinical models and clinical trials over the past two decades. However, the thorough understanding of the HAdV-5 interaction with human subjects has uncovered major concerns about its product applicability. High vector-associated toxicity and widespread preexisting immunity have been shown to significantly impede the effectiveness of HAdV-5–mediated gene transfer. It is therefore that the in-depth knowledge attained working on HAdV-5 is currently being used to develop alternative vectors. Here, we provide a comprehensive overview of data obtained in recent years disqualifying the HAdV-5 vector for systemic gene delivery as well as novel strategies being pursued to overcome the limitations observed with particular emphasis on the ongoing vectorization efforts to obtain vectors based on alternative serotypes. PMID:26478249

  12. Adenoviral hemorrhagic disease in California mule deer, 1990-2014.

    Woods, Leslie W; Schumaker, Brant A; Pesavento, Patricia A; Crossley, Beate M; Swift, Pamela K

    2018-03-01

    We reviewed case records from the California Animal Health and Food Safety (CAHFS) laboratory and the California Department of Fish and Wildlife (CDFW) spanning 25 years (1990-2014) for all deer accessions submitted to CAHFS for pathology and/or histopathology, with and without a diagnosis of adenoviral hemorrhagic disease (AHD), in order to determine the prevalence of AHD in California. We also examined spatial and temporal distribution, age, and mule deer subspecies in deer that died from AHD. Of 483 deer submitted to CAHFS for diagnostic testing in 1990-2014, 17.2% were diagnosed with confirmed AHD, and 26.5% were confirmed plus suspected cases of AHD. Columbian black-tailed deer ( Odocoileus hemionus columbianus), particularly fawns and juveniles, were most frequently affected. Deer adenovirus ( Odocoileus adenovirus 1; OdAdV-1) was detected by immunohistochemistry in archived CDFW formalin-fixed, paraffin-embedded tissues from deer that died in mortality events in 1981, 1983, and 1986-1987. OdAdV-1 is a common cause of hemorrhagic disease mortality events in California deer, and mortality as a result of AHD is documented as early as 1981.

  13. Adenoviral protein V promotes a process of viral assembly through nucleophosmin 1

    Ugai, Hideyo; Dobbins, George C.; Wang, Minghui [Division of Human Gene Therapy, Departments of Medicine, Obstetrics and Gynecology, Pathology, and Surgery, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Le, Long P. [Massachusetts General Hospital, Pathology Service, 55 Fruit St.-GRJ 249, Boston, MA 02114 (United States); Matthews, David A. [School of Cellular and Molecular Medicine, Medical Sciences Building, University of Bristol, Bristol BS8 1TD (United Kingdom); Curiel, David T., E-mail: dcuriel@radonc.wustl.edu [Division of Human Gene Therapy, Departments of Medicine, Obstetrics and Gynecology, Pathology, and Surgery, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); The Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL 35294 (United States)

    2012-10-25

    Adenoviral infection induces nucleoplasmic redistribution of a nucleolar nucleophosmin 1/NPM1/B23.1. NPM1 is preferentially localized in the nucleoli of normal cells, whereas it is also present at the nuclear matrix in cancer cells. However, the biological roles of NPM1 during infection are unknown. Here, by analyzing a pV-deletion mutant, Ad5-dV/TSB, we demonstrate that pV promotes the NPM1 translocation from the nucleoli to the nucleoplasm in normal cells, and the NPM1 translocation is correlated with adenoviral replication. Lack of pV causes a dramatic reduction of adenoviral replication in normal cells, but not cancer cells, and Ad5-dV/TSB was defective in viral assembly in normal cells. NPM1 knockdown inhibits adenoviral replication, suggesting an involvement of NPM1 in adenoviral biology. Further, we show that NPM1 interacts with empty adenovirus particles which are an intermediate during virion maturation by immunoelectron microscopy. Collectively, these data implicate that pV participates in a process of viral assembly through NPM1.

  14. Suppression of inflammation by dexamethasone prolongs adenoviral vector-mediated transgene expression in the facial nucleus of the rat

    Hermens, W.T.J.M.C.; Verhaagen, J

    1998-01-01

    Adenoviral vector directed gene transfer to rat facial motoneurons occurs efficiently following intra-parenchymal injection of relatively high dosages (> or =10(7) pfu per injection) of a prototype first generation adenoviral vector. However, high level of transgene expression, as observed during

  15. Transient gene transfer to neurons and glia : analysis of adenoviral vector performance in the CNS and PNS

    Hermens, W.T.J.M.C.; Giger, Roman J; Holtmaat, Anthony J D G; Dijkhuizen, Paul A; Houweling, D A; Verhaagen, J

    In this paper a detailed protocol is presented for neuroscientists planning to start work on first generation recombinant adenoviral vectors as gene transfer agents for the nervous system. The performance of a prototype adenoviral vector encoding the bacterial lacZ gene as a reporter was studied,

  16. Efficient adenoviral vector directed expression of a foreign gene to neurons and sustentacular cells in the mouse olfactory neuroepithelium

    Gispen, W.H.; Holtmaat, A.J.G.D.; Hermens, W.T.J.M.C.; Oestreicher, A.B.; Kaplitt, M.G.; Verhaagen, J.

    1996-01-01

    Replication deficient recombinant adenoviral vectors are efficient gene transfer agents for postmitotic cells, including neurons and glial cells. In this paper we have examined the effectiveness of adenoviral vector-mediated gene transfer to the olfactory epithelium of adult mice. We show that

  17. Efficient adenoviral vector-directed expression of a foreign gene to neurons and sustentacular cells in the mouse olfactory neuroepithelium

    Holtmaat, Anthony J D G; Hermens, W.T.J.M.C.; Oestreicher, A B; Gispen, Willem Hendrik; Kaplitt, M G; Verhaagen, J

    1996-01-01

    Replication deficient recombinant adenoviral vectors are efficient gene transfer agents for postmitotic cells, including neurons and glial cells. In this paper we have examined the effectiveness of adenoviral vector-mediated gene transfer to the olfactory epithelium of adult mice. We show that

  18. Adenoviral vector-mediated gene transfer and neurotransplantation : possibilities and limitations in grafting of the fetal rat suprachiasmatic nucleus

    van Esseveldt, K E; Liu, R.; Hermens, W.T.J.M.C.; Verhaagen, J; Boer, G J

    Several studies have reported on the use of primary neural cells transduced by adenoviral vectors as donor cells in neurotransplantation. In the present investigation, we examined whether adenoviral vector-mediated gene transfer could be used to introduce and express a foreign gene in solid neural

  19. Adenoviral-mediated correction of methylmalonyl-CoA mutase deficiency in murine fibroblasts and human hepatocytes

    Korson Mark

    2007-04-01

    Full Text Available Abstract Background Methylmalonic acidemia (MMA, a common organic aciduria, is caused by deficiency of the mitochondrial localized, 5'deoxyadenosylcobalamin dependent enzyme, methylmalonyl-CoA mutase (MUT. Liver transplantation in the absence of gross hepatic dysfunction provides supportive therapy and metabolic stability in severely affected patients, which invites the concept of using cell and gene delivery as future treatments for this condition. Methods To assess the effectiveness of gene delivery to restore the defective metabolism in this disorder, adenoviral correction experiments were performed using murine Mut embryonic fibroblasts and primary human methylmalonyl-CoA mutase deficient hepatocytes derived from a patient who harbored two early truncating mutations, E224X and R228X, in the MUT gene. Enzymatic and expression studies were used to assess the extent of functional correction. Results Primary hepatocytes, isolated from the native liver after removal subsequent to a combined liver-kidney transplantation procedure, or Mut murine fibroblasts were infected with a second generation recombinant adenoviral vector that expressed the murine methylmalonyl-CoA mutase as well as eGFP from distinct promoters. After transduction, [1-14C] propionate macromolecular incorporation studies and Western analysis demonstrated complete correction of the enzymatic defect in both cell types. Viral reconstitution of enzymatic expression in the human methylmalonyl-CoA mutase deficient hepatocytes exceeded that seen in fibroblasts or control hepatocytes. Conclusion These experiments provide proof of principle for viral correction in methylmalonic acidemia and suggest that hepatocyte-directed gene delivery will be an effective therapeutic treatment strategy in both murine models and in human patients. Primary hepatocytes from a liver that was unsuitable for transplantation provided an important resource for these studies.

  20. Efficient gene transfer into lymphoma cells using adenoviral vectors combined with lipofection.

    Buttgereit, P; Weineck, S; Röpke, G; Märten, A; Brand, K; Heinicke, T; Caselmann, W H; Huhn, D; Schmidt-Wolf, I G

    2000-08-01

    Tumor cells, such as lymphoma cells, are possible targets for gene therapy. In general, gene therapeutic approaches require efficient gene transfer to host cells and sufficient transgene expression. However, lymphoma cells previously have been demonstrated to be resistant to most of the currently available gene transfer methods. The aim of this study was to analyze various methods for transfection of lymphoma cells and to improve the efficiency of gene delivery. In accordance with previously published reports, lymphoma cells were demonstrated to be resistant to lipofection and electroporation. In contrast, we present an improved adenoviral protocol leading to highly efficient gene transfer to lymphoma cell lines derived from B cells as well as primary lymphoma cells being achieved with an adenoviral vector system encoding the beta-galactosidase protein. At a multiplicity of infection of 200, up to 100% of Daudi cells and Raji cells and 70% of OCI-Ly8-LAM53 cells could be transfected. Even at high adenoviral concentrations, no marked toxicity was observed, and the growth characteristics of the lymphoma cell lines were not impaired. The transfection rates in primary cells derived from six patients with non-Hodgkin's lymphoma were 30-65%, respectively. Transfection efficiency could be further increased by addition of cationic liposomes to adenoviral gene transfer. Furthermore, we examined the expression of the Coxsackie-adenoviral receptor (CAR) and the integrin receptors on the lymphoma cell surface. Flow cytometric analysis showed that 88% of Daudi cells, 69% of Raji cells, and 6% of OCI-Ly8-LAM53 cells expressed CAR on the cell surface. According to our data, adenoviral infection of lymphoma cells seems to be mediated by CAR. In contrast, integrin receptors are unlikely to play a major role, because lymphoma cells were negative for alphavbeta3-integrins and negative for alphavbeta5-integrins. In conclusion, this study demonstrates that B-lymphoma cell lines and

  1. Molecular Imaging of Gene Expression and Efficacy following Adenoviral-Mediated Brain Tumor Gene Therapy

    Alnawaz Rehemtulla

    2002-01-01

    Full Text Available Cancer gene therapy is an active area of research relying upon the transfer and subsequent expression of a therapeutic transgene into tumor cells in order to provide for therapeutic selectivity. Noninvasive assessment of therapeutic response and correlation of the location, magnitude, and duration of transgene expression in vivo would be particularly useful in the development of cancer gene therapy protocols by facilitating optimization of gene transfer protocols, vector development, and prodrug dosing schedules. In this study, we developed an adenoviral vector containing both the therapeutic transgene yeast cytosine deaminase (yCD along with an optical reporter gene (luciferase. Following intratumoral injection of the vector into orthotopic 9L gliomas, anatomical and diffusion-weighted MR images were obtained over time in order to provide for quantitative assessment of overall therapeutic efficacy and spatial heterogeneity of cell kill, respectively. In addition, bioluminescence images were acquired to assess the duration and magnitude of gene expression. MR images revealed significant reduction in tumor growth rates associated with yCD/5-fluorocytosine (5FC gene therapy. Significant increases in mean tumor diffusion values were also observed during treatment with 5FC. Moreover, spatial heterogeneity in tumor diffusion changes were also observed revealing that diffusion magnetic resonance imaging could detect regional therapeutic effects due to the nonuniform delivery and/or expression of the therapeutic yCD transgene within the tumor mass. In addition, in vivo bioluminescence imaging detected luciferase gene expression, which was found to decrease over time during administration of the prodrug providing a noninvasive surrogate marker for monitoring gene expression. These results demonstrate the efficacy of the yCD/5FC strategy for the treatment of brain tumors and reveal the feasibility of using multimodality molecular and functional imaging

  2. An episomal vector-based CRISPR/Cas9 system for highly efficient gene knockout in human pluripotent stem cells.

    Xie, Yifang; Wang, Daqi; Lan, Feng; Wei, Gang; Ni, Ting; Chai, Renjie; Liu, Dong; Hu, Shijun; Li, Mingqing; Li, Dajin; Wang, Hongyan; Wang, Yongming

    2017-05-24

    Human pluripotent stem cells (hPSCs) represent a unique opportunity for understanding the molecular mechanisms underlying complex traits and diseases. CRISPR/Cas9 is a powerful tool to introduce genetic mutations into the hPSCs for loss-of-function studies. Here, we developed an episomal vector-based CRISPR/Cas9 system, which we called epiCRISPR, for highly efficient gene knockout in hPSCs. The epiCRISPR system enables generation of up to 100% Insertion/Deletion (indel) rates. In addition, the epiCRISPR system enables efficient double-gene knockout and genomic deletion. To minimize off-target cleavage, we combined the episomal vector technology with double-nicking strategy and recent developed high fidelity Cas9. Thus the epiCRISPR system offers a highly efficient platform for genetic analysis in hPSCs.

  3. Adenoviral DNA replication: DNA sequences and enzymes required for initiation in vitro

    Stillman, B.W.; Tamanoi, F.

    1983-01-01

    In this paper evidence is provided that the 140,000-dalton DNA polymerase is encoded by the adenoviral genome and is required for the initiation of DNA replication in vitro. The DNA sequences in the template DNA that are required for the initiation of replication have also been identified, using both plasmid DNAs and synthetic oligodeoxyribonucleotides. 48 references, 7 figures, 1 table

  4. Ovarian cancer targeted adenoviral-mediated mda-7/IL-24 gene therapy

    Mahasreshti, PJ; Kataram, M; Wu, HJ; Yalavarthy, LP; Carey, D; Dent, P; Chada, S; Alvarez, RD; Haisma, HJ; Fisher, PB; Curiel, DT

    Objective. We have previously shown that adenoviral-mediated melanoma differentiation-associated gene-7 (Ad.mda-7) therapy induces apoptosis in ovarian cancer cells. However, the apoptosis induction was low and directly correlated with infectivity of Ad.mda-7. The objective of this study was to

  5. Quantification of residual host cell DNA in adenoviral vectors produced on PER.C6 cells

    Gijsbers, Linda; Koel, Björn; Weggeman, Miranda; Goudsmit, Jaap; Havenga, Menzo; Marzio, Giuseppe

    2005-01-01

    Recombinant adenoviral vectors for gene therapy and vaccination are routinely prepared on cultures of immortalized cells, allowing the production of vector batches of high titer and consistent quality. Quantification of residual DNA from the producing cell line is part of the purity tests for

  6. The effects of combining ionizing radiation and adenoviral p53 therapy in nasopharyngeal carcinoma

    Li Jianhua; Lax, Stuart A.; Kim, John; Klamut, Henry; Liu Feifei

    1999-01-01

    Purpose: Nasopharyngeal carcinoma (NPC) is a malignant disease of the head/neck region, with a 5-year survival level of approximately 65%. To explore gene therapy as a novel approach which might improve outcome, we have shown previously that introduction of human recombinant wild-type p53 mediated by the adenoviral vector (Ad5CMV-p53) was cytotoxic in two human nasopharyngeal carcinoma (NPC) cell lines (CNE-1 and CNE-2Z). The current work was designed to determine whether this strategy, combined with ionizing radiation (XRT), was more effective than either treatment alone. Methods and Materials: CNE-1, CNE-2Z, and a normal human nasopharyngeal fibroblast strain, KS1, were infected with 2- and 6-plaque-forming units (pfu)/cell of Ad5CMV-p53, respectively. These doses were iso-effective for β-galactosidase activity in the CNE-1 and CNE-2Z cells. XRT was administered 24 h post-infection, and Western blot analyses were conducted for p53, p21 WAF1/CIP1 , bax, and bcl-2 2 days after XRT. Cell survival was assessed using a clonogenic assay. Presence of DNA ladders reflecting apoptosis was detected using DNA agarose gel electrophoresis, and cell cycle was analyzed using flow cytometry. Results: The combination of Ad5CMV-p53 plus XRT (2, 4, and 6 Gy) resulted in an approximately 1-log greater level of cytotoxicity compared to that observed with XRT alone for both NPC cell lines. The two modalities appear to be interacting in a synergistic manner in cancer cells, but not in KS1 fibroblasts. XRT alone stimulated minimal p53 expression in control cells; Ad5CMV-p53 alone induced significant recombinant p53 expression, which was not further enhanced by the addition of XRT. Similar observations were made for p21 WAF1/CIP1 expression. No changes were observed for bax or bcl-2 expression with any of these treatments. Apoptosis was induced following 4 Gy of XRT alone, but was observed after only 2 Gy when combined with Ad5CMV-p53. Cell cycle analysis indicated that Ad5CMV-p53

  7. Radiation-Induced Upregulation of Gene Expression From Adenoviral Vectors Mediated by DNA Damage Repair and Regulation

    Nokisalmi, Petri; Rajecki, Maria; Pesonen, Sari; Escutenaire, Sophie; Soliymani, Rabah; Tenhunen, Mikko; Ahtiainen, Laura; Hemminki, Akseli

    2012-01-01

    Purpose: In the present study, we evaluated the combination of replication-deficient adenoviruses and radiotherapy in vitro. The purpose of the present study was to analyze the mechanism of radiation-mediated upregulation of adenoviral transgene expression. Methods and Materials: Adenoviral transgene expression (luciferase or green fluorescent protein) was studied with and without radiation in three cell lines: breast cancer M4A4-LM3, prostate cancer PC-3MM2, and lung cancer LNM35/enhanced green fluorescent protein. The effect of the radiation dose, modification of the viral capsid, and five different transgene promoters were studied. The cellular responses were studied using mass spectrometry and immunofluorescence analysis. Double strand break repair was modulated by inhibitors of heat shock protein 90, topoisomerase-I, and DNA protein kinase, and transgene expression was measured. Results: We found that a wide range of radiation doses increased adenoviral transgene expression regardless of the cell line, transgene, promoter, or viral capsid modification. Treatment with adenovirus, radiation, and double strand break repair inhibitors resulted in persistence of double strand breaks and subsequent increases in adenovirus transgene expression. Conclusions: Radiation-induced enhancement of adenoviral transgene expression is linked to DNA damage recognition and repair. Radiation induces a global cellular response that results in increased production of RNA and proteins, including adenoviral transgene products. This study provides a mechanistic rationale for combining radiation with adenoviral gene delivery.

  8. Gene Therapy with Helper-Dependent Adenoviral Vectors: Current Advances and Future Perspectives

    Philip Ng

    2010-09-01

    Full Text Available Recombinant Adenoviral vectors represent one of the best gene transfer platforms due to their ability to efficiently transduce a wide range of quiescent and proliferating cell types from various tissues and species. The activation of an adaptive immune response against the transduced cells is one of the major drawbacks of first generation Adenovirus vectors and has been overcome by the latest generation of recombinant Adenovirus, the Helper-Dependent Adenoviral (HDAd vectors. HDAds have innovative features including the complete absence of viral coding sequences and the ability to mediate high level transgene expression with negligible chronic toxicity. This review summarizes the many aspects of HDAd biology and structure with a major focus on in vivo gene therapy application and with an emphasis on the unsolved issues that these vectors still presents toward clinical application.

  9. Isolation of proteins involved in the replication of adenoviral DNA in vitro

    Lichy, J.H.; Nagata, K.; Friefeld, B.R.; Enomoto, T.; Field, J.; Guggenheimer, R.A.; Ikeda, J.E.; Horwitz, M.S.; Hurwitz, J.

    1983-01-01

    The simple mechanism of replication of adenoviral DNA has made adenovirus an especially useful model system for studies of eukaryotic replication mechanisms. The availability of this in vitro system that replicates exogenously added Ad DNA-pro has made it possible to characterize the factors involved in replication. The results presented in this paper summarize our further fractionation of the in vitro system. First, the properties of two factors purified from the uninfected nuclear extract are described. Second, the separation of the pTP/Ad Pol complex into subunits and the properties of the isolated subunits are presented. The 140K protein is shown to possess the Ad DNA polymerase activity. The results suggest that the only DNA polymerase required for adenoviral DNA replication in vitro is the 140K Ad DNA polymerase and that this enzyme is probably a viral gene product. 50 references, 10 figures, 3 tables

  10. Treatment for Retinopathy of Prematurity in an Infant with Adenoviral Conjunctivitis

    Murat Gunay

    2015-01-01

    Full Text Available Retinopathy of prematurity (ROP has been a major problematic disorder during childhood. Laser photocoagulation (LPC has been proven to be effective in most of the ROP cases. Adenoviral conjunctivitis (AVC is responsible for epidemics among adult and pediatric population. It has also been reported to be a cause of outbreaks in neonatal intensive care units (NICU several times. We herein demonstrate a case with AVC who underwent LPC for ROP. And we discuss the treatment methodology in such cases.

  11. When should adenoviral non-gonococcal urethritis be suspected? Two case reports.

    Avolio, Manuela; De Rosa, Rita; Modolo, Maria Luisa; Stano, Paola; Camporese, Alessandro

    2014-01-01

    The impact of Adenovirus as agent of non-gonococcal urethritis (NGU) is still poorly documented in the literature. We describe two cases showing that adenoviral infection should be reasonably hypothesized in men with dysuria and scant urethral discharge in addition to meatus inflammation and/or edema (meatitis) or conjunctivitis. Case 1: a 55-year-old man came to our observation in July 2012 referring a 5-day-history of intense dysuria and scant mucoid urethral discharge. Physical examination revealed the urethral discharge referred, but also modest meatitis and an intense conjunctival hyperemia on his right eye. Adenoviral infection was investigated and Adenovirus DNA (type 37) was detected in both the urethral and conjunctival swabs. Case 2: a 43-year-old man with intense dysuria, started 4-5 days earlier, came to our attention with his wife in August 2012. Scant urethral mucoid secretions, severe meatal inflammation of the male patient were revealed during physical examination. His wife instead complained of a 2-day history of intense burning eyes. Adenoviral infection was investigated and Adenovirus DNA (type 37) was positive both in the male urethral swab and in his wife's conjunctival swab. Adenovirus seems to cause a distinct and recognisable clinical syndrome in men presenting with urethritis. Studies on the prevalence and role of Adenovirus as a causative agent of urethritis are limited. Moreover, as rapid advanced molecular microbiology is now available, we believe that extending the search to Adenovirus in sexually active men with dysuria, scant discharge in addition to meatitis or conjunctivitis, should be a useful approach improving our understanding about adenoviral NGU, and especially avoiding or stopping unnecessary empirical antibiotic therapy.

  12. Generation of a functional and durable vascular niche by the adenoviral E4ORF1 gene

    Seandel, Marco; Butler, Jason M.; Kobayashi, Hideki; Hooper, Andrea T.; White, Ian A.; Zhang, Fan; Vertes, Eva L.; Kobayashi, Mariko; Zhang, Yan; Shmelkov, Sergey V.; Hackett, Neil R.; Rabbany, Sina; Boyer, Julie L.; Rafii, Shahin

    2008-01-01

    Vascular cells contribute to organogenesis and tumorigenesis by producing unknown factors. Primary endothelial cells (PECs) provide an instructive platform for identifying factors that support stem cell and tumor homeostasis. However, long-term maintenance of PECs requires stimulation with cytokines and serum, resulting in loss of their angiogenic properties. To circumvent this hurdle, we have discovered that the adenoviral E4ORF1 gene product maintains long-term survival and facilitates orga...

  13. Adenoviral infection in a collection of juvenile inland bearded dragons (Pogona vitticeps).

    Doneley, R J T; Buckle, K N; Hulse, L

    2014-01-01

    Juvenile inland bearded dragons (Pogona vitticeps) from a breeding collection in south-east Queensland were presented at age 6-10 weeks with neurological signs, poor growth and occasional deaths. Histopathological examination revealed that six of eight lizards had multifocal non-suppurative hepatitis associated with 5-10 μm diameter, smudgy, basophilic, hyaline intranuclear inclusion bodies that marginated the nuclear chromatin. These histological lesions were considered consistent with adenoviral hepatitis. Infection with adenovirus was confirmed positive in one of the eight dragons by PCR for adenoviral DNA. DNA was extracted from formalin-fixed paraffin-embedded pooled tissues of the juvenile inland bearded dragons and tested using a nested-PCR protocol with primers specific for identification of adenovirus. Sequencing of the one PCR-positive dragon showed 95% nucleotide sequence alignment with agamid atadenovirus 1. Further investigation involved testing the breeding population, including the parents of the affected juveniles. Blood and cloacal samples were collected from the adult population, DNA was extracted and tested by PCR for adenovirus. There was a high percentage of positive results from the samples collected from the breeding population. This is the first reported group outbreak of adenoviral disease in bearded dragons in Australia. © 2014 Australian Veterinary Association.

  14. Advances and Future Challenges in Recombinant Adenoviral Vectored H5N1 Influenza Vaccines

    Jianfeng Zhang

    2012-11-01

    Full Text Available The emergence of a highly pathogenic avian influenza virus H5N1 has increased the potential for a new pandemic to occur. This event highlights the necessity for developing a new generation of influenza vaccines to counteract influenza disease. These vaccines must be manufactured for mass immunization of humans in a timely manner. Poultry should be included in this policy, since persistent infected flocks are the major source of avian influenza for human infections. Recombinant adenoviral vectored H5N1 vaccines are an attractive alternative to the currently licensed influenza vaccines. This class of vaccines induces a broadly protective immunity against antigenically distinct H5N1, can be manufactured rapidly, and may allow mass immunization of human and poultry. Recombinant adenoviral vectors derived from both human and non-human adenoviruses are currently being investigated and appear promising both in nonclinical and clinical studies. This review will highlight the current status of various adenoviral vectored H5N1 vaccines and will outline novel approaches for the future.

  15. Heterologous prime-boost regimens with a recombinant chimpanzee adenoviral vector and adjuvanted F4 protein elicit polyfunctional HIV-1-specific T-Cell responses in macaques.

    Lorin, Clarisse; Vanloubbeeck, Yannick; Baudart, Sébastien; Ska, Michaël; Bayat, Babak; Brauers, Geoffroy; Clarinval, Géraldine; Donner, Marie-Noëlle; Marchand, Martine; Koutsoukos, Marguerite; Mettens, Pascal; Cohen, Joe; Voss, Gerald

    2015-01-01

    HIV-1-specific CD4+ and CD8+ T lymphocytes are important for HIV-1 replication control. F4/AS01 consists of F4 recombinant fusion protein (containing clade B Gag/p24, Pol/RT, Nef and Gag/p17) formulated in AS01 Adjuvant System, and was shown to induce F4-specific polyfunctional CD4+ T-cell responses in humans. While replication-incompetent recombinant HIV-1/SIV antigen-expressing human adenoviral vectors can elicit high-frequency antigen-specific CD8+ T-cell responses, their use is hampered by widespread pre-existing immunity to human serotypes. Non-human adenovirus serotypes associated with lower prevalence may offer an alternative strategy. We evaluated the immunogenicity of AdC7-GRN ('A'), a recombinant chimpanzee adenovirus type 7 vector expressing clade B Gag, RT and Nef, and F4/AS01 ('P'), when delivered intramuscularly in homologous (PP or AA) and heterologous (AAPP or PPAA) prime-boost regimens, in macaques and mice. Vaccine-induced HIV-1-antigen-specific T cells in peripheral blood (macaques), liver, spleen, and intestinal and genital mucosa (mice) were characterized by intracellular cytokine staining. Vaccine-specific IgG antibodies (macaques) were detected using ELISA. In macaques, only the heterologous prime-boost regimens induced polyfunctional, persistent and balanced CD4+ and CD8+ T-cell responses specific to each HIV-1 vaccine antigen. AdC7-GRN priming increased the polyfunctionality of F4/AS01-induced CD4+ T cells. Approximately 50% of AdC7-GRN-induced memory CD8+ T cells exhibited an effector-memory phenotype. HIV-1-specific antibodies were detected with each regimen. In mice, antigen-specific CD4+ and CD8+ T-cell responses were detected in the mucosal and systemic anatomical compartments assessed. When administered in heterologous prime-boost regimens, AdC7-GRN and F4/AS01 candidate vaccines acted complementarily in inducing potent and persistent peripheral blood HIV-1-specific CD4+ and CD8+ T-cell responses and antibodies in macaques. Besides

  16. Mucosal immunization with recombinant adenoviral vectors expressing murine gammaherpesvirus-68 genes M2 and M3 can reduce latent viral load

    Hoegh-Petersen, Mette; Thomsen, Allan R; Christensen, Jan P

    2009-01-01

    -68 (MHV-68) is a member of the Gammaherpesvirinae subfamily and represents a useful murine model for this category of infections, in which new vaccination strategies may initially be evaluated. Two attenuated variants of MHV-68 have successfully been used as vaccines, but the oncogenic potential...... of the gammaherpesvirinae speaks against using a similar approach in humans. DNA immunization with plasmids encoding the MHV-68 genes M2 or M3 caused a reduction in either acute or early latent viral load, respectively, but neither immunization had an effect at times later than 14 days post-infection. Adenovirus......-based vaccines are substantially more immunogenic than DNA vaccines and can be applied to induce mucosal immunity. Here we show that a significant reduction of the late viral load in the spleens, at 60 days post-infection, was achieved when immunizing mice both intranasally and subcutaneously with adenoviral...

  17. Enhanced and sustained CD8+ T cell responses with an adenoviral vector-based hepatitis C virus vaccine encoding NS3 linked to the MHC class II chaperone protein invariant chain

    Mikkelsen, Marianne; Holst, Peter Johannes; Bukh, Jens

    2011-01-01

    memory. Functionally, the AdIiNS3-vaccinated mice had a significantly increased cytotoxic capacity compared with the AdNS3 group. The AdIiNS3-induced CD8(+) T cells protected mice from infection with recombinant vaccinia virus expressing HCV NS3 of heterologous 1b strains, and studies in knockout mice...

  18. Microsphere-liposome complexes protect adenoviral vectors from neutralising antibody without losses in transfection efficiency, in-vitro.

    Steel, Jason C; Cavanagh, Heather M A; Burton, Mark A; Kalle, Wouter H J

    2004-11-01

    Adenoviral vectors have been commonly used in gene therapy protocols but the success of their use is often limited by the induction of host immunity to the vector. Following exposure to the adenoviral vector, adenoviral-specific neutralising antibodies are produced, which limits further administration. This study examines the effectiveness of a novel combination of microspheres and liposomes for the shielding of adenovirus from neutralising antibodies in an in-vitro setting. We show that liposomes are effective in the protection of adenovirus from neutralising antibody and that the conjugation of these complexes to microspheres augments the level of protection. This study further reveals that previously neutralised adenovirus may still be transported into the cell via liposome-cell interactions and is still capable of expressing its genes, making this vector an effective tool for circumvention of the humoral immune response. We also looked at possible side effects of using the complexes, namely increases in cytotoxicity and reductions in transfection efficiency. Our results showed that varying the liposome:adenovirus ratio can reduce the cytotoxicity of the vector as well as increase the transfection efficiency. In addition, in cell lines that are adenoviral competent, transfection efficiencies on par with uncomplexed adenoviral vectors were achievable with the combination vector.

  19. Adenoviral vector-mediated gene expression in the nervous system of immunocompetent Wistar and T cell-deficient nude rats : preferential survival of transduced astroglial cells in nude rats

    Hermens, W.T.J.M.C.; Verhaagen, J

    1997-01-01

    In the present paper, we examined the effect of the adenoviral vector dosage, the role of T cells, and the influence of the presence of replication-competent adenovirus (RCA) in adenoviral vector stocks, on the efficacy of adenoviral vector-directed transgene expression in the facial nucleus of

  20. Two Hop Adaptive Vector Based Quality Forwarding for Void Hole Avoidance in Underwater WSNs.

    Javaid, Nadeem; Ahmed, Farwa; Wadud, Zahid; Alrajeh, Nabil; Alabed, Mohamad Souheil; Ilahi, Manzoor

    2017-08-01

    Underwater wireless sensor networks (UWSNs) facilitate a wide range of aquatic applications in various domains. However, the harsh underwater environment poses challenges like low bandwidth, long propagation delay, high bit error rate, high deployment cost, irregular topological structure, etc. Node mobility and the uneven distribution of sensor nodes create void holes in UWSNs. Void hole creation has become a critical issue in UWSNs, as it severely affects the network performance. Avoiding void hole creation benefits better coverage over an area, less energy consumption in the network and high throughput. For this purpose, minimization of void hole probability particularly in local sparse regions is focused on in this paper. The two-hop adaptive hop by hop vector-based forwarding (2hop-AHH-VBF) protocol aims to avoid the void hole with the help of two-hop neighbor node information. The other protocol, quality forwarding adaptive hop by hop vector-based forwarding (QF-AHH-VBF), selects an optimal forwarder based on the composite priority function. QF-AHH-VBF improves network good-put because of optimal forwarder selection. QF-AHH-VBF aims to reduce void hole probability by optimally selecting next hop forwarders. To attain better network performance, mathematical problem formulation based on linear programming is performed. Simulation results show that by opting these mechanisms, significant reduction in end-to-end delay and better throughput are achieved in the network.

  1. Double-stranded RNA transcribed from vector-based oligodeoxynucleotide acts as transcription factor decoy

    Xiao, Xiao; Gang, Yi; Wang, Honghong; Wang, Jiayin; Zhao, Lina; Xu, Li; Liu, Zhiguo

    2015-01-01

    Highlights: • A shRNA vector based transcription factor decoy, VB-ODN, was designed. • VB-ODN for NF-κB inhibited cell viability in HEK293 cells. • VB-ODN inhibited expression of downstream genes of target transcription factors. • VB-ODN may enhance nuclear entry ratio for its feasibility of virus production. - Abstract: In this study, we designed a short hairpin RNA vector-based oligodeoxynucleotide (VB-ODN) carrying transcription factor (TF) consensus sequence which could function as a decoy to block TF activity. Specifically, VB-ODN for Nuclear factor-κB (NF-κB) could inhibit cell viability and decrease downstream gene expression in HEK293 cells without affecting expression of NF-κB itself. The specific binding between VB-ODN produced double-stranded RNA and NF-κB was evidenced by electrophoretic mobility shift assay. Moreover, similar VB-ODNs designed for three other TFs also inhibit their downstream gene expression but not that of themselves. Our study provides a new design of decoy for blocking TF activity

  2. Double-stranded RNA transcribed from vector-based oligodeoxynucleotide acts as transcription factor decoy

    Xiao, Xiao [State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi Province (China); Gang, Yi [State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi Province (China); Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, Shaanxi Province (China); Wang, Honghong [No. 518 Hospital of Chinese People’s Liberation Army, Xi’an 710043, Shaanxi Province (China); Wang, Jiayin [The Genome Institute, Washington University in St. Louis, St. Louis, MO 63108 (United States); Zhao, Lina [Department of Radiation Oncology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi Province (China); Xu, Li, E-mail: lxuhelen@163.com [State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi Province (China); Liu, Zhiguo, E-mail: liuzhiguo@fmmu.edu.cn [State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi Province (China)

    2015-02-06

    Highlights: • A shRNA vector based transcription factor decoy, VB-ODN, was designed. • VB-ODN for NF-κB inhibited cell viability in HEK293 cells. • VB-ODN inhibited expression of downstream genes of target transcription factors. • VB-ODN may enhance nuclear entry ratio for its feasibility of virus production. - Abstract: In this study, we designed a short hairpin RNA vector-based oligodeoxynucleotide (VB-ODN) carrying transcription factor (TF) consensus sequence which could function as a decoy to block TF activity. Specifically, VB-ODN for Nuclear factor-κB (NF-κB) could inhibit cell viability and decrease downstream gene expression in HEK293 cells without affecting expression of NF-κB itself. The specific binding between VB-ODN produced double-stranded RNA and NF-κB was evidenced by electrophoretic mobility shift assay. Moreover, similar VB-ODNs designed for three other TFs also inhibit their downstream gene expression but not that of themselves. Our study provides a new design of decoy for blocking TF activity.

  3. Reversal of experimental colitis disease activity in mice following administration of an adenoviral IL-10 vector.

    Sasaki, Makoto; Mathis, J Michael; Jennings, Merilyn H; Jordan, Paul; Wang, Yuping; Ando, Tomoaki; Joh, Takashi; Alexander, J Steven

    2005-10-31

    Genetic deficiency in the expression of interleukin-10 (IL-10) is associated with the onset and progression of experimental inflammatory bowel disease (IBD). The clinical significance of IL-10 expression is supported by studies showing that immune-augmentation of IL-10 prevents inflammation and mucosal damage in animal models of colitis and in human colitis. Interleukin-10 (IL-10), an endogenous anti-inflammatory and immunomodulating cytokine, has been shown to prevent some inflammation and injury in animal and clinical studies, but the efficacy of IL-10 treatment remains unsatisfactory. We found that intra-peritoneal administration of adenoviral IL-10 to mice significantly reversed colitis induced by administration of 3% DSS (dextran sulfate), a common model of colitis. Adenoviral IL-10 (Ad-IL10) transfected mice developed high levels of IL-10 (394 +/- 136 pg/ml) within the peritoneal cavity where the adenovirus was expressed. Importantly, when given on day 4 (after the induction of colitis w/DSS), Ad-IL10 significantly reduced disease activity and weight loss and completely prevented histopathologic injury to the colon at day 10. Mechanistically, compared to Ad-null and DSS treated mice, Ad-IL10 and DSS-treated mice were able to suppress the expression of MAdCAM-1, an endothelial adhesion molecule associated with IBD. Our results suggest that Ad-IL10 (adenoviral IL-10) gene therapy of the intestine or peritoneum may be useful in the clinical treatment of IBD, since we demonstrated that this vector can reverse the course of an existing gut inflammation and markers of inflammation.

  4. Reversal of experimental colitis disease activity in mice following administration of an adenoviral IL-10 vector

    Ando Tomoaki

    2005-10-01

    Full Text Available Abstract Genetic deficiency in the expression of interleukin-10 (IL-10 is associated with the onset and progression of experimental inflammatory bowel disease (IBD. The clinical significance of IL-10 expression is supported by studies showing that immune-augmentation of IL-10 prevents inflammation and mucosal damage in animal models of colitis and in human colitis. Interleukin-10 (IL-10, an endogenous anti-inflammatory and immunomodulating cytokine, has been shown to prevent some inflammation and injury in animal and clinical studies, but the efficacy of IL-10 treatment remains unsatisfactory. We found that intra-peritoneal administration of adenoviral IL-10 to mice significantly reversed colitis induced by administration of 3% DSS (dextran sulfate, a common model of colitis. Adenoviral IL-10 (Ad-IL10 transfected mice developed high levels of IL-10 (394 +/- 136 pg/ml within the peritoneal cavity where the adenovirus was expressed. Importantly, when given on day 4 (after the induction of colitis w/DSS, Ad-IL10 significantly reduced disease activity and weight loss and completely prevented histopathologic injury to the colon at day 10. Mechanistically, compared to Ad-null and DSS treated mice, Ad-IL10 and DSS-treated mice were able to suppress the expression of MAdCAM-1, an endothelial adhesion molecule associated with IBD. Our results suggest that Ad-IL10 (adenoviral IL-10 gene therapy of the intestine or peritoneum may be useful in the clinical treatment of IBD, since we demonstrated that this vector can reverse the course of an existing gut inflammation and markers of inflammation.

  5. Purification of adenoviral vectors by combined anion exchange and gel filtration chromatography.

    Eglon, Marc N; Duffy, Aoife M; O'Brien, Timothy; Strappe, Padraig M

    2009-11-01

    Adenoviral vectors are used extensively in human gene therapy trials and in vaccine development. Large-scale GMP production requires a downstream purification process, and liquid chromatography is emerging as the most powerful mode of purification, enabling the production of vectors at a clinically relevant scale and quality. The present study describes the development of a two-step high-performance liquid chromatography (HPLC) process combining anion exchange (AIEX) and gel filtration (GF) in comparison with the caesium chloride density gradient method. HEK-293 cells were cultured in ten-layer CellStacks() and infected with 10 pfu/cell of adenoviral vector expressing green fluorescent protein (Ad5-GFP). Cell-bound virus was harvested and benzonase added to digest DNA, crude lysate was clarified by centrifugation and filtration prior to HPLC. Chromatography fractions were added to HEK-293 cells and GFP expression measured using a fluorescent plate reader. Using AIEX then GF resulted in an adenoviral vector with purity comparable to Ad5-GFP purified by CsCl, whereas the reverse process (GF-AIEX) showed a reduced purity by electrophoresis and required further buffer exchange of the product. The optimal process (AIEX-GF) resulted in a vector yield of 2.3 x 10(7) pfu/cm(2) of cell culture harvested compared to 3.3 x 10(7) pfu/cm(2) for CsCl. The process recovery for the HPLC process was 36% compared to 27.5% for CsCl and total virion to infectious particle ratios of 18 and 11, respectively, were measured. We present a simple two-step chromatography process that is capable of producing high-quality adenovirus at a titre suitable for scale-up and clinical translation.

  6. Sensitivity and specificity of the AdenoPlus test for diagnosing adenoviral conjunctivitis.

    Sambursky, Robert; Trattler, William; Tauber, Shachar; Starr, Christopher; Friedberg, Murray; Boland, Thomas; McDonald, Marguerite; DellaVecchia, Michael; Luchs, Jodi

    2013-01-01

    To compare the clinical sensitivity and specificity of the AdenoPlus test with those of both viral cell culture (CC) with confirmatory immunofluorescence assay (IFA) and polymerase chain reaction (PCR) at detecting the presence of adenovirus in tear fluid. A prospective, sequential, masked, multicenter clinical trial enrolled 128 patients presenting with a clinical diagnosis of acute viral conjunctivitis from a combination of 8 private ophthalmology practices and academic centers. Patients were tested with AdenoPlus, CC-IFA, and PCR to detect the presence of adenovirus. The sensitivity and specificity of AdenoPlus were assessed for identifying cases of adenoviral conjunctivitis. Of the 128 patients enrolled, 36 patients' results were found to be positive by either CC-IFA or PCR and 29 patients' results were found to be positive by both CC-IFA and PCR. When compared only with CC-IFA, AdenoPlus showed a sensitivity of 90% (28/31) and specificity of 96% (93/97). When compared only with PCR, AdenoPlus showed a sensitivity of 85% (29/34) and specificity of 98% (89/91). When compared with both CC-IFA and PCR, AdenoPlus showed a sensitivity of 93% (27/29) and specificity of 98% (88/90). When compared with PCR, CC-IFA showed a sensitivity of 85% (29/34) and specificity of 99% (90/91). AdenoPlus is sensitive and specific at detecting adenoviral conjunctivitis. An accurate and rapid in-office test can prevent the misdiagnosis of adenoviral conjunctivitis that leads to the spread of disease, unnecessary antibiotic use, and increased health care costs. Additionally, AdenoPlus may help a clinician make a more informed treatment decision regarding the use of novel therapeutics. clinicaltrials.gov Identifier: NCT00921895.

  7. Adenoviral vectors for highly selective gene expression in central serotonergic neurons reveal quantal characteristics of serotonin release in the rat brain

    Teschemacher Anja G

    2009-03-01

    Full Text Available Abstract Background 5-hydroxytryptamine (5 HT, serotonin is one of the key neuromodulators in mammalian brain, but many fundamental properties of serotonergic neurones and 5 HT release remain unknown. The objective of this study was to generate an adenoviral vector system for selective targeting of serotonergic neurones and apply it to study quantal characteristics of 5 HT release in the rat brain. Results We have generated adenoviral vectors which incorporate a 3.6 kb fragment of the rat tryptophan hydroxylase-2 (TPH-2 gene which selectively (97% co-localisation with TPH-2 target raphe serotonergic neurones. In order to enhance the level of expression a two-step transcriptional amplification strategy was employed. This allowed direct visualization of serotonergic neurones by EGFP fluorescence. Using these vectors we have performed initial characterization of EGFP-expressing serotonergic neurones in rat organotypic brain slice cultures. Fluorescent serotonergic neurones were identified and studied using patch clamp and confocal Ca2+ imaging and had features consistent with those previously reported using post-hoc identification approaches. Fine processes of serotonergic neurones could also be visualized in un-fixed tissue and morphometric analysis suggested two putative types of axonal varicosities. We used micro-amperometry to analyse the quantal characteristics of 5 HT release and found that central 5 HT exocytosis occurs predominantly in quanta of ~28000 molecules from varicosities and ~34000 molecules from cell bodies. In addition, in somata, we observed a minority of large release events discharging on average ~800000 molecules. Conclusion For the first time quantal release of 5 HT from somato-dendritic compartments and axonal varicosities in mammalian brain has been demonstrated directly and characterised. Release from somato-dendritic and axonal compartments might have different physiological functions. Novel vectors generated in this

  8. Support-vector-based emergent self-organising approach for emotional understanding

    Nguwi, Yok-Yen; Cho, Siu-Yeung

    2010-12-01

    This study discusses the computational analysis of general emotion understanding from questionnaires methodology. The questionnaires method approaches the subject by investigating the real experience that accompanied the emotions, whereas the other laboratory approaches are generally associated with exaggerated elements. We adopted a connectionist model called support-vector-based emergent self-organising map (SVESOM) to analyse the emotion profiling from the questionnaires method. The SVESOM first identifies the important variables by giving discriminative features with high ranking. The classifier then performs the classification based on the selected features. Experimental results show that the top rank features are in line with the work of Scherer and Wallbott [(1994), 'Evidence for Universality and Cultural Variation of Differential Emotion Response Patterning', Journal of Personality and Social Psychology, 66, 310-328], which approached the emotions physiologically. While the performance measures show that using the full features for classifications can degrade the performance, the selected features provide superior results in terms of accuracy and generalisation.

  9. Increased tumor localization and reduced immune response to adenoviral vector formulated with the liposome DDAB/DOPE.

    Steel, Jason C; Cavanagh, Heather M A; Burton, Mark A; Abu-Asab, Mones S; Tsokos, Maria; Morris, John C; Kalle, Wouter H J

    2007-04-01

    We aimed to increase the efficiency of adenoviral vectors by limiting adenoviral spread from the target site and reducing unwanted host immune responses to the vector. We complexed adenoviral vectors with DDAB-DOPE liposomes to form adenovirus-liposomal (AL) complexes. AL complexes were delivered by intratumoral injection in an immunocompetent subcutaneous rat tumor model and the immunogenicity of the AL complexes and the expression efficiency in the tumor and other organs was examined. Animals treated with the AL complexes had significantly lower levels of beta-galactosidase expression in systemic tissues compared to animals treated with the naked adenovirus (NA) (P<0.05). The tumor to non-tumor ratio of beta-galactosidase marker expression was significantly higher for the AL complex treated animals. NA induced significantly higher titers of adenoviral-specific antibodies compared to the AL complexes (P<0.05). The AL complexes provided protection (immunoshielding) to the adenovirus from neutralizing antibody. Forty-seven percent more beta-galactosidase expression was detected following intratumoral injection with AL complexes compared to the NA in animals pre-immunized with adenovirus. Complexing of adenovirus with liposomes provides a simple method to enhance tumor localization of the vector, decrease the immunogenicity of adenovirus, and provide protection of the virus from pre-existing neutralizing antibodies.

  10. Radiolabeled adenoviral sub-unit proteins for molecular imaging and therapeutic applications in oncology

    Srivastava, Suresh C.

    2005-01-01

    Full text: Our group has initiated investigations on the use of radiolabeled adenoviral (Ad) sub-unit proteins for delivering suitable radionuclides into tumor cells for molecular imaging as well as for combined gene/radionuclide therapy of cancer. A number of issues involved in developing combined gene/radionuclide delivery into tumors mediated by Ad vectors have been identified and are being addressed. Whereas current clinical trials of gene therapy using Ad vectors involve non-systemic delivery of therapeutic genes, the delivery of radionuclides preferably would involve systemic (i.v.) administration. The distribution and delivery of Ad sub-unit proteins following i.v. administration is not understood and must be studied and optimized. In addition, retention of the selective binding and internalization into tumor cells of the radiolabeled viral vectors remains an unmet challenge. We used the intact adenovirus (Ad, ∼80 nm diameter), native adenoviral fiber protein (AdFP, 180 kD trimer, purified from infected human cultured cells) and the adenoviral fiber 'knob' protein (recombinant AdFKP, 60 kD, synthesized in E. Coli), all of which interact with the in-vivo cellular receptor, coxsackie and adenovirus receptor (CAR) through the knob domain of the adenovirus fiber protein. Our initial studies were aimed at optimizing the labeling conditions using I-131 and In-111 to maintain CAR binding activity of the radiolabeled preparations. The CAR-binding was retained as determined using reaction with biotinylated CAR followed by chemiluminescence detection. The biodistribution results in mice and rats following i.v. administration (autoradiography, tissue counting) showed that all three vectors localized preferentially in CAR-expressing organs (liver, lung, heart, kidney), as expected. The CAR-binding of Ad-2 wild serotype was better (∼8 x stronger) than Ad-12, in particular following radiolabeling. Based on the above results, we further focused on the recombinant knob

  11. Current error vector based prediction control of the section winding permanent magnet linear synchronous motor

    Hong Junjie, E-mail: hongjjie@mail.sysu.edu.cn [School of Engineering, Sun Yat-Sen University, Guangzhou 510006 (China); Li Liyi, E-mail: liliyi@hit.edu.cn [Dept. Electrical Engineering, Harbin Institute of Technology, Harbin 150000 (China); Zong Zhijian; Liu Zhongtu [School of Engineering, Sun Yat-Sen University, Guangzhou 510006 (China)

    2011-10-15

    Highlights: {yields} The structure of the permanent magnet linear synchronous motor (SW-PMLSM) is new. {yields} A new current control method CEVPC is employed in this motor. {yields} The sectional power supply method is different to the others and effective. {yields} The performance gets worse with voltage and current limitations. - Abstract: To include features such as greater thrust density, higher efficiency without reducing the thrust stability, this paper proposes a section winding permanent magnet linear synchronous motor (SW-PMLSM), whose iron core is continuous, whereas winding is divided. The discrete system model of the motor is derived. With the definition of the current error vector and selection of the value function, the theory of the current error vector based prediction control (CEVPC) for the motor currents is explained clearly. According to the winding section feature, the motion region of the mover is divided into five zones, in which the implementation of the current predictive control method is proposed. Finally, the experimental platform is constructed and experiments are carried out. The results show: the current control effect has good dynamic response, and the thrust on the mover remains constant basically.

  12. The development of vector based 2.5D print methods for a painting machine

    Parraman, Carinna

    2013-02-01

    Through recent trends in the application of digitally printed decorative finishes to products, CAD, 3D additive layer manufacturing and research in material perception, [1, 2] there is a growing interest in the accurate rendering of materials and tangible displays. Although current advances in colour management and inkjet printing has meant that users can take for granted high-quality colour and resolution in their printed images, digital methods for transferring a photographic coloured image from screen to paper is constrained by pixel count, file size, colorimetric conversion between colour spaces and the gamut limits of input and output devices. This paper considers new approaches to applying alternative colour palettes by using a vector-based approach through the application of paint mixtures, towards what could be described as a 2.5D printing method. The objective is to not apply an image to a textured surface, but where texture and colour are integral to the mark, that like a brush, delineates the contours in the image. The paper describes the difference between the way inks and paints are mixed and applied. When transcribing the fluid appearance of a brush stroke, there is a difference between a halftone printed mark and a painted mark. The issue of surface quality is significant to subjective qualities when studying the appearance of ink or paint on paper. The paper provides examples of a range of vector marks that are then transcribed into brush stokes by the painting machine.

  13. Smart DNA vectors based on cyclodextrin polymers: compaction and endosomal release.

    Wintgens, Véronique; Leborgne, Christian; Baconnais, Sonia; Burckbuchler, Virginie; Le Cam, Eric; Scherman, Daniel; Kichler, Antoine; Amiel, Catherine

    2012-02-01

    Neutral β-cyclodextrin polymers (polyβCD) associated with cationic adamantyl derivatives (Ada) can be used to deliver plasmid DNA into cells. In absence of an endosomolytic agent, transfection efficiency remains low because most complexes are trapped in the endosomal compartment. We asked whether addition of an imidazole-modified Ada can increase efficiency of polyβCD/cationic Ada-based delivery system. We synthesized two adamantyl derivatives: Ada5, which has a spacer arm between the Ada moiety and a bi-cationic polar head group, and Ada6, which presents an imidazole group. Strength of association between polyβCD and Ada derivatives was evaluated by fluorimetric titration. Gel mobility shift assay, zeta potential, and dark field transmission electron microscopy experiments demonstrated the system allowed for efficient DNA compaction. In vitro transfection experiments performed on HepG2 and HEK293 cells revealed the quaternary system polyβCD/Ada5/Ada6/DNA has efficiency comparable to cationic lipid DOTAP. We successfully designed fine-tuned DNA vectors based on cyclodextrin polymers combined with two new adamantyl derivatives, leading to significant transfection associated with low toxicity.

  14. MAPPING LOCAL CLIMATE ZONES WITH A VECTOR-BASED GIS METHOD

    E. Lelovics

    2013-03-01

    Full Text Available In this study we determined Local Climate Zones in a South-Hungarian city, using vector-based and raster-based databases. We calculated seven of the originally proposed ten physical (geometric, surface cover and radiative properties for areas which are based on the mobile temperature measurement campaigns earlier carried out in this city.As input data we applied 3D building database (earlier created with photogrammetric methods, 2D road database, topographic map, aerial photographs, remotely sensed reflectance information from RapidEye satellite image and our local knowledge about the area. The values of the properties were calculated by GIS methods developed for this purpose.We derived for the examined areas and applied for classification sky view factor, mean building height, terrain roughness class, building surface fraction, pervious surface fraction, impervious surface fraction and albedo.Six built and one land cover LCZ classes could be detected with this method on our study area. From each class one circle area was selected, which is representative for that class. Their thermal reactions were examined with the application of mobile temperature measurement dataset. The comparison was made in cases, when the weather was clear and calm and the surface was dry. We found that compact built-in types have more temperature surplus than open ones, and midrise types also have more than lowrise ones. According to our primary results, these categories provide a useful opportunity for intra- and inter-urban comparisons.

  15. Isolation, culture and adenoviral transduction of parietal cells from mouse gastric mucosa

    Gliddon, Briony L; Nguyen, Nhung V; Gunn, Priscilla A; Gleeson, Paul A; Driel, Ian R van

    2008-01-01

    Here we describe a method for the isolation of intact gastric glands from mice and primary culture and transfection of mouse gastric epithelial cells. Collagenase digestion of PBS-perfused mouse stomachs released large intact gastric glands that were plated on a basement membrane matrix. The heterogeneous gland cell cultures typically contain ∼60% parietal cells. Isolated mouse parietal cells remain viable in culture for up to 5 days and react strongly with an antibody specific to the gastric H + /K + ATPase. Isolated intact mouse gastric glands and primary cultures of mouse parietal cells respond to the secretagogue, histamine. Typical morphological changes from a resting to an acid-secreting active parietal cell were observed. In resting cultures of mouse parietal cells, the H + /K + ATPase displayed a cytoplasmic punctate staining pattern consistent with tubulovesicle element structures. Following histamine stimulation, an expansion of internal apical vacuole structures was observed together with a pronounced redistribution of the H + /K + ATPase from the cytoplasm to the apical vacuoles. A reproducible procedure to express genes of interest exogenously in these cultures of mouse parietal cells was also established. This method combines recombinant adenoviral transduction with magnetic field-assisted transfection resulting in ∼30% transduced parietal cells. Adenoviral-transduced parietal cells maintain their ability to undergo agonist-induced activation. This protocol will be useful for the isolation, culture and expression of genes in parietal cells from genetically modified mice and as such will be an invaluable tool for studying the complex exocytic and endocytic trafficking events of the H + /K + ATPase which underpin the regulation of acid secretion

  16. Adenoviral vector-mediated GM-CSF gene transfer improves anti-mycobacterial immunity in mice - role of regulatory T cells.

    Singpiel, Alena; Kramer, Julia; Maus, Regina; Stolper, Jennifer; Bittersohl, Lara Friederike; Gauldie, Jack; Kolb, Martin; Welte, Tobias; Sparwasser, Tim; Maus, Ulrich A

    2018-03-01

    Granulocyte macrophage-colony stimulating factor (GM-CSF) is a hematopoietic growth factor involved in differentiation, survival and activation of myeloid and non-myeloid cells with important implications for lung antibacterial immunity. Here we examined the effect of pulmonary adenoviral vector-mediated delivery of GM-CSF (AdGM-CSF) on anti-mycobacterial immunity in M. bovis BCG infected mice. Exposure of M. bovis BCG infected mice to AdGM-CSF either applied on 6h, or 6h and 7days post-infection substantially increased alveolar recruitment of iNOS and IL-12 expressing macrophages, and significantly increased accumulation of IFNγ pos T cells and particularly regulatory T cells (Tregs). This was accompanied by significantly reduced mycobacterial loads in the lungs of mice. Importantly, diphtheria toxin-induced depletion of Tregs did not influence mycobacterial loads, but accentuated immunopathology in AdGM-CSF-exposed mice infected with M. bovis BCG. Together, the data demonstrate that AdGM-CSF therapy improves lung protective immunity against M. bovis BCG infection in mice independent of co-recruited Tregs, which however critically contribute to limit lung immunopathology in BCG-infected mice. These data may be relevant to the development of immunomodulatory strategies to limit immunopathology-based lung injury in tuberculosis in humans. Copyright © 2017 Elsevier GmbH. All rights reserved.

  17. CRISPR/Cas9 delivery with one single adenoviral vector devoid of all viral genes.

    Ehrke-Schulz, Eric; Schiwon, Maren; Leitner, Theo; Dávid, Stephan; Bergmann, Thorsten; Liu, Jing; Ehrhardt, Anja

    2017-12-07

    The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system revolutionized the field of gene editing but viral delivery of the CRISPR/Cas9 system has not been fully explored. Here we adapted clinically relevant high-capacity adenoviral vectors (HCAdV) devoid of all viral genes for the delivery of the CRISPR/Cas9 machinery using a single viral vector. We present a platform enabling fast transfer of the Cas9 gene and gRNA expression units into the HCAdV genome including the option to choose between constitutive or inducible Cas9 expression and gRNA multiplexing. Efficacy and versatility of this pipeline was exemplified by producing different CRISPR/Cas9-HCAdV targeting the human papillomavirus (HPV) 18 oncogene E6, the dystrophin gene causing Duchenne muscular dystrophy (DMD) and the HIV co-receptor C-C chemokine receptor type 5 (CCR5). All CRISPR/Cas9-HCAdV proved to be efficient to deliver the respective CRISPR/Cas9 expression units and to introduce the desired DNA double strand breaks at their intended target sites in immortalized and primary cells.

  18. Treatment of osteoarthritis using a helper-dependent adenoviral vector retargeted to chondrocytes

    Merry ZC Ruan

    2016-01-01

    Full Text Available Osteoarthritis (OA is a joint disease characterized by degeneration of the articular cartilage, subchondral bone remodeling, and secondary inflammation. It is among the top three causes of chronic disability, and currently there are no treatment options to prevent disease progression. The localized nature of OA makes it an ideal candidate for gene and cell therapy. However, gene and cell therapy of OA is impeded by inefficient gene transduction of chondrocytes. In this study, we developed a broadly applicable system that retargets cell surface receptors by conjugating antibodies to the capsid of helper-dependent adenoviral vectors (HDVs. Specifically, we applied this system to retarget chondrocytes by conjugating an HDV to an α-10 integrin monoclonal antibody (a10mab. We show that a10mab-conjugated HDV (a10mabHDV-infected chondrocytes efficiently in vitro and in vivo while detargeting other cell types. The therapeutic index of an intra-articular injection of 10mabHDV-expressing proteoglycan 4 (PRG4 into a murine model of post-traumatic OA was 10-fold higher than with standard HDV. Moreover, we show that PRG4 overexpression from articular, superficial zone chondrocytes is effective for chondroprotection in postinjury OA and that α-10 integrin is an effective protein for chondrocyte targeting.

  19. Detection and phylogenetic analysis of a new adenoviral polymerase gene in reptiles in Korea.

    Bak, Eun-Jung; Jho, Yeonsook; Woo, Gye-Hyeong

    2018-06-01

    Over a period of 7 years (2004-2011), samples from 34 diseased reptiles provided by local governments, zoos, and pet shops were tested for viral infection. Animals were diagnosed based on clinical signs, including loss of appetite, diarrhea, rhinorrhea, and unexpected sudden death. Most of the exotic animals had gastrointestinal problems, such as mucosal redness and ulcers, while the native animals had no clinical symptoms. Viral sequences were found in seven animals. Retroviral genes were amplified from samples from five Burmese pythons (Python molurus bivittatus), an adenovirus was detected in a panther chameleon (Furcifer pardalis), and an adenovirus and a paramyxovirus were detected in a tropical girdled lizard (Cordylus tropidosternum). Phylogenetic analysis of retroviruses and paramyxoviruses showed the highest sequence identity to both a Python molurus endogenous retrovirus and a Python curtus endogenous retrovirus and to a lizard isolate, respectively. Partial sequencing of an adenoviral DNA polymerase gene from the lizard isolate suggested that the corresponding virus was a novel isolate different from the reference strain (accession no. AY576677.1). The virus was not isolated but was detected, using molecular genetic techniques, in a lizard raised in a pet shop. This animal was also coinfected with a paramyxovirus.

  20. Factors involved in the maturation of murine dendritic cells transduced with adenoviral vector variants

    Kanagawa, Naoko; Koretomo, Ryosuke; Murakami, Sayaka; Sakurai, Fuminori; Mizuguchi, Hiroyuki; Nakagawa, Shinsaku; Fujita, Takuya; Yamamoto, Akira; Okada, Naoki

    2008-01-01

    Adenoviral vector (Ad)-mediated gene transfer is an attractive method for manipulating the immunostimulatory properties of dendritic cells (DCs) for cancer immunotherapy. DCs treated with Ad have phenotype alterations (maturation) that facilitate T cell sensitization. We investigated the mechanisms of DC maturation with Ad transduction. Expression levels of a maturation marker (CD40) on DCs treated with conventional Ad, fiber-modified Ads (AdRGD, AdF35, AdF35ΔRGD), or a different serotype Ad (Ad35) were correlated with their transduction efficacy. The α v -integrin directional Ad, AdRGD, exhibited the most potent ability to enhance both foreign gene expression and CD40 expression, and induced secretion of interleukin-12, tumor necrosis factor-α, and interferon-α in DCs. The presence of a foreign gene expression cassette in AdRGD was not necessary for DC maturation. Maturation of DCs treated with AdRGD was suppressed by destruction of the Ad genome, inhibition of endocytosis, or endosome acidification, whereas proteasome inhibition increased CD40 expression levels on DCs. Moreover, inhibition of α v -integrin signal transduction and blockade of cytokine secretion affected the maturation of DCs treated with AdRGD only slightly or not at all, respectively. Thus, our data provide evidence that Ad-induced DC maturation is due to Ad invasion of the DCs, followed by nuclear transport of the Ad genome, and not to the expression of foreign genes

  1. Lipofectamine and related cationic lipids strongly improve adenoviral infection efficiency of primitive human hematopoietic cells.

    Byk, T; Haddada, H; Vainchenker, W; Louache, F

    1998-11-20

    Adenoviral vectors have the potential to infect a large number of cell types including quiescent cells. Their use in hematopoietic cells is limited by the episomal form of their DNA, leading to transgene loss in the progeny cells. However, the use of this vector may be interesting for short-term in vitro modifications of primitive human hematopoietic cells. Therefore, we have investigated the ability of adenovirus to transduce cord blood CD34+ cells. Several promoters were tested using the lacZ reporter gene. The PGK and CMV promoters induced transgene expression in 18-25% of the cells, whereas the HTLV-I and especially the RSV promoter were almost inactive. To improve infection efficiency, adenovirus was complexed with cationic lipids. Lipofectamine, Cellfectin, and RPR120535b, but not Lipofectin, Lipofectace, or DOTAP, markedly improved transgene expression in CD34+ cells (from 19 to 35%). Lipofectamine strongly enhanced infection efficiency of the poorly infectable primitive CD34+CD38low cells (from 11 to 28%) whereas the more mature CD34+CD38+ cells were only slightly affected (from 24 to 31%). Lipofectamine tripled the infection of CFU-GMs and LTC-ICs derived from the CD34+CD38low cell fraction (from 4 to 12% and from 5 to 16%, respectively) and doubled that of BFU-Es (from 13 to 26%). We conclude that cationic lipids can markedly increase the efficiency of adenovirus-mediated gene transfer into primitive hematopoietic cells.

  2. Stokes vector based interpolation method to improve the efficiency of bio-inspired polarization-difference imaging in turbid media

    Guan, Jinge; Ren, Wei; Cheng, Yaoyu

    2018-04-01

    We demonstrate an efficient polarization-difference imaging system in turbid conditions by using the Stokes vector of light. The interaction of scattered light with the polarizer is analyzed by the Stokes-Mueller formalism. An interpolation method is proposed to replace the mechanical rotation of the polarization axis of the analyzer theoretically, and its performance is verified by the experiment at different turbidity levels. We show that compared with direct imaging, the Stokes vector based imaging method can effectively reduce the effect of light scattering and enhance the image contrast.

  3. Imaging expression of adenoviral HSV1-tk suicide gene transfer using the nucleoside analogue FIRU

    Nanda, Dharmin; Jong, Marion de; Bakker, Willem; Bijster, Magda; Cox, Peter; Vogels, Ronald; Havenga, Menzo; Driesse, Maarten; Avezaat, Cees; Morin, Kevin; Naimi, Ebrahim; Knaus, Edward; Wiebe, Leonard; Smitt, Peter Sillevis

    2002-01-01

    Substrates for monitoring HSV1-tk gene expression include uracil and acycloguanosine derivatives.The most commonly used uracil derivative to monitor HSV1-tk gene transfer is 1-(2-fluoro-2-deoxy-β-D-arabinofuranosyl)-5-[*I]iodouracil (fialuridine; I*-FIAU), where the asterisk denotes any of the radioactive iodine isotopes that can be used. We have previously studied other nucleosides with imaging properties as good as or better than FIAU, including 1-(2-fluoro-2-deoxy-β-D-ribofuranosyl)-5-[*I]iodouracil (FIRU). The first aim of this study was to extend the biodistribution data of 123 I-labelled FIRU. Secondly, we assessed the feasibility of detecting differences in HSV1-tk gene expression levels following adenoviral gene transfer in vivo with 123 I-FIRU. 9L rat gliosarcoma cells were stably transfected with the HSV1-tk gene (9L-tk+). 123 I-FIRU was prepared by radioiodination of 1-(2-fluoro-2-deoxy-β-D-ribofuranosyl)-5-tributylstannyl uracil (FTMRSU; precursor compound) and purified using an activated Sep-Pak column. Incubation of 9L-tk+ cells and the parental 9L cells with 123 I-FIRU resulted in a 100-fold higher accumulation of radioactivity in the 9L-tk+ cells after an optimum incubation time of 4 h. NIH-bg-nu-xid mice were then inoculated subcutaneously with HSV1-tk (-) 9L cells or HSV1-tk (+) 9L-tk+ cells into both flanks. Biodistribution studies and gamma camera imaging were performed at 15 min and 1, 2, 4 and 24 h p.i. At 15 min, the tumour/muscle, tumour/blood and tumour/brain ratios were 5.2, 1.0 and 30.3 respectively. Rapid renal clearance of the tracer from the body resulted in increasing tumour/muscle, tumour/blood and tumour/brain ratios, reaching values of 32.2, 12.5 and 171.6 at 4 h p.i. A maximum specific activity of 22%ID/g tissue was reached in the 9L-tk+ tumours 4 h after 123 I-FIRU injection. Two Ad5-based adenoviral vectors containing the HSV1-tk gene were constructed: a replication-incompetent vector with the transgene in the former E1

  4. Imaging expression of adenoviral HSV1-tk suicide gene transfer using the nucleoside analogue FIRU

    Nanda, Dharmin [Department of Neurology, Daniel den Hoed Cancer Centre, University Hospital Rotterdam (Netherlands); Department of Neurosurgery, University Hospital Rotterdam (Netherlands); Jong, Marion de; Bakker, Willem; Bijster, Magda; Cox, Peter [Department of Nuclear Medicine, University Hospital Rotterdam (Netherlands); Vogels, Ronald; Havenga, Menzo [Crucell Holland BV, Leiden (Netherlands); Driesse, Maarten; Avezaat, Cees [Department of Neurosurgery, University Hospital Rotterdam (Netherlands); Morin, Kevin; Naimi, Ebrahim; Knaus, Edward; Wiebe, Leonard [Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton (Canada); Smitt, Peter Sillevis [Department of Neurology, Daniel den Hoed Cancer Centre, University Hospital Rotterdam (Netherlands)

    2002-07-01

    Substrates for monitoring HSV1-tk gene expression include uracil and acycloguanosine derivatives.The most commonly used uracil derivative to monitor HSV1-tk gene transfer is 1-(2-fluoro-2-deoxy-{beta}-D-arabinofuranosyl)-5-[*I]iodouracil (fialuridine; I*-FIAU), where the asterisk denotes any of the radioactive iodine isotopes that can be used. We have previously studied other nucleosides with imaging properties as good as or better than FIAU, including 1-(2-fluoro-2-deoxy-{beta}-D-ribofuranosyl)-5-[*I]iodouracil (FIRU). The first aim of this study was to extend the biodistribution data of {sup 123}I-labelled FIRU. Secondly, we assessed the feasibility of detecting differences in HSV1-tk gene expression levels following adenoviral gene transfer in vivo with {sup 123}I-FIRU. 9L rat gliosarcoma cells were stably transfected with the HSV1-tk gene (9L-tk+). {sup 123}I-FIRU was prepared by radioiodination of 1-(2-fluoro-2-deoxy-{beta}-D-ribofuranosyl)-5-tributylstannyl uracil (FTMRSU; precursor compound) and purified using an activated Sep-Pak column. Incubation of 9L-tk+ cells and the parental 9L cells with {sup 123}I-FIRU resulted in a 100-fold higher accumulation of radioactivity in the 9L-tk+ cells after an optimum incubation time of 4 h. NIH-bg-nu-xid mice were then inoculated subcutaneously with HSV1-tk (-) 9L cells or HSV1-tk (+) 9L-tk+ cells into both flanks. Biodistribution studies and gamma camera imaging were performed at 15 min and 1, 2, 4 and 24 h p.i. At 15 min, the tumour/muscle, tumour/blood and tumour/brain ratios were 5.2, 1.0 and 30.3 respectively. Rapid renal clearance of the tracer from the body resulted in increasing tumour/muscle, tumour/blood and tumour/brain ratios, reaching values of 32.2, 12.5 and 171.6 at 4 h p.i. A maximum specific activity of 22%ID/g tissue was reached in the 9L-tk+ tumours 4 h after {sup 123}I-FIRU injection. Two Ad5-based adenoviral vectors containing the HSV1-tk gene were constructed: a replication-incompetent vector with

  5. Fetal muscle gene transfer is not enhanced by an RGD capsid modification to high-capacity adenoviral vectors.

    Bilbao, R; Reay, D P; Hughes, T; Biermann, V; Volpers, C; Goldberg, L; Bergelson, J; Kochanek, S; Clemens, P R

    2003-10-01

    High levels of alpha(v) integrin expression by fetal muscle suggested that vector re-targeting to integrins could enhance adenoviral vector-mediated transduction, thereby increasing safety and efficacy of muscle gene transfer in utero. High-capacity adenoviral (HC-Ad) vectors modified by an Arg-Gly-Asp (RGD) peptide motif in the HI loop of the adenoviral fiber (RGD-HC-Ad) have demonstrated efficient gene transfer through binding to alpha(v) integrins. To test integrin targeting of HC-Ad vectors for fetal muscle gene transfer, we compared unmodified and RGD-modified HC-Ad vectors. In vivo, unmodified HC-Ad vector transduced fetal mouse muscle with four-fold higher efficiency compared to RGD-HC-Ad vector. Confirming that the difference was due to muscle cell autonomous factors and not mechanical barriers, transduction of primary myogenic cells isolated from murine fetal muscle in vitro demonstrated a three-fold better transduction by HC-Ad vector than by RGD-HC-Ad vector. We hypothesized that the high expression level of coxsackievirus and adenovirus receptor (CAR), demonstrated in fetal muscle cells both in vitro and in vivo, was the crucial variable influencing the relative transduction efficiencies of HC-Ad and RGD-HC-Ad vectors. To explore this further, we studied transduction by HC-Ad and RGD-HC-Ad vectors in paired cell lines that expressed alpha(v) integrins and differed only by the presence or absence of CAR expression. The results increase our understanding of factors that will be important for retargeting HC-Ad vectors to enhance gene transfer to fetal muscle.

  6. Radiosensitization effect of recombinant adenoviral-mediated PUMA gene on pancreatic carcinoma cells

    Zhu Dongming; Zhang Kejun; Li Dechun; Zhu Xuefeng; Yang Yong

    2009-01-01

    Objective: To study the effect of PUMA gene mediated by recombinant adenovirus vector combined with radiation on the pancreatic carcinoma. Methods: The PANC-1 cells were infected with Ad- PUMA (MOI=10, 50 and 100, respectively) for 48 h. The expression of PUMA mRNA and protein was detected by RT-PCR and Western blot, respectively. PANC-1 cells were divided into 4 groups: control group, transfection group, irradiation group and combined treatment group. The cell growth inhibition rate and apoptotic rate of PANC-1 cells were assessed by MTT assay and flow cytometry. Human pancreatic carcinomas were transplanted subcutaneously in nude mice, which were randomized into 4 groups: control group, transfection group, irradiation group and combined treatment group. Tumor growth rate and apoptotic index at different time points were recorded in 35 days. Results: The expression of PUMA mRNA and protein was increased with the increase of MOI of Ad-PUMA, which was does-dependant (MOI=10, mRNA=0.46± 0.02, protein=0.75± 0.09; MOI=50, mRNA=1.12±0.09, protein=1.01±0.18; MOI=100, mRNA=1.50±0.08, protein= 1.80±0.15; P 3 , (39.5±9.23)mm 3 , (33.6±10.3)mm 3 and (52.0±11.43)mm 3 , respectively, P<0.05]. And the apoptotic index was increased in the same manner (AI=0.43±0.05, 0.29±0.10, 0.24±0.05 and 0.00±0.00, respectively, P<0.05). Conclusions: Recombinant adenoviral-mediated PUMA gene combined with irradiation could increase the cell-killing effect on pancreatic carcinoma. It is better than that of either one kind of therapy. (authors)

  7. A novel minicircle vector based system for inhibting the replication and gene expression of enterovirus 71 and coxsackievirus A16.

    Yang, Zhuo; Li, Guodong; Zhang, Yingqiu; Liu, Xiaoman; Tien, Po

    2012-11-01

    Enterovirus 71 (EV 71) and Coxsackievirus A16 (CA 16) are two major causative agents of hand, foot and mouth disease (HFMD). They have been associated with severe neurological and cardiological complications worldwide, and have caused significant mortalities during large-scale outbreaks in China. Currently, there are no effective treatments against EV 71 and CA 16 infections. We now describe the development of a novel minicircle vector based RNA interference (RNAi) system as a therapeutic approach to inhibiting EV 71 and CA 16 replication. Small interfering RNA (siRNA) molecules targeting the conserved regions of the 3C(pro) and 3D(pol) function gene of the EV 71 and CA 16 China strains were designed based on their nucleotide sequences available in GenBank. This RNAi system was found to effectively block the replication and gene expression of these viruses in rhabdomyosarcoma (RD) cells and virus-infected mice model. The inhibitory effects were confirmed by a corresponding decrease in viral RNA, viral protein, and progeny virus production. In addition, no significant adverse off-target silencing or cytotoxic effects were observed. These results demonstrated the potential and feasibility of this novel minicircle vector based RNAi system for antiviral therapy against EV 71 and CA 16 infection. Copyright © 2012 Elsevier B.V. All rights reserved.

  8. Advances in Viral Vector-Based TRAIL Gene Therapy for Cancer

    Norian, Lyse A.; James, Britnie R.; Griffith, Thomas S.

    2011-01-01

    Numerous biologic approaches are being investigated as anti-cancer therapies in an attempt to induce tumor regression while circumventing the toxic side effects associated with standard chemo- or radiotherapies. Among these, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown particular promise in pre-clinical and early clinical trials, due to its preferential ability to induce apoptotic cell death in cancer cells and its minimal toxicity. One limitation of TRAIL use is the fact that many tumor types display an inherent resistance to TRAIL-induced apoptosis. To circumvent this problem, researchers have explored a number of strategies to optimize TRAIL delivery and to improve its efficacy via co-administration with other anti-cancer agents. In this review, we will focus on TRAIL-based gene therapy approaches for the treatment of malignancies. We will discuss the main viral vectors that are being used for TRAIL gene therapy and the strategies that are currently being attempted to improve the efficacy of TRAIL as an anti-cancer therapeutic

  9. Mucosal immunization with recombinant adenoviral vectors expressing murine gammaherpesvirus-68 genes M2 and M3 can reduce latent viral load.

    Hoegh-Petersen, Mette; Thomsen, Allan R; Christensen, Jan P; Holst, Peter J

    2009-11-12

    Gammaherpesviruses establish life-long latent infections in their hosts. If the host becomes immunosuppressed, these viruses may reactivate and cause severe disease, and even in immunocompetent individuals the gammaherpesviruses are presumed to have an oncogenic potential. Murine gammaherpesvirus-68 (MHV-68) is a member of the Gammaherpesvirinae subfamily and represents a useful murine model for this category of infections, in which new vaccination strategies may initially be evaluated. Two attenuated variants of MHV-68 have successfully been used as vaccines, but the oncogenic potential of the gammaherpesvirinae speaks against using a similar approach in humans. DNA immunization with plasmids encoding the MHV-68 genes M2 or M3 caused a reduction in either acute or early latent viral load, respectively, but neither immunization had an effect at times later than 14 days post-infection. Adenovirus-based vaccines are substantially more immunogenic than DNA vaccines and can be applied to induce mucosal immunity. Here we show that a significant reduction of the late viral load in the spleens, at 60 days post-infection, was achieved when immunizing mice both intranasally and subcutaneously with adenoviral vectors encoding both M2 and M3. Additionally we show that M3 immunization prevented the usual development of virus-induced splenomegaly at 2-3 weeks post-infection. This is the first time that immunization with a non-replicating vaccine has lead to a significantly reduced viral load at time points beyond 14 days post-infection, and thus demonstrates that a non-replicating vaccine may successfully be employed to reduce the viral burden during chronic gammaherpesvirus infection.

  10. Generation of a functional and durable vascular niche by the adenoviral E4ORF1 gene.

    Seandel, Marco; Butler, Jason M; Kobayashi, Hideki; Hooper, Andrea T; White, Ian A; Zhang, Fan; Vertes, Eva L; Kobayashi, Mariko; Zhang, Yan; Shmelkov, Sergey V; Hackett, Neil R; Rabbany, Sina; Boyer, Julie L; Rafii, Shahin

    2008-12-09

    Vascular cells contribute to organogenesis and tumorigenesis by producing unknown factors. Primary endothelial cells (PECs) provide an instructive platform for identifying factors that support stem cell and tumor homeostasis. However, long-term maintenance of PECs requires stimulation with cytokines and serum, resulting in loss of their angiogenic properties. To circumvent this hurdle, we have discovered that the adenoviral E4ORF1 gene product maintains long-term survival and facilitates organ-specific purification of PECs, while preserving their vascular repertoire for months, in serum/cytokine-free cultures. Lentiviral introduction of E4ORF1 into human PECs (E4ORF1(+) ECs) increased the long-term survival of these cells in serum/cytokine-free conditions, while preserving their in vivo angiogenic potential for tubulogenesis and sprouting. Although E4ORF1, in the absence of mitogenic signals, does not induce proliferation of ECs, stimulation with VEGF-A and/or FGF-2 induced expansion of E4ORF1(+) ECs in a contact-inhibited manner. Indeed, VEGF-A-induced phospho MAPK activation of E4ORF1(+) ECs is comparable with that of naive PECs, suggesting that the VEGF receptors remain functional upon E4ORF1 introduction. E4ORF1(+) ECs inoculated in implanted Matrigel plugs formed functional, patent, humanized microvessels that connected to the murine circulation. E4ORF1(+) ECs also incorporated into neo-vessels of human tumor xenotransplants and supported serum/cytokine-free expansion of leukemic and embryonal carcinoma cells. E4ORF1 augments survival of PECs in part by maintaining FGF-2/FGF-R1 signaling and through tonic Ser-473 phosphorylation of Akt, thereby activating the mTOR and NF-kappaB pathways. Therefore, E4ORF1(+) ECs establish an Akt-dependent durable vascular niche not only for expanding stem and tumor cells but also for interrogating the roles of vascular cells in regulating organ-specific vascularization and tumor neo-angiogenesis.

  11. Generation of a functional and durable vascular niche by the adenoviral E4ORF1 gene

    Seandel, Marco; Butler, Jason M.; Kobayashi, Hideki; Hooper, Andrea T.; White, Ian A.; Zhang, Fan; Vertes, Eva L.; Kobayashi, Mariko; Zhang, Yan; Shmelkov, Sergey V.; Hackett, Neil R.; Rabbany, Sina; Boyer, Julie L.; Rafii, Shahin

    2008-01-01

    Vascular cells contribute to organogenesis and tumorigenesis by producing unknown factors. Primary endothelial cells (PECs) provide an instructive platform for identifying factors that support stem cell and tumor homeostasis. However, long-term maintenance of PECs requires stimulation with cytokines and serum, resulting in loss of their angiogenic properties. To circumvent this hurdle, we have discovered that the adenoviral E4ORF1 gene product maintains long-term survival and facilitates organ-specific purification of PECs, while preserving their vascular repertoire for months, in serum/cytokine-free cultures. Lentiviral introduction of E4ORF1 into human PECs (E4ORF1+ ECs) increased the long-term survival of these cells in serum/cytokine-free conditions, while preserving their in vivo angiogenic potential for tubulogenesis and sprouting. Although E4ORF1, in the absence of mitogenic signals, does not induce proliferation of ECs, stimulation with VEGF-A and/or FGF-2 induced expansion of E4ORF1+ ECs in a contact-inhibited manner. Indeed, VEGF-A-induced phospho MAPK activation of E4ORF1+ ECs is comparable with that of naive PECs, suggesting that the VEGF receptors remain functional upon E4ORF1 introduction. E4ORF1+ ECs inoculated in implanted Matrigel plugs formed functional, patent, humanized microvessels that connected to the murine circulation. E4ORF1+ ECs also incorporated into neo-vessels of human tumor xenotransplants and supported serum/cytokine-free expansion of leukemic and embryonal carcinoma cells. E4ORF1 augments survival of PECs in part by maintaining FGF-2/FGF-R1 signaling and through tonic Ser-473 phosphorylation of Akt, thereby activating the mTOR and NF-κB pathways. Therefore, E4ORF1+ ECs establish an Akt-dependent durable vascular niche not only for expanding stem and tumor cells but also for interrogating the roles of vascular cells in regulating organ-specific vascularization and tumor neo-angiogenesis. PMID:19036927

  12. Coating with spermine-pullulan polymer enhances adenoviral transduction of mesenchymal stem cells

    Wan L

    2016-12-01

    coating could enhance adenoviral transduction of MSCs without detectable cytotoxicity or effects on differentiation. Our results argue in favor of the potentiality of the SP-coated Adv as a prototype vector for efficient and safe transduction of MSCs. Keywords: mesenchymal stem cells, adenovirus vectors, spermine-pullulan, polymer, gene transduction

  13. Toxicity and biodistribution of a first-generation recombinant adenoviral vector, in the presence of hydroxychloroquine, following retroductal delivery to a single rat submandibular gland

    Zheng, C.; Voutetakis, A.; Kok, M. R.; Goldsmith, C. M.; Smith, G. B. J.; Elmore, S.; Nyska, A.; Vallant, M.; Irwin, R. D.; Baum, B. J.

    2006-01-01

    We examined the toxicity and biodistribution associated with a single administration of a first-generation, serotype 5, adenoviral vector encoding human growth hormone (hGH; AdCMVhGH) to a single rat submandibular gland in the presence of hydroxychloroquine (HCQ). Previously, we showed that hGH is

  14. Biological activity and safety of adenoviral vector-expressed wild-type p53 after intratumoral injection in melanoma and breast cancer patients with p53-overexpressing tumors

    Dummer, R; Bergh, J; Karlsson, Y; Horovitz, JA; Mulder, NH; Huinin, DT; Burg, G; Hofbauer, G; Osanto, S

    p53 mutations are common genetic alterations in human cancer. Gene transfer of a wild-type (wt) p53 gene reverses the loss of normal p53 function in vitro and in vivo. A phase I dose escalation study of single intratumoral (i.t.) injection of a replication-defective adenoviral expression vector

  15. Induction of Human Somatostatin Receptor Subtype 2 on Breast Tumors with an Adenoviral Vector for Their Treatment and Detection with a Radiolabeled Peptide

    Rogers, Buck

    2002-01-01

    .... An adenoviral vector encoding the human somatostatin receptor subtype 2 (AdSSTr2) has been produced. The MDA- MB-468 and BT-474 human breast cancer cells were infected with AdSSTr2 and harvested 48 h later for membrane preparations...

  16. Adenoviral vector-mediated expression of B-50/GAP-43 induces alterations in the membrane organization of olfactory axon terminals in vivo

    Holtmaat, Anthony J D G; Hermens, W.T.J.M.C.; Sonnemans, M.A.F.; Giger, Roman J; Van Leeuwen, F W; Kaplitt, M G; Oestreicher, A B; Gispen, Willem Hendrik; Verhaagen, J

    1997-01-01

    B-50/GAP-43 is an intraneuronal membrane-associated growth cone protein with an important role in axonal growth and regeneration. By using adenoviral vector-directed expression of B-50/GAP-43 we studied the morphogenic action of B-50/GAP-43 in mature primary olfactory neurons that have established

  17. Post-spinal cord injury astrocyte-mediated functional recovery in rats after intraspinal injection of the recombinant adenoviral vectors Ad5-VEGF and Ad5-ANG.

    Povysheva, Tatyana; Shmarov, Maksim; Logunov, Denis; Naroditsky, Boris; Shulman, Ilya; Ogurcov, Sergey; Kolesnikov, Pavel; Islamov, Rustem; Chelyshev, Yuri

    2017-07-01

    OBJECTIVE The most actively explored therapeutic strategy for overcoming spinal cord injury (SCI) is the delivery of genes encoding molecules that stimulate regeneration. In a mouse model of amyotrophic lateral sclerosis and in preliminary clinical trials in patients with amyotrophic lateral sclerosis, the combined administration of recombinant adenoviral vectors (Ad5-VEGF+Ad5-ANG) encoding the neurotrophic/angiogenic factors vascular endothelial growth factor ( VEGF) and angiogenin ( ANG) was found to slow the development of neurological deficits. These results suggest that there may be positive effects of this combination of genes in posttraumatic spinal cord regeneration. The objective of the present study was to determine the effects of Ad5-VEGF+Ad5-ANG combination therapy on motor function recovery and reactivity of astrocytes in a rat model of SCI. METHODS Spinal cord injury was induced in adult Wistar rats by the weight-drop method. Rats (n = 51) were divided into 2 groups: the experimental group (Ad5-VEGF+Ad5-ANG) and the control group (Ad5-GFP [green fluorescent protein]). Recovery of motor function was assessed using the Basso, Beattie, and Bresnahan scale. The duration and intensity of infectivity and gene expression from the injected vectors were assessed by immunofluorescent detection of GFP. Reactivity of glial cells was assessed by changes in the number of immunopositive cells expressing glial fibrillary acidic protein (GFAP), S100β, aquaporin 4 (AQP4), oligodendrocyte transcription factor 2, and chondroitin sulfate proteoglycan 4. The level of S100β mRNA expression in the spinal cord was estimated by real-time polymerase chain reaction. RESULTS Partial recovery of motor function was observed 30 days after surgery in both groups. However, Basso, Beattie, and Bresnahan scores were 35.9% higher in the Ad5-VEGF+Ad5-ANG group compared with the control group. Specific GFP signal was observed at distances of up to 5 mm in the rostral and caudal

  18. A nonintegrative lentiviral vector-based vaccine provides long-term sterile protection against malaria.

    Frédéric Coutant

    Full Text Available Trials testing the RTS,S candidate malaria vaccine and radiation-attenuated sporozoites (RAS have shown that protective immunity against malaria can be induced and that an effective vaccine is not out of reach. However, longer-term protection and higher protection rates are required to eradicate malaria from the endemic regions. It implies that there is still a need to explore new vaccine strategies. Lentiviral vectors are very potent at inducing strong immunological memory. However their integrative status challenges their safety profile. Eliminating the integration step obviates the risk of insertional oncogenesis. Providing they confer sterile immunity, nonintegrative lentiviral vectors (NILV hold promise as mass pediatric vaccine by meeting high safety standards. In this study, we have assessed the protective efficacy of NILV against malaria in a robust pre-clinical model. Mice were immunized with NILV encoding Plasmodium yoelii Circumsporozoite Protein (Py CSP and challenged with sporozoites one month later. In two independent protective efficacy studies, 50% (37.5-62.5 of the animals were fully protected (p = 0.0072 and p = 0.0008 respectively when compared to naive mice. The remaining mice with detectable parasitized red blood cells exhibited a prolonged patency and reduced parasitemia. Moreover, protection was long-lasting with 42.8% sterile protection six months after the last immunization (p = 0.0042. Post-challenge CD8+ T cells to CSP, in contrast to anti-CSP antibodies, were associated with protection (r = -0.6615 and p = 0.0004 between the frequency of IFN-g secreting specific T cells in spleen and parasitemia. However, while NILV and RAS immunizations elicited comparable immunity to CSP, only RAS conferred 100% of sterile protection. Given that a better protection can be anticipated from a multi-antigen vaccine and an optimized vector design, NILV appear as a promising malaria vaccine.

  19. A novel vector-based method for exclusive overexpression of star-form microRNAs.

    Bo Qu

    Full Text Available The roles of microRNAs (miRNAs as important regulators of gene expression have been studied intensively. Although most of these investigations have involved the highly expressed form of the two mature miRNA species, increasing evidence points to essential roles for star-form microRNAs (miRNA*, which are usually expressed at much lower levels. Owing to the nature of miRNA biogenesis, it is challenging to use plasmids containing miRNA coding sequences for gain-of-function experiments concerning the roles of microRNA* species. Synthetic microRNA mimics could introduce specific miRNA* species into cells, but this transient overexpression system has many shortcomings. Here, we report that specific miRNA* species can be overexpressed by introducing artificially designed stem-loop sequences into short hairpin RNA (shRNA overexpression vectors. By our prototypic plasmid, designed to overexpress hsa-miR-146b-3p, we successfully expressed high levels of hsa-miR-146b-3p without detectable change of hsa-miR-146b-5p. Functional analysis involving luciferase reporter assays showed that, like natural miRNAs, the overexpressed hsa-miR-146b-3p inhibited target gene expression by 3'UTR seed pairing. Our demonstration that this method could overexpress two other miRNAs suggests that the approach should be broadly applicable. Our novel strategy opens the way for exclusively stable overexpression of miRNA* species and analyzing their unique functions both in vitro and in vivo.

  20. Loss of Endothelial Barrier in Marfan Mice (mgR/mgR Results in Severe Inflammation after Adenoviral Gene Therapy.

    Philipp Christian Seppelt

    Full Text Available Marfan syndrome is an autosomal dominant inherited disorder of connective tissue. The vascular complications of Marfan syndrome have the biggest impact on life expectancy. The aorta of Marfan patients reveals degradation of elastin layers caused by increased proteolytic activity of matrix metalloproteinases (MMPs. In this study we performed adenoviral gene transfer of human tissue inhibitor of matrix metalloproteinases-1 (hTIMP-1 in aortic grafts of fibrillin-1 deficient Marfan mice (mgR/mgR in order to reduce elastolysis.We performed heterotopic infrarenal transplantation of the thoracic aorta in female mice (n = 7 per group. Before implantation, mgR/mgR and wild-type aortas (WT, C57BL/6 were transduced ex vivo with an adenoviral vector coding for human TIMP-1 (Ad.hTIMP-1 or β-galactosidase (Ad.β-Gal. As control mgR/mgR and wild-type aortas received no gene therapy. Thirty days after surgery, overexpression of the transgene was assessed by immunohistochemistry (IHC and collagen in situ zymography. Histologic staining was performed to investigate inflammation, the neointimal index (NI, and elastin breaks. Endothelial barrier function of native not virus-exposed aortas was evaluated by perfusion of fluorescent albumin and examinations of virus-exposed tissue were performed by transmission electron microscopy (TEM.IHC and ISZ revealed sufficient expression of the transgene. Severe cellular inflammation and intima hyperplasia were seen only in adenovirus treated mgR/mgR aortas (Ad.β-Gal, Ad.hTIMP-1 NI: 0.23; 0.43, but not in native and Ad.hTIMP-1 treated WT (NI: 0.01; 0.00. Compared to native mgR/mgR and Ad.hTIMP-1 treated WT aorta, the NI is highly significant greater in Ad.hTIMP-1 transduced mgR/mgR aorta (p = 0.001; p = 0.001. As expected, untreated Marfan grafts showed significant more elastolysis compared to WT (p = 0.001. However, elastolysis in Marfan aortas was not reduced by adenoviral overexpression of hTIMP-1 (compared to untreated

  1. Novel approach to abuse the hyperactive K-Ras pathway for adenoviral gene therapy of colorectal cancer

    Naumov, Inna; Kazanov, Dina; Lisiansky, Victoria; Starr, Alex; Aroch, Ilan; Shapira, Shiran; Kraus, Sarah; Arber, Nadir

    2012-01-01

    Background: Functional activation of oncogenic K-Ras signaling pathway plays an important role in the early events of colorectal carcinogenesis (CRC). K-Ras proto-oncogene is involved in 35–40% of CRC cases. Mutations in the Ras gene trigger the transduction of proliferative and anti-apoptotic signals, even in the absence of extra cellular stimuli. The objective of the current study was to use a gene-targeting approach to kill human CRC cells selectively harboring mutated K-Ras. Results: A recombinant adenovirus that carries a lethal gene, PUMA, under the control of a Ras responsive promoter (Ad-Py4-SV40-PUMA) was used selectively to target CRC cells (HCT116, SW480, DLD1 and RIE-Ras) that possess a hyperactive Ras pathway while using HT29 and RIE cells as a control that harbors wild type Ras and exhibit very low Ras activity. Control vector, without the Ras responsive promoter elements was used to assess the specificity of our “gene therapy” approach. Both adenoviral vectors were assed in vitro and in xenograft model in vivo. Ad-Py4-SV40-PUMA showed high potency to induce ∼ 50% apoptosis in vitro, to abolish completely tumor formation by infecting cells with the Ad-Py4-SV40-PUMA prior xenografting them in nude mice and high ability to suppress by ∼ 35% tumor progression in vivo in already established tumors. Conclusions: Selective targeting of CRC cells with the activated Ras pathway may be a novel and effective therapy in CRC. The high potency of this adenoviral vector may help to overcome an undetectable micro metastasis that is the major hurdle in challenging with CRC.

  2. Adenoviral Mediated Expression of BMP2 by Bone Marrow Stromal Cells Cultured in 3D Copolymer Scaffolds Enhances Bone Formation.

    Sharma, Sunita; Sapkota, Dipak; Xue, Ying; Sun, Yang; Finne-Wistrand, Anna; Bruland, Ove; Mustafa, Kamal

    2016-01-01

    Selection of appropriate osteoinductive growth factors, suitable delivery method and proper supportive scaffold are critical for a successful outcome in bone tissue engineering using bone marrow stromal cells (BMSC). This study examined the molecular and functional effect of a combination of adenoviral mediated expression of bone morphogenetic protein-2 (BMP2) in BMSC and recently developed and characterized, biodegradable Poly(L-lactide-co-є-caprolactone){poly(LLA-co-CL)}scaffolds in osteogenic molecular changes and ectopic bone formation by using in vitro and in vivo approaches. Pathway-focused custom PCR array, validation using TaqMan based quantitative RT-PCR (qRT-PCR) and ALP staining showed significant up-regulation of several osteogenic and angiogenic molecules, including ALPL and RUNX2 in ad-BMP2 BMSC group grown in poly(LLA-co-CL) scaffolds both at 3 and 14 days. Micro CT and histological analyses of the subcutaneously implanted scaffolds in NOD/SCID mice revealed significantly increased radiopaque areas, percentage bone volume and formation of vital bone in ad-BMP2 scaffolds as compared to the control groups both at 2 and 8 weeks. The increased bone formation in the ad-BMP2 group in vivo was paralleled at the molecular level with concomitant over-expression of a number of osteogenic and angiogenic genes including ALPL, RUNX2, SPP1, ANGPT1. The increased bone formation in ad-BMP2 explants was not found to be associated with enhanced endochondral activity as evidenced by qRT-PCR (SOX9 and FGF2) and Safranin O staining. Taken together, combination of adenoviral mediated BMP-2 expression in BMSC grown in the newly developed poly(LLA-co-CL) scaffolds induced expression of osteogenic markers and enhanced bone formation in vivo.

  3. Novel approach to abuse the hyperactive K-Ras pathway for adenoviral gene therapy of colorectal cancer

    Naumov, Inna [Integrated Cancer Prevention Center, Tel Aviv (Israel); Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Kazanov, Dina [Integrated Cancer Prevention Center, Tel Aviv (Israel); Lisiansky, Victoria [Integrated Cancer Prevention Center, Tel Aviv (Israel); Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Starr, Alex [Lung and Allergy Institute, Tel Aviv Sourasky Medical Center, Tel Aviv (Israel); Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Aroch, Ilan; Shapira, Shiran; Kraus, Sarah [Integrated Cancer Prevention Center, Tel Aviv (Israel); Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Arber, Nadir, E-mail: narber@post.tau.ac.il [Integrated Cancer Prevention Center, Tel Aviv (Israel); Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv (Israel); Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel)

    2012-01-15

    Background: Functional activation of oncogenic K-Ras signaling pathway plays an important role in the early events of colorectal carcinogenesis (CRC). K-Ras proto-oncogene is involved in 35-40% of CRC cases. Mutations in the Ras gene trigger the transduction of proliferative and anti-apoptotic signals, even in the absence of extra cellular stimuli. The objective of the current study was to use a gene-targeting approach to kill human CRC cells selectively harboring mutated K-Ras. Results: A recombinant adenovirus that carries a lethal gene, PUMA, under the control of a Ras responsive promoter (Ad-Py4-SV40-PUMA) was used selectively to target CRC cells (HCT116, SW480, DLD1 and RIE-Ras) that possess a hyperactive Ras pathway while using HT29 and RIE cells as a control that harbors wild type Ras and exhibit very low Ras activity. Control vector, without the Ras responsive promoter elements was used to assess the specificity of our 'gene therapy' approach. Both adenoviral vectors were assed in vitro and in xenograft model in vivo. Ad-Py4-SV40-PUMA showed high potency to induce {approx} 50% apoptosis in vitro, to abolish completely tumor formation by infecting cells with the Ad-Py4-SV40-PUMA prior xenografting them in nude mice and high ability to suppress by {approx} 35% tumor progression in vivo in already established tumors. Conclusions: Selective targeting of CRC cells with the activated Ras pathway may be a novel and effective therapy in CRC. The high potency of this adenoviral vector may help to overcome an undetectable micro metastasis that is the major hurdle in challenging with CRC.

  4. Homology Requirements for Efficient, Footprintless Gene Editing at the CFTR Locus in Human iPSCs with Helper-dependent Adenoviral Vectors

    Donna J Palmer

    2016-01-01

    Full Text Available Helper-dependent adenoviral vectors mediate high efficiency gene editing in induced pluripotent stem cells without needing a designer nuclease thereby avoiding off-target cleavage. Because of their large cloning capacity of 37 kb, helper-dependent adenoviral vectors with long homology arms are used for gene editing. However, this makes vector construction and recombinant analysis difficult. Conversely, insufficient homology may compromise targeting efficiency. Thus, we investigated the effect of homology length on helper-dependent adenoviral vector targeting efficiency at the cystic fibrosis transmembrane conductance regulator locus in induced pluripotent stem cells and found a positive correlation. With 23.8 and 21.4 kb of homology, the frequencies of targeted recombinants were 50–64.6% after positive selection for vector integration, and 97.4–100% after negative selection against random integrations. With 14.8 kb, the frequencies were 26.9–57.1% after positive selection and 87.5–100% after negative selection. With 9.6 kb, the frequencies were 21.4 and 75% after positive and negative selection, respectively. With only 5.6 kb, the frequencies were 5.6–16.7% after positive selection and 50% after negative selection, but these were more than high enough for efficient identification and isolation of targeted clones. Furthermore, we demonstrate helper-dependent adenoviral vector-mediated footprintless correction of cystic fibrosis transmembrane conductance regulator mutations through piggyBac excision of the selectable marker. However, low frequencies (≤ 1 × 10−3 necessitated negative selection for piggyBac-excision product isolation.

  5. Improved vaccine protection against retrovirus infection after co-administration of adenoviral vectors encoding viral antigens and type I interferon subtypes

    Groitl Peter

    2011-09-01

    Full Text Available Abstract Background Type I interferons (IFNs exhibit direct antiviral effects, but also distinct immunomodulatory properties. In this study, we analyzed type I IFN subtypes for their effect on prophylactic adenovirus-based anti-retroviral vaccination of mice against Friend retrovirus (FV or HIV. Results Mice were vaccinated with adenoviral vectors encoding FV Env and Gag proteins alone or in combination with vectors encoding IFNα1, IFNα2, IFNα4, IFNα5, IFNα6, IFNα9 or IFNβ. Only the co-administration of adenoviral vectors encoding IFNα2, IFNα4, IFNα6 and IFNα9 resulted in strongly improved immune protection of vaccinated mice from subsequent FV challenge infection with high control over FV-induced splenomegaly and reduced viral loads. The level of protection correlated with augmented virus-specific CD4+ T cell responses and enhanced antibody titers. Similar results were obtained when mice were vaccinated against HIV with adenoviral vectors encoding HIV Env and Gag-Pol in combination with various type I IFN encoding vectors. Here mainly CD4+ T cell responses were enhanced by IFNα subtypes. Conclusions Our results indicate that certain IFNα subtypes have the potential to improve the protective effect of adenovirus-based vaccines against retroviruses. This correlated with augmented virus-specific CD4+ T cell and antibody responses. Thus, co-expression of select type I IFNs may be a valuable tool for the development of anti-retroviral vaccines.

  6. 5-Fluorouracil-related enhancement of adenoviral infection is Coxsackievirus-adenovirus receptor independent and associated with morphological changes in lipid membranes

    Cabrele, Chiara; Vogel, Mandy; Piso, Pompiliu; Rentsch, Markus; Schröder, Josef; Jauch, Karl W; Schlitt, Hans J; Beham, Alexander

    2006-01-01

    AIM: To evaluate the mechanism underlying the effects of 5-Fluorouracil (5-FU) on adenoviral infection. METHODS: Low and high Coxsackievirus-Adenovirus Receptor (CAR) expressing human colon carcinoma cell lines were treated with 5-FU and two E1-deleted adenoviral constructs, one transferring GFP (Ad/CMV-GFP) the other bax (Ad/CEA-bax). The number of infected cells were monitored by GFP expression. To evaluate the effects of 5-FU in a receptor free system, Ad/GFP were encapsulated in liposomes and treated with 5-FU. Ad/GFP release was estimated with PCR and infection of 293 cells with the supernatant. Electron microscopy of the Ad5-GFP-liposome complex was made to investigate morphological changes of the liposomes after 5-FU. RESULTS: Infection rates of all cell lines increased from 50% to 98% with emerging 5-FU concentrations. The enhanced viral uptake was independent of the CAR expression. Additionally, 5-FU treated liposomes released 2-2.5 times more adenoviruses. Furthermore, 5-FU-treated liposomes appeared irregular and porous-like. CONCLUSION: adenoviral uptake is enhanced in the presence of 5-FU irrespective of CAR and is associated with morphological changes in membranes making the combination of both a promising option in gene therapy. PMID:16937527

  7. Deep vector-based convolutional neural network approach for automatic recognition of colonies of induced pluripotent stem cells.

    Muthu Subash Kavitha

    Full Text Available Pluripotent stem cells can potentially be used in clinical applications as a model for studying disease progress. This tracking of disease-causing events in cells requires constant assessment of the quality of stem cells. Existing approaches are inadequate for robust and automated differentiation of stem cell colonies. In this study, we developed a new model of vector-based convolutional neural network (V-CNN with respect to extracted features of the induced pluripotent stem cell (iPSC colony for distinguishing colony characteristics. A transfer function from the feature vectors to the virtual image was generated at the front of the CNN in order for classification of feature vectors of healthy and unhealthy colonies. The robustness of the proposed V-CNN model in distinguishing colonies was compared with that of the competitive support vector machine (SVM classifier based on morphological, textural, and combined features. Additionally, five-fold cross-validation was used to investigate the performance of the V-CNN model. The precision, recall, and F-measure values of the V-CNN model were comparatively higher than those of the SVM classifier, with a range of 87-93%, indicating fewer false positives and false negative rates. Furthermore, for determining the quality of colonies, the V-CNN model showed higher accuracy values based on morphological (95.5%, textural (91.0%, and combined (93.2% features than those estimated with the SVM classifier (86.7, 83.3, and 83.4%, respectively. Similarly, the accuracy of the feature sets using five-fold cross-validation was above 90% for the V-CNN model, whereas that yielded by the SVM model was in the range of 75-77%. We thus concluded that the proposed V-CNN model outperforms the conventional SVM classifier, which strongly suggests that it as a reliable framework for robust colony classification of iPSCs. It can also serve as a cost-effective quality recognition tool during culture and other experimental

  8. Adenoviral transfer of the heme oxygenase-1 gene protects striatal astrocytes from heme-mediated oxidative injury.

    Teng, Zhi-Ping; Chen, Jing; Chau, Lee-Young; Galunic, Nicholas; Regan, Raymond F

    2004-11-01

    Heme oxygenase-1 (HO-1) is induced in the CNS after hemorrhage, and may have an effect on injury to surrounding tissue. Hemin, the preferred substrate of HO, is a neurotoxin that is present in intracranial hematomas. In a prior study, we observed that HO inhibitors increased the vulnerability of cultured cortical astrocytes to heme-mediated oxidative injury. To investigate the effect of HO more specifically, we used an adenoviral vector encoding the human HO-1 gene to specifically increase HO-1 expression. Incubation with 100 MOI of the HO-1 adenovirus (Adv-HHO-1) for 24 h increased both HO-1 protein and HO activity; a control adenovirus lacking the HO-1 gene had no effect. Using a DNA probe that was specific for human HO-1, 80.5 +/- 7.2% of astrocytes were observed to be infected by in situ hybridization. The cell death produced by 30-60 microM hemin was significantly reduced by pretreatment with 100 MOI Adv-HHO-1, as assessed by LDH release, propidium iodide exclusion, and MTT reduction assay. The threefold increase in cell protein oxidation produced by hemin was also attenuated in cultures pretreated with Adv-HHO-1. These results support the hypothesis that HO-1 protects astrocytes from heme-mediated oxidative injury. Specifically increasing astrocytic HO-1 by gene transfer may have a beneficial effect on hemorrhagic CNS injury.

  9. Adenoviral overexpression of Lhx2 attenuates cell viability but does not preserve the stem cell like phenotype of hepatic stellate cells

    Genz, Berit [Institute for Experimental Surgery, Rostock University Medical Center, Rostock (Germany); Thomas, Maria [Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart (Germany); Pützer, Brigitte M. [Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock (Germany); Siatkowski, Marcin; Fuellen, Georg [Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock (Germany); Vollmar, Brigitte [Institute for Experimental Surgery, Rostock University Medical Center, Rostock (Germany); Abshagen, Kerstin, E-mail: kerstin.abshagen@uni-rostock.de [Institute for Experimental Surgery, Rostock University Medical Center, Rostock (Germany)

    2014-11-01

    Hepatic stellate cells (HSC) are well known initiators of hepatic fibrosis. After liver cell damage, HSC transdifferentiate into proliferative myofibroblasts, representing the major source of extracellular matrix in the fibrotic organ. Recent studies also demonstrate a role of HSC as progenitor or stem cell like cells in liver regeneration. Lhx2 is described as stem cell maintaining factor in different organs and as an inhibitory transcription factor in HSC activation. Here we examined whether a continuous expression of Lhx2 in HSC could attenuate their activation and whether Lhx2 could serve as a potential target for antifibrotic gene therapy. Therefore, we evaluated an adenoviral mediated overexpression of Lhx2 in primary HSC and investigated mRNA expression patterns by qRT-PCR as well as the activation status by different in vitro assays. HSC revealed a marked increase in activation markers like smooth muscle actin alpha (αSMA) and collagen 1α independent from adenoviral transduction. Lhx2 overexpression resulted in attenuated cell viability as shown by a slightly hampered migratory and contractile phenotype of HSC. Expression of stem cell factors or signaling components was also unaffected by Lhx2. Summarizing these results, we found no antifibrotic or stem cell maintaining effect of Lhx2 overexpression in primary HSC. - Highlights: • We performed adenoviral overexpression of Lhx2 in primary hepatic stellate cells. • Hepatic stellate cells expressed stem cell markers during cultivation. • Cell migration and contractility was slightly hampered upon Lhx2 overexpression. • Lhx2 overexpression did not affect stem cell character of hepatic stellate cells.

  10. Adenoviral overexpression of Lhx2 attenuates cell viability but does not preserve the stem cell like phenotype of hepatic stellate cells

    Genz, Berit; Thomas, Maria; Pützer, Brigitte M.; Siatkowski, Marcin; Fuellen, Georg; Vollmar, Brigitte; Abshagen, Kerstin

    2014-01-01

    Hepatic stellate cells (HSC) are well known initiators of hepatic fibrosis. After liver cell damage, HSC transdifferentiate into proliferative myofibroblasts, representing the major source of extracellular matrix in the fibrotic organ. Recent studies also demonstrate a role of HSC as progenitor or stem cell like cells in liver regeneration. Lhx2 is described as stem cell maintaining factor in different organs and as an inhibitory transcription factor in HSC activation. Here we examined whether a continuous expression of Lhx2 in HSC could attenuate their activation and whether Lhx2 could serve as a potential target for antifibrotic gene therapy. Therefore, we evaluated an adenoviral mediated overexpression of Lhx2 in primary HSC and investigated mRNA expression patterns by qRT-PCR as well as the activation status by different in vitro assays. HSC revealed a marked increase in activation markers like smooth muscle actin alpha (αSMA) and collagen 1α independent from adenoviral transduction. Lhx2 overexpression resulted in attenuated cell viability as shown by a slightly hampered migratory and contractile phenotype of HSC. Expression of stem cell factors or signaling components was also unaffected by Lhx2. Summarizing these results, we found no antifibrotic or stem cell maintaining effect of Lhx2 overexpression in primary HSC. - Highlights: • We performed adenoviral overexpression of Lhx2 in primary hepatic stellate cells. • Hepatic stellate cells expressed stem cell markers during cultivation. • Cell migration and contractility was slightly hampered upon Lhx2 overexpression. • Lhx2 overexpression did not affect stem cell character of hepatic stellate cells

  11. Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction

    Li, Longhu; Haider, Husnain Kh.; Wang, Linlin; Lu, Gang

    2012-01-01

    We previously showed that treatment with tadalafil, a long-acting phosphodiesterase-5a (PDE5a) inhibitor, effectively prevented adverse left ventricular (LV) remodeling of the infarcted heart. We hypothesized that short-hairpin RNA (shRNA) therapy targeting PDE5a would simulate the effects of pharmacological intervention for treatment of postinfarction LV remodeling and dysfunction. Experimental model of myocardial infarction was developed in female mice by permanent ligation of left coronary artery. Immediately after that, an adenoviral vector encoding for shRNA sequence targeting PDE5a (Ad-shPDE5a) was injected intramyocardially, which specifically inhibited PDE5a in the heart. Four weeks later, Ad-shPDE5a treated mice showed significant mitigation of the left ventricle (LV) dilatation and dysfunction as indicated by smaller LV cavity and more preserved ejection fraction and fractional shortening. Infarction size and fibrosis were significantly reduced in Ad-shPDE5a-treated mice. Additionally, more salvaged cardiomyocytes, significantly reduced collagen contents, and higher blood vessel density were observed in Ad-shPDE5a-treated mice. The cytoprotective effects of Ad-shPDE5a were demonstrated in vitro in Ad-shPDE5a transfected cardiomyocytes cultured under oxygen glucose deprivation. Among downstream mediators of PDE5a signaling, cyclic GMP (cGMP) and cGMP-dependent protein kinase G (PKG) were activated with concomitant reduction in caspase-3 activity. However, no significant change in PKA and cAMP activities were observed in Ad-shPDE5a-treated hearts. Inhibition with shRNA improved cardiac remodeling and dysfunction by reducing infarction size and cardiac fibrosis and increased cGMP and PKG activity. These findings suggest that PDE5 inhibition with Ad-shPDE5a is a novel approach for treatment of myocardial infarction. PMID:22447941

  12. Lysyl Oxidase-Like 1 Protein Deficiency Protects Mice from Adenoviral Transforming Growth Factor-β1-induced Pulmonary Fibrosis.

    Bellaye, Pierre-Simon; Shimbori, Chiko; Upagupta, Chandak; Sato, Seidai; Shi, Wei; Gauldie, Jack; Ask, Kjetil; Kolb, Martin

    2018-04-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by excessive deposition of extracellular matrix (ECM) in the lung parenchyma. The abnormal ECM deposition slowly overtakes normal lung tissue, disturbing gas exchange and leading to respiratory failure and death. ECM cross-linking and subsequent stiffening is thought to be a major contributor of disease progression and also promotes the activation of transforming growth factor (TGF)-β1, one of the main profibrotic growth factors. Lysyl oxidase-like (LOXL) 1 belongs to the cross-linking enzyme family and has been shown to be up-regulated in active fibrotic regions of bleomycin-treated mice and patients with IPF. We demonstrate in this study that LOXL1-deficient mice are protected from experimental lung fibrosis induced by overexpression of TGF-β1 using adenoviral (Ad) gene transfer (AdTGF-β1). The lack of LOXL1 prevented accumulation of insoluble cross-linked collagen in the lungs, and therefore limited lung stiffness after AdTGF-β1. In addition, we applied mechanical stretch to lung slices from LOXL1 +/+ and LOXL1 -/- mice treated with AdTGF-β1. Lung stiffness (Young's modulus) of LOXL1 -/- lung slices was significantly lower compared with LOXL1 +/+ lung slices. Moreover, the release of activated TGF-β1 after mechanical stretch was significantly lower in LOXL1 -/- mice compared with LOXL1 +/+ mice after AdTGF-β1. These data support the concept that cross-linking enzyme inhibition represents an interesting therapeutic target for drug development in IPF.

  13. Hexon-modified recombinant E1-deleted adenoviral vectors as bivalent vaccine carriers for Coxsackievirus A16 and Enterovirus 71.

    Zhang, Chao; Yang, Yong; Chi, Yudan; Yin, Jieyun; Yan, Lijun; Ku, Zhiqiang; Liu, Qingwei; Huang, Zhong; Zhou, Dongming

    2015-09-22

    Hand, foot and mouth disease (HFMD) is a major public health concern in Asia; more efficient vaccines against HFMD are urgently required. Adenoviral (Ad) capsids have been used widely for the presentation of foreign antigens to induce specific immune responses in the host. Here, we describe a novel bivalent vaccine for HFMD based on the hexon-modified, E1-deleted chimpanzee adenovirus serotype 68 (AdC68). The novel vaccine candidate was generated by incorporating the neutralising epitope of Coxsackievirus A16 (CA16), PEP71, into hypervariable region 1 (HVR1), and a shortened neutralising epitope of Enterovirus 71 (EV71), sSP70, into HVR2 of the AdC68 hexon. In order to enhance the immunogenicity of EV71, VP1 of EV71 was cloned into the E1-region of the AdC68 vectors. The results demonstrated that these two epitopes were well presented on the virion surface and had high affinity towards specific antibodies, and VP1 of EV71 was also significantly expressed. In pre-clinical mouse models, the hexon-modified AdC68 elicited neutralising antibodies against both CA16 and EV71, which conferred protection to suckling mice against a lethal challenge of CA16 and EV71. In summary, this study demonstrates that the hexon-modified AdC68 may represent a promising bivalent vaccine carrier against EV71 and CA16 and an epitope-display platform for other pathogens. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Use of Cre/loxP recombination to swap cell binding motifs on the adenoviral capsid protein IX

    Poulin, Kathy L.; Tong, Grace; Vorobyova, Olga; Pool, Madeline; Kothary, Rashmi; Parks, Robin J.

    2011-01-01

    We used Cre/loxP recombination to swap targeting ligands present on the adenoviral capsid protein IX (pIX). A loxP-flanked sequence encoding poly-lysine (pK-binds heparan sulfate proteoglycans) was engineered onto the 3'-terminus of pIX, and the resulting fusion protein allowed for routine virus propagation. Growth of this virus on Cre-expressing cells removed the pK coding sequence, generating virus that could only infect through alternative ligands, such as a tyrosine kinase receptor A (TrkA)-binding motif engineered into the capsid fibre protein for enhanced infection of neuronal cells. We used a similar approach to swap the pK motif on pIX for a sequence encoding a single-domain antibody directed towards CD66c for targeted infection of cancer cells; Cre-mediated removal of the pK-coding sequence simultaneously placed the single-domain antibody coding sequence in frame with pIX. Thus, we have developed a simple method to propagate virus lacking native viral tropism but containing cell-specific binding ligands. - Highlights: → We describe a method to grow virus lacking native tropism but containing novel cell-binding ligands. → Cre/loxP recombination was used to modify the adenovirus genome. → A targeting ligand present on capsid protein IX was removed or replaced using recombination. → Cre-loxP was also used to 'swap' the identity of the targeting ligand present on pIX.

  15. Characterization of adenoviral transduction profile in prostate cancer cells and normal prostate tissue.

    Ai, Jianzhong; Tai, Phillip W L; Lu, Yi; Li, Jia; Ma, Hong; Su, Qin; Wei, Qiang; Li, Hong; Gao, Guangping

    2017-09-01

    Prostate diseases are common in males worldwide with high morbidity. Gene therapy is an attractive therapeutic strategy for prostate diseases, however, it is currently underdeveloped. As well known, adeno virus (Ad) is the most widely used gene therapy vector. The aims of this study are to explore transduction efficiency of Ad in prostate cancer cells and normal prostate tissue, thus further providing guidance for future prostate pathophysiological studies and therapeutic development of prostate diseases. We produced Ad expressing enhanced green fluorescence protein (EGFP), and characterized the transduction efficiency of Ad in both human and mouse prostate cancer cell lines in vitro, as well as prostate tumor xenograft, and wild-type mouse prostate tissue in vivo. Ad transduction efficiency was determined by EGFP fluorescence using microscopy and flow cytometry. Cell type-specific transduction was examined by immunofluorescence staining of cell markers. Our data showed that Ad efficiently transduced human and mouse prostate cancer cells in vitro in a dose dependent manner. Following intratumoral and intraprostate injection, Ad could efficiently transduce prostate tumor xenograft and the major prostatic cell types in vivo, respectively. Our findings suggest that Ad can efficiently transduce prostate tumor cells in vitro as well as xenograft and normal prostate tissue in vivo, and further indicate that Ad could be a potentially powerful toolbox for future gene therapy of prostate diseases. © 2017 Wiley Periodicals, Inc.

  16. Adenoviral overexpression of Lhx2 attenuates cell viability but does not preserve the stem cell like phenotype of hepatic stellate cells.

    Genz, Berit; Thomas, Maria; Pützer, Brigitte M; Siatkowski, Marcin; Fuellen, Georg; Vollmar, Brigitte; Abshagen, Kerstin

    2014-11-01

    Hepatic stellate cells (HSC) are well known initiators of hepatic fibrosis. After liver cell damage, HSC transdifferentiate into proliferative myofibroblasts, representing the major source of extracellular matrix in the fibrotic organ. Recent studies also demonstrate a role of HSC as progenitor or stem cell like cells in liver regeneration. Lhx2 is described as stem cell maintaining factor in different organs and as an inhibitory transcription factor in HSC activation. Here we examined whether a continuous expression of Lhx2 in HSC could attenuate their activation and whether Lhx2 could serve as a potential target for antifibrotic gene therapy. Therefore, we evaluated an adenoviral mediated overexpression of Lhx2 in primary HSC and investigated mRNA expression patterns by qRT-PCR as well as the activation status by different in vitro assays. HSC revealed a marked increase in activation markers like smooth muscle actin alpha (αSMA) and collagen 1α independent from adenoviral transduction. Lhx2 overexpression resulted in attenuated cell viability as shown by a slightly hampered migratory and contractile phenotype of HSC. Expression of stem cell factors or signaling components was also unaffected by Lhx2. Summarizing these results, we found no antifibrotic or stem cell maintaining effect of Lhx2 overexpression in primary HSC. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Vector-based RNA interference against vascular endothelial growth factor-A significantly limits vascularization and growth of prostate cancer in vivo.

    Wannenes, Francesca; Ciafré, Silvia Anna; Niola, Francesco; Frajese, Gaetano; Farace, Maria Giulia

    2005-12-01

    RNA interference technology is emerging as a very potent tool to obtain a cellular knockdown of a desired gene. In this work we used vector-based RNA interference to inhibit vascular endothelial growth factor (VEGF) expression in prostate cancer in vitro and in vivo. We demonstrated that transduction with a plasmid carrying a small interfering RNA targeting all isoforms of VEGF, dramatically impairs the expression of this growth factor in the human prostate cancer cell line PC3. As a consequence, PC3 cells loose their ability to induce one of the fundamental steps of angiogenesis, namely the formation of a tube-like network in vitro. Most importantly, our "therapeutic" vector is able to impair tumor growth rate and vascularization in vivo. We show that a single injection of naked plasmid in developing neoplastic mass significantly decreases microvessel density in an androgen-refractory prostate xenograft and is able to sustain a long-term slowing down of tumor growth. In conclusion, our results confirm the basic role of VEGF in the angiogenic development of prostate carcinoma, and suggest that the use of our vector-based RNA interference approach to inhibit angiogenesis could be an effective tool in view of future gene therapy applications for prostate cancer.

  18. Amelioration of carbon tetrachloride-induced cirrhosis and portal hypertension in rat using adenoviral gene transfer of Akt.

    Deng, Gang; Huang, Xiang-Jun; Luo, Hong-Wu; Huang, Fei-Zhou; Liu, Xun-Yang; Wang, Yong-Heng

    2013-01-01

    To investigate whether a virus constitutively expressing active Akt is useful to prevent cirrhosis induced by carbon tetrachloride (CCl4). Using cre-loxp technique, we created an Ad-myr-HA-Akt virus, in which Akt is labeled by a HA tag and its expression is driven by myr promoter. Further, through measuring enzyme levels and histological structure, we determined the efficacy of this Ad-myr-HA-Akt virus in inhibiting the development of cirrhosis induced by CCl4 in rats. Lastly, using western blotting, we examined the expression levels and/or phosphorylation status of Akt, apoptotic mediators, endothelial nitric oxide synthase (eNOS), and markers for hepatic stellate cells activation to understand the underlying mechanisms of protective role of this virus. The Ad-myr-HA-Akt virus was confirmed using polymerase chain reaction amplification of inserted Akt gene and sequencing for full length of inserted fragment, which was consistent with the sequence reported in the GenBank. The concentrations of Ad-myr-HA-Akt and adenoviral enhanced green fluorescent protein (Ad-EGFP) virus used in the current study were 5.5 × 10(11) vp/mL. The portal vein diameter, peak velocity of blood flow, portal blood flow and congestion index were significantly increased in untreated, saline and Ad-EGFP cirrhosis groups when compared to normal control after the virus was introduced to animal through tail veil injection. In contrast, these parameters in the Akt cirrhosis group were comparable to normal control group. Compared to the normal control, the liver function (Alanine aminotransferase, Aspartate aminotransferase and Albumin) was significantly impaired in the untreated, saline and Ad-EGFP cirrhosis groups. The Akt cirrhosis group showed significant improvement of liver function when compared to the untreated, saline and Ad-EGFP cirrhosis groups. The Hyp level and portal vein pressure in Akt cirrhosis groups were also significantly lower than other cirrhosis groups. The results of HE and

  19. Comparison of [{sup 18}F]FHBG and [{sup 14}C]FIAU for imaging of HSV1-tk reporter gene expression: adenoviral infection vs stable transfection

    Min, Jung-Jun; Iyer, Meera [The Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, UCLA School of Medicine, B3-399A BRI 700 Westwood Plaza, CA 90095-1770, Los Angeles (United States); Gambhir, Sanjiv S. [The Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, UCLA School of Medicine, B3-399A BRI 700 Westwood Plaza, CA 90095-1770, Los Angeles (United States); Department of Radiology, Bio-X Program, Stanford University, Stanford, California (United States)

    2003-11-01

    Earlier studies involving comparison of different reporter probes have shown conflicting results between pyrimidine nucleosides [e.g., 2'-fluoro-2'-deoxy-1-{beta}-d-arabinofuranosyl-5-iodouracil (FIAU)] and acycloguanosine derivatives [e.g., penciclovir (PCV), 9-(4-fluoro-3-hydroxymethylbutyl)guanine (FHBG)]. We hypothesized that this reported discrepancy may be related to how the reporter gene is delivered to the cells - stably transfected vs adenoviral infection. We directly compared the uptake characteristics of [{sup 18}F]FHBG, [{sup 3}H]PCV, and [{sup 14}C]FIAU in cell culture and in vivo using an adenoviral mediated gene transfer model and stably transfected cells. We further compared the uptake of three reporter probes using both HSV1-tk and a mutant HSV1-sr39tk expressing cells to assess the optimal reporter probe/reporter gene combination. [{sup 14}C]FIAU accumulation was greater than that of [{sup 3}H]PCV and [{sup 18}F]FHBG in control cells and in HSV1-tk stably transfected cells (P<0.001). After infection of C6 cells with AdCMV-HSV1-tk (1.5 x 10{sup 8} pfu), [{sup 18}F]FHBG and [{sup 3}H]PCV accumulation was significantly greater than that of [{sup 14}C]FIAU (P<0.01). [{sup 18}F]FHBG and [{sup 3}H]PCV accumulated to a significantly greater extent than [{sup 14}C]FIAU in C6-stb-sr39tk+ and AdCMV-HSV1-sr39tk infected C6 cells (P<0.001). Results from the nude mice supported the results in cell culture. [{sup 14}C]FIAU led to significantly higher %ID/g in C6-stb-tk+ xenografts than [{sup 18}F]FHBG (P<0.05); however, compared with [{sup 14}C]FIAU, [{sup 18}F]FHBG led to as high %ID/g in HSV1-tk expressing hepatocytes and to significantly greater %ID/g in C6-stb-sr39tk+ xenografts and HSV1-sr39tk expressing hepatocytes. Dynamic sequential images showed that [{sup 18}F]FHBG was well retained in HSV1-sr39tk expressing cells (C6-stb-sr39tk+) for at least 4 h after injection, while it was rapidly cleared from HSV1-tk expressing cells (MH3924A

  20. An easy method for preparation of Cre-loxP regulated fluorescent adenoviral expression vectors and its application for direct reprogramming into hepatocytes

    Chitose Kurihara

    2016-12-01

    Full Text Available The recombinant adenoviral gene expression system is a powerful tool for gene delivery. However, it is difficult to obtain high titers of infectious virus, principally due to the toxicity of the expressed gene which affects on virus replication in the host HEK293 cells. To avoid these problems, we generated a Cre-loxP-regulated fluorescent universal vector (termed pAxCALRL. This vector produces recombinant adenoviruses that express the red fluorescent protein (RFP instead of the inserted gene during proliferation, which limits toxicity and can be used to monitor viral replication. Expression of the gene of interest is induced by co-infection with an adenovirus that expresses Cre-recombinase (AxCANCre. Recombinant adenovirus produced by this system that express Hnf4α and Foxa2 were used to reprogram mouse embryo fibroblast (MEF into induced-hepatocyte-like cells (iHep following several rounds of infection, demonstrating the efficacy of this new system.

  1. Micro-computed tomography of pulmonary fibrosis in mice induced by adenoviral gene transfer of biologically active transforming growth factor-β1

    Gauldie Jack

    2010-12-01

    Full Text Available Abstract Background Micro-computed tomography (micro-CT is a novel tool for monitoring acute and chronic disease states in small laboratory animals. Its value for assessing progressive lung fibrosis in mice has not been reported so far. Here we examined the importance of in vivo micro-CT as non-invasive tool to assess progression of pulmonary fibrosis in mice over time. Methods Pulmonary fibrosis was induced in mice by intratracheal delivery of an adenoviral gene vector encoding biologically active TGF-ß1 (AdTGF-ß1. Respiratory gated and ungated micro-CT scans were performed at 1, 2, 3, and 4 weeks post pulmonary adenoviral gene or control vector delivery, and were then correlated with respective histopathology-based Ashcroft scoring of pulmonary fibrosis in mice. Visual assessment of image quality and consolidation was performed by 3 observers and a semi-automated quantification algorithm was applied to quantify aerated pulmonary volume as an inverse surrogate marker for pulmonary fibrosis. Results We found a significant correlation between classical Ashcroft scoring and micro-CT assessment using both visual assessment and the semi-automated quantification algorithm. Pulmonary fibrosis could be clearly detected in micro-CT, image quality values were higher for respiratory gated exams, although differences were not significant. For assessment of fibrosis no significant difference between respiratory gated and ungated exams was observed. Conclusions Together, we show that micro-CT is a powerful tool to assess pulmonary fibrosis in mice, using both visual assessment and semi-automated quantification algorithms. These data may be important in view of pre-clinical pharmacologic interventions for the treatment of lung fibrosis in small laboratory animals.

  2. Down-regulation of viral replication by adenoviral-mediated expression of siRNA against cellular cofactors for hepatitis C virus

    Zhang Jing; Yamada, Osamu; Sakamoto, Takashi; Yoshida, Hiroshi; Iwai, Takahiro; Matsushita, Yoshihisa; Shimamura, Hideo; Araki, Hiromasa; Shimotohno, Kunitada

    2004-01-01

    Small interfering RNA (siRNA) is currently being evaluated not only as a powerful tool for functional genomics, but also as a potentially promising therapeutic agent for cancer and infectious diseases. Inhibitory effect of siRNA on viral replication has been demonstrated in multiple pathogenic viruses. However, because of the high sequence specificity of siRNA-mediated RNA degradation, antiviral efficacy of siRNA directed to viral genome will be largely limited by emergence of escape variants resistant to siRNA due to high mutation rates of virus, especially RNA viruses such as poliovirus and hepatitis C virus (HCV). To investigate the therapeutic feasibility of siRNAs specific for the putative cellular cofactors for HCV, we constructed adenovirus vectors expressing siRNAs against La, polypyrimidine tract-binding protein (PTB), subunit gamma of human eukaryotic initiation factors 2B (eIF2Bγ), and human VAMP-associated protein of 33 kDa (hVAP-33). Adenoviral-mediated expression of siRNAs markedly diminished expression of the endogenous genes, and silencing of La, PTB, and hVAP-33 by siRNAs substantially blocked HCV replication in Huh-7 cells. Thus, our studies demonstrate the feasibility and potential of adenoviral-delivered siRNAs specific for cellular cofactors in combating HCV infection, which can be used either alone or in combination with siRNA against viral genome to prevent the escape of mutant variants and provide additive or synergistic anti-HCV effects

  3. Priming of CD8 T Cells by Adenoviral Vectors Is Critically Dependent on B7 and Dendritic Cells but Only Partially Dependent on CD28 Ligation on CD8 T Cells

    Nielsen, Karen N; Steffensen, Maria A; Christensen, Jan P

    2014-01-01

    expression resulted in a delayed primary response, whereas memory CD8 T cells generated in CD28-deficient mice appeared almost normal in terms of both phenotype and effector cytokine profile, but they exhibited a significantly reduced proliferative capacity upon secondary challenge while retaining immediate...... in vivo effector capabilities: in vivo cytotoxicity and short-term in vivo protective capacity. Overall, our data point to an absolute requirement for professional APCs and the expression of the costimulatory molecules CD80/86 for efficient CD8 T cell priming by adenoviral vectors. Additionally, our......Adenoviral vectors have long been forerunners in the development of effective CD8 T cell-based vaccines; therefore, it is imperative that we understand the factors controlling the induction of robust and long-lasting transgene-specific immune responses by these vectors. In this study, we...

  4. Optimization and physicochemical characterization of a cationic lipid-phosphatidylcholine mixed emulsion formulated as a highly efficient vehicle that facilitates adenoviral gene transfer

    Kim SY

    2017-10-01

    Full Text Available Soo-Yeon Kim,1,2 Sang-Jin Lee,2 Jin-Ki Kim,3 Han-Gon Choi,3 Soo-Jeong Lim1 1Department of Bioscience and Bioengineering, Sejong University, Seoul, Kwangjin-gu, Seoul, 2Immunotherapeutics Branch, Research Institute, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, 3College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, Sangnok-gu, Ansan, Republic of Korea Abstract: Cationic lipid-based nanoparticles enhance viral gene transfer by forming electrostatic complexes with adenoviral vectors. We recently demonstrated the superior complexation capabilities of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP emulsion compared with a liposomal counterpart but the cytotoxicity of DOTAP emulsions remained a challenge. The present study is aimed at formulating an emulsion capable of acting as a highly effective viral gene transfer vehicle with reduced cytotoxicity and to physicochemically characterize the structures of virus-emulsion complexes in comparison with virus–liposome complexes when the only difference between emulsions and liposomes was the presence or absence of inner oil core. The emulsion formulation was performed by 1 reducing the content of DOTAP while increasing the content of zwitterionic lipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC, and 2 optimizing the oil content. The complexation capability of formulated DOTAP:DMPC mixed emulsions was similar to those of emulsions containing DOTAP alone while displaying significantly lower cytotoxicity. The complexation capabilities of the DOTAP:DMPC mixed emulsion were serum-compatible and were monitored in a variety of cell types, whereas its liposomal counterpart was totally ineffective. Characterization by scanning electron microscopy, transmission electron microscopy, atomic force microscopy, and dynamic light scattering studies indicated that the optimized emulsions spontaneously surrounded the virus particles to generate emulsions that

  5. Comparing vector-based and Bayesian memory models using large-scale datasets: User-generated hashtag and tag prediction on Twitter and Stack Overflow.

    Stanley, Clayton; Byrne, Michael D

    2016-12-01

    The growth of social media and user-created content on online sites provides unique opportunities to study models of human declarative memory. By framing the task of choosing a hashtag for a tweet and tagging a post on Stack Overflow as a declarative memory retrieval problem, 2 cognitively plausible declarative memory models were applied to millions of posts and tweets and evaluated on how accurately they predict a user's chosen tags. An ACT-R based Bayesian model and a random permutation vector-based model were tested on the large data sets. The results show that past user behavior of tag use is a strong predictor of future behavior. Furthermore, past behavior was successfully incorporated into the random permutation model that previously used only context. Also, ACT-R's attentional weight term was linked to an entropy-weighting natural language processing method used to attenuate high-frequency words (e.g., articles and prepositions). Word order was not found to be a strong predictor of tag use, and the random permutation model performed comparably to the Bayesian model without including word order. This shows that the strength of the random permutation model is not in the ability to represent word order, but rather in the way in which context information is successfully compressed. The results of the large-scale exploration show how the architecture of the 2 memory models can be modified to significantly improve accuracy, and may suggest task-independent general modifications that can help improve model fit to human data in a much wider range of domains. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  6. Adenoviral gene transfer of PLD1-D4 enhances insulin sensitivity in mice by disrupting phospholipase D1 interaction with PED/PEA-15.

    Angela Cassese

    Full Text Available Over-expression of phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (PED/PEA-15 causes insulin resistance by interacting with the D4 domain of phospholipase D1 (PLD1. Indeed, the disruption of this association restores insulin sensitivity in cultured cells over-expressing PED/PEA-15. Whether the displacement of PLD1 from PED/PEA-15 improves insulin sensitivity in vivo has not been explored yet. In this work we show that treatment with a recombinant adenoviral vector containing the human D4 cDNA (Ad-D4 restores normal glucose homeostasis in transgenic mice overexpressing PED/PEA-15 (Tg ped/pea-15 by improving both insulin sensitivity and secretion. In skeletal muscle of these mice, D4 over-expression inhibited PED/PEA-15-PLD1 interaction, decreased Protein Kinase C alpha activation and restored insulin induced Protein Kinase C zeta activation, leading to amelioration of insulin-dependent glucose uptake. Interestingly, Ad-D4 administration improved insulin sensitivity also in high-fat diet treated obese C57Bl/6 mice. We conclude that PED/PEA-15-PLD1 interaction may represent a novel target for interventions aiming at improving glucose tolerance.

  7. Initial preclinical safety of non-replicating human endogenous retrovirus envelope protein-coated baculovirus vector-based vaccines against human papillomavirus.

    Han, Su-Eun; Kim, Mi-Gyeong; Lee, Soondong; Cho, Hee-Jeong; Byun, Youngro; Kim, Sujeong; Kim, Young Bong; Choi, Yongseok; Oh, Yu-Kyoung

    2013-12-01

    Human endogenous retrovirus (HERV) envelope protein-coated, baculovirus vector-based HPV 16 L1 (AcHERV-HPV16L1) is a non-replicating recombinant baculoviral vaccine. Here, we report an initial evaluation of the preclinical safety of AcHERV-HPV16L1 vaccine. In an acute toxicity study, a single administration of AcHERV-HPV16L1 DNA vaccine given intramuscularly (i.m.) to mice at a dose of 1 × 10(8) plaque-forming units (PFU) did not cause significant changes in body weight compared with vehicle-treated controls. It did cause a brief increase in the weights of some organs on day 15 post-treatment, but by day 30, all organ weights were not significantly different from those in the vehicle-treated control group. No hematological changes were observed on day 30 post-treatment. In a range-finding toxicity study with three doses of 1 × 10(7) , 2 × 10(7) and 5 × 10(7) PFU once daily for 5 days, the group treated with 5 × 10(7) PFU showed a transient decrease in the body weights from day 5 to day 15 post-treatment, but recovery to the levels similar to those in the vehicle-treated control group by post-treatment day 20. Organ weights were slightly higher for lymph nodes, spleen, thymus and liver after repeated dosing with 5 × 10(7) PFU on day 15, but had normalized by day 30. Moreover, repeated administration of AcHERV-HPV16L1 did not induce myosin-specific autoantibody in serum, and did not cause immune complex deposition or tissue damage at injection sites. Taken together, these results provide preliminary evidence of the preclinical safety of AcHERV-based HPV16L1 DNA vaccines in mice. Copyright © 2012 John Wiley & Sons, Ltd.

  8. A unified triangle carrier based PWM strategy for three-phase N-level diode clamped inverters

    Li, Kai; Xie, Chuan; Wei, Min

    2017-01-01

    The triangle carrier based pulse width modulation (TCB-PWM) can be functionally equivalent to space vector base PWM (SVB-PWM). For multi-level inverter, it is very difficult to realize the SVB-PWM because its vector space is very complex. In this paper, a unified TCB-PWM strategy for three-phase ...

  9. INGN 201: Ad-p53, Ad5CMV-p53, Adenoviral p53, INGN 101, p53 gene therapy--Introgen, RPR/INGN 201.

    2003-01-01

    Introgen's adenoviral p53 gene therapy [INGN 201, ADVEXIN] is in clinical development for the treatment of various cancers. The p53 tumour suppressor gene is deleted or mutated in many tumour cells and is one of the most frequently mutated genes in human tumours. INGN 201 has been shown to kill cancer cells directly. In August 2002, Introgen announced plans to file an application for INGN 201 with the European Agency for the Evaluation of Medicinal Products (EMEA) for the treatment of head and neck cancer; the European filing will be submitted simultaneously with the previously scheduled (planned for 2004) submission of a Biologics License Application (BLA) for ADVEXIN to the US FDA. On 20 February 2003, INGN 201 received orphan drug designation from the US FDA for head and neck cancer. INGN 201 is available for licensing although Introgen favours retaining partial or full rights to the therapy in the US. Introgen Therapeutics and its collaborative partner for the p53 programme, Aventis Gencell, have been developing p53 gene therapy products. The agreement was originally signed by Rhône-Poulenc Rorer's Gencell division, which became Aventis Gencell after Rhône-Poulenc Rorer merged with Hoechst Marion Roussel to form Aventis Pharma. According to the original agreement, Introgen was responsible for phase I and preclinical development in North America, while Aventis Gencell was responsible for clinical trials conducted in Europe and for clinical trials in North America beyond phase I. In April 2001, Aventis Gencell and Introgen restructured their existing collaboration agreement for p53 gene therapy products. Aventis Gencell indicated that p53 research had suffered from internal competition for resources and was pulling back from its development agreement with Introgen for p53 gene therapy products. Introgen will assume responsibility for worldwide development of all p53 programmes and will obtain exclusive worldwide commercial rights to p53-based gene therapy

  10. Human Articular Cartilage Progenitor Cells Are Responsive to Mechanical Stimulation and Adenoviral-Mediated Overexpression of Bone-Morphogenetic Protein 2.

    Alexander J Neumann

    Full Text Available Articular cartilage progenitor cells (ACPCs represent a new and potentially powerful alternative cell source to commonly used cell sources for cartilage repair, such as chondrocytes and bone-marrow derived mesenchymal stem cells (MSCs. This is particularly due to the apparent resistance of ACPCs to hypertrophy. The current study opted to investigate whether human ACPCs (hACPCs are responsive towards mechanical stimulation and/or adenoviral-mediated overexpression of bone morphogenetic protein 2 (BMP-2. hACPCs were cultured in fibrin-polyurethane composite scaffolds. Cells were cultured in a defined chondro-permissive medium, lacking exogenous growth factors. Constructs were cultured, for 7 or 28 days, under free-swelling conditions or with the application of complex mechanical stimulation, using a custom built bioreactor that is able to generate joint-like movements. Outcome parameters were quantification of BMP-2 and transforming growth factor beta 1 (TGF-β1 concentration within the cell culture medium, biochemical and gene expression analyses, histology and immunohistochemistry. The application of mechanical stimulation alone resulted in the initiation of chondrogenesis, demonstrating the cells are mechanoresponsive. This was evidenced by increased GAG production, lack of expression of hypertrophic markers and a promising gene expression profile (significant up-regulation of cartilaginous marker genes, specifically collagen type II, accompanied by no increase in the hypertrophic marker collagen type X or the osteogenic marker alkaline phosphatase. To further investigate the resistance of ACPCs to hypertrophy, overexpression of a factor associated with hypertrophic differentiation, BMP-2, was investigated. A novel, three-dimensional, transduction protocol was used to transduce cells with an adenovirus coding for BMP-2. Over-expression of BMP-2, independent of load, led to an increase in markers associated with hypertropy. Taken together ACPCs

  11. Regulation of epithelial differentiation in rat intestine by intraluminal delivery of an adenoviral vector or silencing RNA coding for Schlafen 3.

    Pavlo L Kovalenko

    Full Text Available Although we stimulate enterocytic proliferation to ameliorate short gut syndrome or mucosal atrophy, less effort has been directed at enterocytic differentiation. Schlafen 3 (Slfn3 is a poorly understood protein induced during IEC-6 enterocytic differentiation. We hypothesized that exogenous manipulation of Slfn3 would regulate enterocytic differentiation in vivo. Adenoviral vector coding for Slfn3 cDNA (Ad-GFP-Slfn3 or silencing RNA for Slfn3 (siSlfn3 was introduced intraluminally into rat intestine. We assessed Slfn3, villin, sucrase-isomaltase (SI, Dpp4, and Glut2 by qRT-PCR, Western blot, and immunohistochemistry. We also studied Slfn3 and these differentiation markers in atrophic defunctionalized jejunal mucosa and the crypt-villus axis of normal jejunum. Ad-GFP-Slfn3 but not Ad-GFP increased Slfn3, villin and Dpp4 expression in human Caco-2 intestinal epithelial cells. Injecting Ad-GFP-Slfn3 into rat jejunum in vivo increased mucosal Slfn3 mRNA three days later vs. intraluminal Ad-GFP. This Slfn3 overexpression was associated with increases in all four differentiation markers. Injecting siSlfn3 into rat jejunum in vivo substantially reduced Slfn3 and all four intestinal mucosal differentiation markers three days later, as well as Dpp4 specific activity. Endogenous Slfn3 was reduced in atrophic mucosa from a blind-end Roux-en-Y anastomosis in parallel with differentiation marker expression together with AKT and p38 signaling. Slfn3 was more highly expressed in the villi than the crypts, paralleling Glut2, SI and Dpp4. Slfn3 is a key intracellular regulator of rat enterocytic differentiation. Understanding how Slfn3 works may identify targets to promote enterocytic differentiation and maintain mucosal function in vivo, facilitating enteral nutrition and improving survival in patients with mucosal atrophy or short gut syndrome.

  12. Effect of adenovirus infection on transgene expression under the adenoviral MLP/TPL and the CMVie promoter/enhancer in CHO cells

    Mohamed A. El-Mogy

    2017-06-01

    Full Text Available The adenovirus major late promoter (MLP and its translational regulator – the tripartite leader (TPL sequence – can actively drive efficient gene expression during adenoviral infection. However, both elements have not been widely tested in transgene expression outside of the adenovirus genome context. In this study, we tested whether the combination of MLP and TPL would enhance transgene expression beyond that of the most widely used promoter in transgene expression in mammalian cells, the cytomegalovirus immediate early (CMVie promoter/enhancer. The activity of these two regulatory elements was compared in Chinese hamster ovary (CHO cells. Although transient expression was significantly higher under the control of the CMVie promoter/enhance compared to the MLP/TPL, this difference was greater at the level of transcription (30 folds than translation (11 folds. Even with adenovirus infection to provide additional elements (in trans, CMVie promoter/enhancer exhibited significantly higher activity relative to MLP/TPL. Interestingly, the CMVie promoter/enhancer was 1.9 folds more active in adenovirus-infected cells than in non-infected cells. Our study shows that the MLP-TPL drives lower transgene expression than the CMVie promoter/enhancer particularly at the transcription level. The data also highlight the utility of the TPL sequence at the translation level and/or possible overwhelming of the cellular translational machinery by the high transcription activity of the CMVie promoter/enhancer. In addition, here we present data that show stimulation of the CMVie promoter/enhancer by adenovirus infection, which may prove interesting in future work to test the combination of CMVie/TPL sequence, and additional adenovirus elements, for transgene expression.

  13. Electric cell-substrate impedance sensing (ECIS) based real-time measurement of titer dependent cytotoxicity induced by adenoviral vectors in an IPI-2I cell culture model.

    Müller, Jakob; Thirion, Christian; Pfaffl, Michael W

    2011-01-15

    Recombinant viral vectors are widespread tools for transfer of genetic material in various modern biotechnological applications like for example RNA interference (RNAi). However, an accurate and reproducible titer assignment represents the basic step for most downstream applications regarding a precise multiplicity of infection (MOI) adjustment. As necessary scaffold for the studies described in this work we introduce a quantitative real-time PCR (qPCR) based approach for viral particle measurement. Still an implicated problem concerning physiological effects is that the appliance of viral vectors is often attended by toxic effects on the individual target. To determine the critical viral dose leading to cell death we developed an electric cell-substrate impedance sensing (ECIS) based assay. With ECIS technology the impedance change of a current flow through the cell culture medium in an array plate is measured in a non-invasive manner, visualizing effects like cell attachment, cell-cell contacts or proliferation. Here we describe the potential of this online measurement technique in an in vitro model using the porcine ileal epithelial cell line IPI-2I in combination with an adenoviral transfection vector (Ad5-derivate). This approach shows a clear dose-depending toxic effect, as the amount of applied virus highly correlates (p<0.001) with the level of cell death. Thus this assay offers the possibility to discriminate the minimal non-toxic dose of the individual transfection method. In addition this work suggests that the ECIS-device bears the feasibility to transfer this assay to multiple other cytotoxicological questions. Copyright © 2010 Elsevier B.V. All rights reserved.

  14. Adenovirally delivered shRNA strongly inhibits Na+-Ca2+ exchanger expression but does not prevent contraction of neonatal cardiomyocytes.

    Hurtado, Cecilia; Ander, Bradley P; Maddaford, Thane G; Lukas, Anton; Hryshko, Larry V; Pierce, Grant N

    2005-04-01

    The cardiac Na(+)-Ca(2+) exchanger (NCX1) is the main mechanism for Ca(2+) efflux in the heart and is thought to serve an essential role in cardiac excitation-contraction (E-C) coupling. The demonstration that an NCX1 gene knock-out is embryonic lethal provides further support for this essential role. However, a recent report employing the Cre/loxP technique for cardiac specific knock-out of NCX1 has revealed that cardiac function is remarkably preserved in these mice, which survived to adulthood. This controversy highlights the necessity for further investigation of NCX1 function in the heart. In this study, we report on a novel approach for depletion of NCX1 in postnatal rat myocytes that utilizes RNA interference (RNAi), administered with high efficiency via adenoviral transfection. Depletion of NCX1 was confirmed by immunocytochemical detection, Western blots and radioisotopic assays of Na(+)-Ca(2+) exchange activity. Exchanger expression was inhibited by up to approximately 94%. Surprisingly, spontaneous beating of these cardiomyocytes was still maintained, although at a lower frequency. Electrical stimulation could elicit a normal beating rhythm, although NCX depleted cells exhibited a depressed Ca(2+) transient amplitude, a depressed rate of Ca(2+) rise and decline, elevated diastolic [Ca(2+)], and shorter action potentials. We also observed a compensatory increase in sarcolemmal Ca(2+) pump expression. Our data support an important, though non-essential, role for the NCX1 in E-C coupling in these neonatal heart cells. Furthermore, this approach provides a valuable means for assessing the role of NCX1 and could be utilized to examine other cardiac proteins in physiological and pathological studies.

  15. Experimental study on the effects of recombinant adenoviral-mediated mI{kappa}B{alpha} gene combined with irradiation on the treatment of hepatocarcinoma

    Kejun, Zhang; Dechun, Li; Dongming, Zhu [The First Affiliated Hospital to Suzhou Univ., Suzhou (China); Caixia, Song

    2007-10-15

    Objective: To explore the effect of recombinant adenovirus vector mediated mutant I{kappa}B{alpha} (mI{kappa}B{alpha}) combined with radiation on the hepatocarcinoma. Methods: Limited dilution method was used to test the virus titer in 293 cells. The HCC9204 cells were infected with MOI 10,20,30 and 50 for 48 h, respectively. The expression of p65 and mI{kappa}B{alpha} protein was analyzed by Western blot. Transfected HCC9204 cells and controls were treated with 4 Gy {gamma} rays. The inhibition rate of HCC9204 cells was examined by MTT. Rat models of HCC9204 was constructed. AdmI{kappa}B{alpha} plasmids were injected into tumor tissue and the tumors were administered with 6 Gy {gamma} irradiation 48 hours later. Tumor growth at different time points was recorded during 28 days. Results: The titer of AdmI{kappa}B{alpha} is 1.252 x 10{sup 9} pfu/ml. The expression of mI{kappa}B{alpha} protein was increased with titer of AdmI{kappa}B{alpha}, and p65 protein began to decrease when MOI was 10, and reached the lowest when MOI was 50, they were all dose-dependent. The proliferation of HCC9204 cell lines were suppressed, as was more significant combined with radiation, and the effect was in a viral dose-dependent manner. From days 7 to 28 after AdmI{kappa}B{alpha} gene and radiotherapy, the tumor growth was significantly slower than after irradiation or gene therapy alone. Conclusions: Recombinant adenoviral-mediated mI{kappa}B{alpha} gene, combined with irradiation, can increase the cell-killing effect. It is better than that of either one alone. (authors)

  16. Experimental study on the effects of recombinant adenoviral-mediated mIκBα gene combined with irradiation on the treatment of hepatocarcinoma

    Zhang Kejun; Li Dechun; Zhu Dongming; Song Caixia

    2007-01-01

    Objective: To explore the effect of recombinant adenovirus vector mediated mutant IκBα (mIκBα) combined with radiation on the hepatocarcinoma. Methods: Limited dilution method was used to test the virus titer in 293 cells. The HCC9204 cells were infected with MOI 10,20,30 and 50 for 48 h, respectively. The expression of p65 and mIκBα protein was analyzed by Western blot. Transfected HCC9204 cells and controls were treated with 4 Gy γ rays. The inhibition rate of HCC9204 cells was examined by MTT. Rat models of HCC9204 was constructed. AdmIκBα plasmids were injected into tumor tissue and the tumors were administered with 6 Gy γ irradiation 48 hours later. Tumor growth at different time points was recorded during 28 days. Results: The titer of AdmIκBΑ is 1.252 x 10 9 pfu/ml. The expression of mIκBα protein was increased with titer of AdmIκBα, and p65 protein began to decrease when MOI was 10, and reached the lowest when MOI was 50, they were all dose-dependent. The proliferation of HCC9204 cell lines were suppressed, as was more significant combined with radiation, and the effect was in a viral dose-dependent manner. From days 7 to 28 after AdmIκBα gene and radiotherapy, the tumor growth was significantly slower than after irradiation or gene therapy alone. Conclusions: Recombinant adenoviral-mediated mIκBα gene, combined with irradiation, can increase the cell-killing effect. It is better than that of either one alone. (authors)

  17. Immunization with Hexon modified adenoviral vectors integrated with gp83 epitope provides protection against Trypanosoma cruzi infection.

    Anitra L Farrow

    2014-08-01

    Full Text Available Trypanosoma cruzi is the causative agent of Chagas disease. Chagas disease is an endemic infection that affects over 8 million people throughout Latin America and now has become a global challenge. The current pharmacological treatment of patients is unsuccessful in most cases, highly toxic, and no vaccines are available. The results of inadequate treatment could lead to heart failure resulting in death. Therefore, a vaccine that elicits neutralizing antibodies mediated by cell-mediated immune responses and protection against Chagas disease is necessary.The "antigen capsid-incorporation" strategy is based upon the display of the T. cruzi epitope as an integral component of the adenovirus' capsid rather than an encoded transgene. This strategy is predicted to induce a robust humoral immune response to the presented antigen, similar to the response provoked by native Ad capsid proteins. The antigen chosen was T. cruzi gp83, a ligand that is used by T. cruzi to attach to host cells to initiate infection. The gp83 epitope, recognized by the neutralizing MAb 4A4, along with His6 were incorporated into the Ad serotype 5 (Ad5 vector to generate the vector Ad5-HVR1-gp83-18 (Ad5-gp83. This vector was evaluated by molecular and immunological analyses. Vectors were injected to elicit immune responses against gp83 in mouse models. Our findings indicate that mice immunized with the vector Ad5-gp83 and challenged with a lethal dose of T. cruzi trypomastigotes confer strong immunoprotection with significant reduction in parasitemia levels, increased survival rate and induction of neutralizing antibodies.This data demonstrates that immunization with adenovirus containing capsid-incorporated T. cruzi antigen elicits a significant anti-gp83-specific response in two different mouse models, and protection against T. cruzi infection by eliciting neutralizing antibodies mediated by cell-mediated immune responses, as evidenced by the production of several Ig isotypes

  18. RNA interference-based therapeutics for human immunodeficiency virus HIV-1 treatment: synthetic siRNA or vector-based shRNA?

    Subramanya, Sandesh; Kim, Sang-Soo; Manjunath, N; Shankar, Premlata

    2010-02-01

    Despite the clinical benefits of highly active antiretroviral therapy (HAART), the prospect of life-long antiretroviral treatment poses significant problems, which has spurred interest in developing new drugs and strategies to treat HIV infection and eliminate persistent viral reservoirs. RNAi has emerged as a therapeutic possibility for HIV. We discuss progress in overcoming hurdles to translating transient and stable RNAi enabling technologies to clinical application for HIV; covering the past 2 - 3 years. HIV inhibition can be achieved by transfection of chemically or enzymatically synthesized siRNAs or by DNA-based vector systems expressing short hairpin RNAs (shRNAs) that are processed intracellularly into siRNA. We compare these approaches, focusing on technical and safety issues that will guide the choice of strategy for clinical use. Introduction of synthetic siRNA into cells or its stable endogenous production using vector-driven shRNA have been shown to suppress HIV replication in vitro and, in some instances, in vivo. Each method has advantages and limitations in terms of ease of delivery, duration of silencing, emergence of escape mutants and potential toxicity. Both appear to have potential as future therapeutics for HIV, once the technical and safety issues of each approach are overcome.

  19. Gene therapy strategy to reduced bone marrow aplasia: evaluation in cynomolgus macaque exposed to a gamma total body irradiation

    Becard, N.

    2003-01-01

    The aim of this work was to assess whether direct intra-marrow injection of an adeno-viral vector expressing human IL-1α gene stimulates hematopoiesis in healthy non-irradiated and gamma irradiated cynomolgus macaques. In the first hand, we have evaluated the feasibility of this gene therapy strategy in two healthy non-irradiated macaques. In this work, we have observed an increase of neutrophil, monocyte and platelets in the two animals treated with the therapeutic construct. This effect was associated with no abnormal clinical side effect. On the other hand, we have evaluated this strategy in non-human primate exposed to a sublethal gamma irradiation. Two of three animals treated by the therapeutic construct reduced significantly the neutropenia, thrombocytopenia and anemia radio-induced. In conclusion, this gene therapy strategy gave a similar clinical benefit comparatively to systemic administration of huIL-1α but without severe side effect. (author) [fr

  20. Adenoviral vectors expressing fusogenic membrane glycoproteins activated via matrix metalloproteinase cleavable linkers have significant antitumor potential in the gene therapy of gliomas.

    Allen, Cory; McDonald, Cari; Giannini, Caterina; Peng, Kah Whye; Rosales, Gabriela; Russell, Stephen J; Galanis, Evanthia

    2004-11-01

    Fusogenic membrane glycoproteins (FMG) such as the gibbon ape leukemia virus envelope (GALV) glycoprotein are potent therapeutic transgenes with potential utility in the gene therapy of gliomas. Transfection of glioma cell lines with FMG expression constructs results in fusion with massive syncytia formation followed by cytotoxic cell death. Nevertheless, ubiquitous expression of the GALV receptor, Pit-1, makes targeting desirable in order to increase the specificity of the observed cytopathic effect. Here we report on use of matrix metalloproteinase (MMP)-cleavable linkers to target the cytotoxicity of FMG-expressing adenoviral vectors against gliomas. Replication-defective adenoviruses (Ad) were constructed expressing the hyperfusogenic version of the GALV glycoprotein linked to a blocking ligand (C-terminal extracellular domain of CD40 ligand) through either an MMP-cleavable linker (AdM40) or a non-cleavable linker (AdN40). Both viruses also co-expressed the green fluorescent protein (GFP) via an internal ribosomal entry site. The glioma cell lines U87, U118, and U251 characterized by zymography and MMP-2 activity assay as high, medium and low MMP expressors, respectively, the MMP-poor cell lines TE671 and normal human astrocytes were infected with AdM40 and AdN40 at different multiplicities of infection (MOIs) from 1-30. Fusion was quantitated by counting both number and size of syncytia. Infection of these cell lines with AdN40 did not result in fusion or cytotoxic cell death, despite the presence of infection, as demonstrated by GFP positivity, therefore indicating that the displayed CD40 ligand blocked GALV-induced fusion. Fusion was restored after infection of glioma cells with AdM40 at an MOI as low as 1 to an extent dependent on MMP expression and coxsackie adenovirus receptor (CAR) expression in the specific cell line. Western immunoblotting demonstrated the presence of the cleaved CD40 ligand in the supernatant of fused glioma cells. Use of the MMP

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

    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.

  2. Simultaneous subcutaneous and conjunctival administration of the influenza viral vector based Brucella abortus vaccine to pregnant heifers provides better protection against B. abortus 544 infection than the commercial B. abortus S19 vaccine.

    Tabynov, Kaissar; Orynbayev, Mukhit; Renukaradhya, Gourapura J; Sansyzbay, Abylai

    2016-09-30

    In this study, we explored possibility of increasing the protective efficacy of our novel influenza viral vector based B. abortus vaccine (Flu-BA) in pregnant heifers by adapting an innovative method of vaccine delivery. We administered the vaccine concurrently via the conjunctival and subcutaneous routes to pregnant heifers, and these routes were previously tested individually. The Flu-BA vaccination of pregnant heifers (n=9) against a challenge B. abortus 544 infection provided protection from abortion, infection of heifers and fetuses/calves by 88.8%, 100% and 100%, respectively (alpha=0.004-0.0007 vs. negative control; n=7). Our candidate vaccine using this delivery method provided slightly better protection than the commercial B. abortus S19 vaccine in pregnant heifers (n=8), which provided protection from abortion, infection of heifers and fetuses/calves by 87.5%, 75% and 87.5%, respectively. This improved method of the Flu-BA vaccine administration is highly recommended for the recovery of farms which has high prevalence of brucellosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Viral vector-based influenza vaccines

    de Vries, Rory D.; Rimmelzwaan, Guus F.

    2016-01-01

    ABSTRACT Antigenic drift of seasonal influenza viruses and the occasional introduction of influenza viruses of novel subtypes into the human population complicate the timely production of effective vaccines that antigenically match the virus strains that cause epidemic or pandemic outbreaks. The development of game-changing vaccines that induce broadly protective immunity against a wide variety of influenza viruses is an unmet need, in which recombinant viral vectors may provide. Use of viral vectors allows the delivery of any influenza virus antigen, or derivative thereof, to the immune system, resulting in the optimal induction of virus-specific B- and T-cell responses against this antigen of choice. This systematic review discusses results obtained with vectored influenza virus vaccines and advantages and disadvantages of the currently available viral vectors. PMID:27455345

  4. Doxycycline-regulated 3T3-L1 preadipocyte cell line with inducible, stable expression of adenoviral E4orf1 gene: a cell model to study insulin-independent glucose disposal.

    Krishnapuram, Rashmi; Dhurandhar, Emily J; Dubuisson, Olga; Hegde, Vijay; Dhurandhar, Nikhil V

    2013-01-01

    Impaired glycemic control and excessive adiposity are major risk factors for Type 2 Diabetes mellitus. In rodent models, Ad36, a human adenovirus, improves glycemic control, independent of dietary fat intake or adiposity. It is impractical to use Ad36 for therapeutic action. Instead, we identified that E4orf1 protein of Ad36, mediates its anti-hyperglycemic action independent of insulin signaling. To further evaluate the therapeutic potential of E4orf1 to improve glycemic control, we established a stable 3T3-L1 cell system in which E4orf1 expression can be regulated. The development and characterization of this cell line is described here. Full-length adenoviral-36 E4orf1 cDNA obtained by PCR was cloned into a tetracycline responsive element containing vector (pTRE-Tight-E4orf1). Upon screening dozens of pTRE-Tight-E4orf1 clones, we identified the one with the highest expression of E4orf1 in response to doxycycline treatment. Furthermore, using this inducible system we characterized the ability of E4orf1 to improve glucose disposal in a time dependent manner. This stable cell line offers a valuable resource to carefully study the novel signaling pathways E4orf1 uses to enhance cellular glucose disposal independent of insulin.

  5. Doxycycline-regulated 3T3-L1 preadipocyte cell line with inducible, stable expression of adenoviral E4orf1 gene: a cell model to study insulin-independent glucose disposal.

    Rashmi Krishnapuram

    Full Text Available Impaired glycemic control and excessive adiposity are major risk factors for Type 2 Diabetes mellitus. In rodent models, Ad36, a human adenovirus, improves glycemic control, independent of dietary fat intake or adiposity. It is impractical to use Ad36 for therapeutic action. Instead, we identified that E4orf1 protein of Ad36, mediates its anti-hyperglycemic action independent of insulin signaling. To further evaluate the therapeutic potential of E4orf1 to improve glycemic control, we established a stable 3T3-L1 cell system in which E4orf1 expression can be regulated. The development and characterization of this cell line is described here. Full-length adenoviral-36 E4orf1 cDNA obtained by PCR was cloned into a tetracycline responsive element containing vector (pTRE-Tight-E4orf1. Upon screening dozens of pTRE-Tight-E4orf1 clones, we identified the one with the highest expression of E4orf1 in response to doxycycline treatment. Furthermore, using this inducible system we characterized the ability of E4orf1 to improve glucose disposal in a time dependent manner. This stable cell line offers a valuable resource to carefully study the novel signaling pathways E4orf1 uses to enhance cellular glucose disposal independent of insulin.

  6. Global Strategy

    Li, Peter Ping

    2013-01-01

    Global strategy differs from domestic strategy in terms of content and process as well as context and structure. The content of global strategy can contain five key elements, while the process of global strategy can have six major stages. These are expounded below. Global strategy is influenced...... by rich and complementary local contexts with diverse resource pools and game rules at the national level to form a broad ecosystem at the global level. Further, global strategy dictates the interaction or balance between different entry strategies at the levels of internal and external networks....

  7. Safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in China: preliminary report of a randomised, double-blind, placebo-controlled, phase 1 trial.

    Zhu, Feng-Cai; Hou, Li-Hua; Li, Jing-Xin; Wu, Shi-Po; Liu, Pei; Zhang, Gui-Rong; Hu, Yue-Mei; Meng, Fan-Yue; Xu, Jun-Jie; Tang, Rong; Zhang, Jin-Long; Wang, Wen-Juan; Duan, Lei; Chu, Kai; Liang, Qi; Hu, Jia-Lei; Luo, Li; Zhu, Tao; Wang, Jun-Zhi; Chen, Wei

    2015-06-06

    Up to now, all tested Ebola virus vaccines have been based on the virus strain from the Zaire outbreak in 1976. We aimed to assess the safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine expressing the glycoprotein of the 2014 epidemic strain. We did this randomised, double-blind, placebo-controlled, phase 1 clinical trial at one site in Taizhou County, Jiangsu Province, China. Healthy adults (aged 18-60 years) were sequentially enrolled and randomly assigned (2:1), by computer-generated block randomisation (block size of six), to receive placebo, low-dose adenovirus type-5 vector-based Ebola vaccine, or high-dose vaccine. Randomisation was pre-stratified by dose group. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was occurrence of solicited adverse reactions within 7 days of vaccination. The primary immunogenicity endpoints were glycoprotein-specific antibody titres and T-cell responses at day 28 after the vaccination. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT02326194. Between Dec 28, 2014, and Jan 9, 2015, 120 participants were enrolled and randomly assigned to receive placebo (n=40), low-dose vaccine (n=40), or high-dose vaccine. Participants were followed up for 28 days. Overall, 82 (68%) participants reported at least one solicited adverse reaction within 7 days of vaccination (n=19 in the placebo group vs n=27 in the low-dose group vs n=36 in the high-dose group; p=0·0002). The most common reaction was mild pain at the injection site, which was reported in eight (20%) participants in the placebo group, 14 (35%) participants in the low-dose group, and 29 (73%) participants in the high-dose vaccine group (pvaccine groups at both day 14 (geometric mean titre 421·4 [95% CI 249·7-711·3] and 820·5 [598·9-1124·0], respectively; pday 28 (682·7 [424·3-1098·5] and 1305·7 [970·1-1757·2

  8. Combining Cell Type-Restricted Adenoviral Targeting with Immunostaining and Flow Cytometry to Identify Cells-of-Origin of Lung Cancer.

    Best, Sarah A; Kersbergen, Ariena; Asselin-Labat, Marie-Liesse; Sutherland, Kate D

    2018-01-01

    Lung cancers display considerable intertumoral heterogeneity, leading to the classification of distinct tumor subtypes. Our understanding of the genetic aberrations that underlie tumor subtypes has been greatly enhanced by recent genomic sequencing studies and state-of-the-art gene targeting technologies, highlighting evidence that distinct lung cancer subtypes may be derived from different "cells-of-origin". Here, we describe the intra-tracheal delivery of cell type-restricted Ad5-Cre viruses into the lungs of adult mice, combined with immunohistochemical and flow cytometry strategies for the detection of lung cancer-initiating cells in vivo.

  9. Combinatorial therapy with adenoviral-mediated PTEN and a PI3K inhibitor suppresses malignant glioma cell growth in vitro and in vivo by regulating the PI3K/AKT signaling pathway.

    Nan, Yang; Guo, Liyun; Song, Yunpeng; Wang, Le; Yu, Kai; Huang, Qiang; Zhong, Yue

    2017-08-01

    Glioblastoma is a highly invasive and challenging tumor of the central nervous system. The mutation/deletion of the tumor suppressor phosphatase and tensin homolog (PTEN) gene is the main genetic change identified in glioblastomas. PTEN plays a critical role in tumorigenesis and has been shown to be an important therapeutic target. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 is commonly used to inhibit glioma cell growth via regulation of the PI3K/AKT signaling pathway. In this study, we examined the growth inhibitory effects of a combinatorial therapy of adenoviral-mediated PTEN (Ad-PTEN) and LY294002 on LN229 and U251 glioma cells in vitro and on tumor xenografts in vivo. In vitro, LN229 and U251 glioma cells were treated by combinatorial therapy with Ad-PTEN and LY294002. The growth ability was determined by MTT assay. The cell cycle distribution was analyzed by flow cytometry. Cell invasive ability was analyzed by transwell invasion assay and cell apoptosis analysis via FITC-Annexin V analysis. In vivo, U251 subcutaneous glioblastoma xenograft was used to assay anti-tumor effect of combinatorial therapy with Ad-PTEN and LY294002 by mean volume of tumors, immunohistochemistry and TUNEL method. The combinatorial treatment clearly suppressed cell proliferation, arrested the cell cycle, reduced cell invasion and promoted cell apoptosis compared with the Ad-PTEN or LY294002 treatment alone. The treatment worked by inhibiting the PI3K/AKT pathway. In addition, the growth of U251 glioma xenografts treated with the combination of Ad-PTEN and LY294002 was significantly inhibited compared with those treated with Ad-PTEN or LY294002 alone. Our data indicated that the combination of Ad-PTEN and LY294002 effectively suppressed the malignant growth of human glioma cells in vitro and in tumor xenografts, suggesting a promising new approach for glioma gene therapy that warrants further investigation.

  10. Adenoviral delivery of pan-caspase inhibitor p35 enhances bystander killing by P450 gene-directed enzyme prodrug therapy using cyclophosphamide+

    Doloff, Joshua C; Su, Ting; Waxman, David J

    2010-01-01

    Cytochrome P450-based suicide gene therapy for cancer using prodrugs such as cyclophosphamide (CPA) increases anti-tumor activity, both directly and via a bystander killing mechanism. Bystander cell killing is essential for the clinical success of this treatment strategy, given the difficulty of achieving 100% efficient gene delivery in vivo using current technologies. Previous studies have shown that the pan-caspase inhibitor p35 significantly increases CPA-induced bystander killing by tumor cells that stably express P450 enzyme CYP2B6 (Schwartz et al, (2002) Cancer Res. 62: 6928-37). To further develop this approach, we constructed and characterized a replication-defective adenovirus, Adeno-2B6/p35, which expresses p35 in combination with CYP2B6 and its electron transfer partner, P450 reductase. The expression of p35 in Adeno-2B6/p35-infected tumor cells inhibited caspase activation, delaying the death of the CYP2B6 'factory' cells that produce active CPA metabolites, and increased bystander tumor cell killing compared to that achieved in the absence of p35. Tumor cells infected with Adeno-2B6/p35 were readily killed by cisplatin and doxorubicin, indicating that p35 expression is not associated with acquisition of general drug resistance. Finally, p35 did not inhibit viral release when the replication-competent adenovirus ONYX-017 was used as a helper virus to facilitate co-replication and spread of Adeno-2B6/p35 and further increase CPA-induced bystander cell killing. The introduction of p35 into gene therapeutic regimens constitutes an effective approach to increase bystander killing by cytochrome P450 gene therapy. This strategy may also be used to enhance other bystander cytotoxic therapies, including those involving the production of tumor cell toxic protein products

  11. Appropriate strategies.

    Halty, M

    1979-01-01

    Technology strategies are concerned with the production, distribution, and consumption of technology. Observation of less developed countries (LDCs) and international organizations shows that little attention is given to the development of a technology strategy. LDCs need to formulate a strategy of self-reliant technological development for the next decade. They should no longer be content to stand in a technologically dependent relationship to the developed countries. Such strategies must balance the ratio between investment in indigenous technologies and expenditure for foreign technology. The strategies change according to the level of industrialization achieved. The following considerations come into development of technology strategies: 1) determination of an appropriate balance among the accumulation, consumption, and distribution of technology; 2) the amount and level of government support; and 3) the balance between depth and breadth of technology to be encouraged.

  12. Environmental strategy

    Zabkar, Vesna; Cater, Tomaz; Bajde, Domen

    2013-01-01

    perspective, appropriate environmental strategies in compliance with environmental requirements aim at building competitive advantages through sustainable development. There is no universal “green” strategy that would be appropriate for each company, regardless of its market requirements and competitive......Environmental issues and the inclusion of environmental strategies in strategic thinking is an interesting subject of investigation. In general, managerial practices organized along ecologically sound principles contribute to a more environmentally sustainable global economy. From the managerial...

  13. Enhanced Differentiation of Three-Gene-Reprogrammed Induced Pluripotent Stem Cells into Adipocytes via Adenoviral-Mediated PGC-1α Overexpression

    Yi-Jen Chen

    2011-11-01

    Full Text Available Induced pluripotent stem cells formed by the introduction of only three factors, Oct4/Sox2/Klf4 (3-gene iPSCs, may provide a safer option for stem cell-based therapy than iPSCs conventionally introduced with four-gene iPSCs. Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α plays an important role during brown fat development. However, the potential roles of PGC-1α in regulating mitochondrial biogenesis and the differentiation of iPSCs are still unclear. Here, we investigated the effects of adenovirus-mediated PGC-1α overexpression in 3-gene iPSCs. PGC-1α overexpression resulted in increased mitochondrial mass, reactive oxygen species production, and oxygen consumption. Microarray-based bioinformatics showed that the gene expression pattern of PGC-1α-overexpressing 3-gene iPSCs resembled the expression pattern observed in adipocytes. Furthermore, PGC-1α overexpression enhanced adipogenic differentiation and the expression of several brown fat markers, including uncoupling protein-1, cytochrome C, and nuclear respiratory factor-1, whereas it inhibited the expression of the white fat marker uncoupling protein-2. Furthermore, PGC-1α overexpression significantly suppressed osteogenic differentiation. These data demonstrate that PGC-1α directs the differentiation of 3-gene iPSCs into adipocyte-like cells with features of brown fat cells. This may provide a therapeutic strategy for the treatment of mitochondrial disorders and obesity.

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

    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.

  15. Evaluation Strategy

    Coto Chotto, Mayela; Wentzer, Helle; Dirckinck-Holmfeld, Lone

    2009-01-01

    The paper presents an evaluation strategy based on deliberate ideals and principles of dialogue design. The evaluation strategy is based on experiential phenomenology taking the point of departure for design and evaluation processes in the experienced practitioners themselves. The article present...... the evaluation strategy and methodology of a research project Making Online Path to Enter new Markets, MOPEM. It is an EU-research project with partners from different Educational Institutions of Technology and Business in five European Countries.......The paper presents an evaluation strategy based on deliberate ideals and principles of dialogue design. The evaluation strategy is based on experiential phenomenology taking the point of departure for design and evaluation processes in the experienced practitioners themselves. The article presents...

  16. Safety strategy

    Schultheiss, G.F.

    1980-01-01

    The basis for safety strategy in nuclear industry and especially nuclear power plants is the prevention of radioactivity release inside or outside of the technical installation. Therefore either technical or administrative measures are combined to a general strategy concept. This introduction will explain in more detail the following topics: - basic principles of safety - lines of assurance (LOA) - defense in depth - deterministic and probabilistic methods. This presentation is seen as an introduction to the more detailed discussion following in this course, nevertheless some selected examples will be used to illustrate the aspects of safety strategy development although they might be repeated later on. (orig.)

  17. Export strategy

    Knudsen, Thorbjørn; Koed Madsen, Tage

    2002-01-01

    It is argued here that traditional export strategy research (encompassing the study of internationalization processes and export performance) is characterized by weak theoretical foundations and could benefit from a reorientation towards a dynamic capabilities perspective (DCP). We seek to draw...... on insights from DCP in order to devise a theoretical basis that could enrich export strategy research. Although our development of DCP insights builds on previous work, it also adds a crucial distinction between knowledge stocks and informational architecture. Changes in architecture are of greater...... importance. Following this elaboration of the dynamic capabilities perspective, we outline some implications and guidelines for future export strategy research....

  18. Malonyl-CoA decarboxylase (MCD) is differentially regulated in subcellular compartments by 5'AMP-activated protein kinase (AMPK). Studies using H9c2 cells overexpressing MCD and AMPK by adenoviral gene transfer technique.

    Sambandam, Nandakumar; Steinmetz, Michael; Chu, Angel; Altarejos, Judith Y; Dyck, Jason R B; Lopaschuk, Gary D

    2004-07-01

    Malonyl-CoA, a potent inhibitor of carnitine pamitoyl transferase-I (CPT-I), plays a pivotal role in fuel selection in cardiac muscle. Malonyl-CoA decarboxylase (MCD) catalyzes the degradation of malonyl-CoA, removes a potent allosteric inhibition on CPT-I and thereby increases fatty acid oxidation in the heart. Although MCD has several Ser/Thr phosphorylation sites, whether it is regulated by AMP-activated protein kinase (AMPK) has been controversial. We therefore overexpressed MCD (Ad.MCD) and constitutively active AMPK (Ad.CA-AMPK) in H9c2 cells, using an adenoviral gene delivery approach in order to examine if MCD is regulated by AMPK. Cells infected with Ad.CA-AMPK demonstrated a fourfold increase in AMPK activity as compared with control cells expressing green fluorescent protein (Ad.GFP). MCD activity increased 40- to 50-fold in Ad.MCD + Ad.GFP cells when compared with Ad.GFP control. Co-expressing AMPK with MCD further augmented MCD expression and activity in Ad.MCD + Ad.CA-AMPK cells compared with the Ad.MCD + Ad.GFP control. Subcellular fractionation further revealed that 54.7 kDa isoform of MCD expression was significantly higher in cytosolic fractions of Ad.MCD + Ad.CA-AMPK cells than of the Ad.MCD +Ad.GFP control. However, the MCD activities in cytosolic fractions were not different between the two groups. Interestingly, in the mitochondrial fractions, MCD activity significantly increased in Ad.MCD + Ad.CA-AMPK cells when compared with Ad.MCD + Ad.GFP cells. Using phosphoserine and phosphothreonine antibodies, no phosphorylation of MCD by AMPK was observed. The increase in MCD activity in mitochondria-rich fractions of Ad.MCD + Ad.CA-AMPK cells was accompanied by an increase in the level of the 50.7 kDa isoform of MCD protein in the mitochondria. This differential regulation of MCD expression and activity in the mitochondria by AMPK may potentially regulate malonyl-CoA levels at sites nearby CPT-I on the mitochondria.

  19. CSR STRATEGIES

    LAURENTIU BARANGA; ION STEGAROIU

    2011-01-01

    Corporate Social Responsibility (CSR) has got three components: economic responsibility of shareholders, corporate environmental responsibility, corporate responsibility of the society. Each component of the CSR has its own features, according to which adequate individual behaviour is established. Knowing these features is very important in CSR strategy development.

  20. Clinical adenoviral gene therapy for prostate cancer

    Schenk, E.; Essand, M.; Bangma, Ch. H.; Barber, Ch.; Behr, J.-P.; Briggs, S.; Carlisle, R.; Cheng, W.-S.; Danielsson, A.; Dautzenberg, I. J. C.; Dzojic, H.; Erbacher, P.; Fisher, K.; Frazier, A.; Georgopoulos, L. J.; Hoeben, R.; Kochanek, S.; Koppers-Lalic, D.; Kraaij, R.; Kreppel, F.; Lindholm, L.; Magnusson, M.; Maitland, N.; Neuberg, P.; Nilsson, B.; Ogris, M.; Remy, J.-S.; Scaife, M.; Schooten, E.; Seymour, L.; Totterman, T.; Uil, T. G.; Ulbrich, Karel; Veldhoven-Zweistra, J. L. M.; de Vrij, J.; van Weerden, W.; Wagner, E.; Willemsen, R.

    2010-01-01

    Roč. 21, č. 7 (2010), s. 807-813 ISSN 1043-0342 EU Projects: European Commission(XE) 512087 - GIANT Keywords : adenovirus * gene delivery * prostate cancer Subject RIV: CD - Macromolecular Chemistry Impact factor: 4.829, year: 2010

  1. Use of adenoviral vectors as veterinary vaccines.

    Ferreira, T B; Alves, P M; Aunins, J G; Carrondo, M J T

    2005-10-01

    Vaccines are the most effective and inexpensive prophylactic tool in veterinary medicine. Ideally, vaccines should induce a lifelong protective immunity against the target pathogen while not causing clinical or pathological signs of diseases in the vaccinated animals. However, such ideal vaccines are rare in the veterinary field. Many vaccines are either of limited effectiveness or have harmful side effects. In addition, there are still severe diseases with no effective vaccines. A very important criterion for an ideal vaccine in veterinary medicine is low cost; this is especially important in developing countries and even more so for poultry vaccination, where vaccines must sell for a few cents a dose. Traditional approaches include inactivated vaccines, attenuated live vaccines and subunit vaccines. Recently, genetic engineering has been applied to design new, improved vaccines. Adenovirus vectors are highly efficient for gene transfer in a broad spectrum of cell types and species. Moreover, adenoviruses often induce humoral, mucosal and cellular immune responses to antigens encoded by the inserted foreign genes. Thus, adenoviruses have become a vector of choice for delivery and expression of foreign proteins for vaccination. Consequently, the market requirements for adenovirus vaccines are increasing, creating a need for production methodologies of concentrated vectors with warranted purity and efficacy. This review summarizes recent developments and approaches of adenovirus production and purification as the application of these vectors, including successes and failures in clinical applications to date.

  2. DOT strategies versus orbiter strategies

    Rutten, R.J.

    2001-01-01

    The Dutch Open Telescope is a high-resolution solar imager coming on-line at La Palma. The definition of the DOT science niche, strategies, and requirements resemble Solar Orbiter considerations and deliberations. I discuss the latter in the light of the former, and claim that multi-line observation

  3. Study Strategies

    Nielsen, Camilla Kirketerp; Noer, Vibeke Røn

    and theory forms the basis of the research. Veterinary students have been followed through alternating learning contexts referring to both the scholastic academic classrooms and workplaces in commercial pig herds as well as to group work and game-based situations in a mandatory master course - ”the pig...... as a student´ and the process of professionalization. By maintaining the position of focusing upon the education as a situated and formative trajectory, the comparative analysis shows how students in profession-oriented educational settings manage the challenges of education and use study strategies......ID: 1277 / 22 SES 06 B: 2 22. Research in Higher Education Format of Presentation: Paper Alternative EERA Network: 19. Ethnography Topics: NW 22: Teaching, learning and assessment in higher education Keywords: Profession-oriented learning, study strategies, professionalisation processes...

  4. Arbitrage strategy

    Kardaras, Constantinos

    2010-01-01

    An arbitrage strategy allows a financial agent to make certain profit out of nothing, i.e., out of zero initial investment. This has to be disallowed on economic basis if the market is in equilibrium state, as opportunities for riskless profit would result in an instantaneous movement of prices of certain financial instruments. The principle of not allowing for arbitrage opportunities in financial markets has far-reaching consequences, most notably the option-pricing and hedging formulas in c...

  5. Marketing Strategy

    Andrýsková, Hana

    2013-01-01

    The aim of this thesis is to examine current marketing efforts of AARON - the leading seller of digital cameras. I will analyze current marketing tools and suggest improvements in efficiency and effectiveness of these tools. Marketing strategy is a method of managing and coordinating efforts in marketing field so that the goals can be reached. The aim is to increase sales, turnover, revenues, profits, drive out competition and also to build up a corporate image and corporate culture. I will a...

  6. Transfusion strategy

    Jakobsen, Carl-Johan

    2014-01-01

    Blood transfusion is associated with increased morbidity and mortality and numerous reports have emphasised the need for reduction. Following this there is increased attention to the concept of patient blood management. However, bleeding is relatively common following cardiac surgery and is furth....... In conclusion the evidence supports that each institution establishes its own patient blood management strategy to both conserve blood products and maximise outcome.......Blood transfusion is associated with increased morbidity and mortality and numerous reports have emphasised the need for reduction. Following this there is increased attention to the concept of patient blood management. However, bleeding is relatively common following cardiac surgery and is further...

  7. NATO strategy

    Tarr, D.W.

    1988-01-01

    Nuclear weapons are for NATO both the primary instrument for deterring a nuclear attack and the fall-back option if, in the event of a conventional assault, NATO's non-nuclear defence forces cannot hold. The dilemma of depending upon potentially self-destructive nuclear responses if deterrence fails and defence falters has always haunted NATO strategy, but after the Soviets achieved nuclear parity with the United States, this dilemma became more intensely perceived. Now the credibility, viability, acceptability, sensibility and morality of nuclear weapons for deterrence and defence are increasingly at issue. As a result, an increasing variety of non-nuclear (conventional) alternatives are being advanced to replace or supplement nuclear deterrence for the Alliance. The thrust of the author of this paper remarks is to attempt to apply the definitions, requirements, and other key conceptual distinctions of nuclear deterrence found in the body of western strategic literature to three categories of non-nuclear alternatives currently in vogue: strengthened conventional forces; deployment of new, high-technology non-nuclear weapons; and adoption of an offensive manoeuvre strategy. Let me, therefore, begin by listing the basic definitions, concepts and apparent requirements of deterrence which the deterrence theory literature offers

  8. Implementation Strategy

    1983-01-01

    Meeting the identified needs of Earth science requires approaching EOS as an information system and not simply as one or more satellites with instruments. Six elements of strategy are outlined as follows: implementation of the individual discipline missions as currently planned; use of sustained observational capabilities offered by operational satellites without waiting for the launch of new mission; put first priority on the data system; deploy an Advanced Data Collection and Location System; put a substantial new observing capability in a low Earth orbit in such a way as to provide for sustained measurements; and group instruments to exploit their capabilities for synergism; maximize the scientific utility of the mission; and minimize the costs of implementation where possible.

  9. Interactive Control System, Intended Strategy, Implemented Strategy dan Emergent Strategy

    Tubagus Ismail

    2012-09-01

    Full Text Available The purpose of this study was to examine the relationship between management control system (MCS and strategy formation processes, namely: intended strategy, emergent strategy and impelemented strategy. The focus of MCS in this study was interactive control system. The study was based on Structural Equation Modeling (SEM as its multivariate analyses instrument. The samples were upper middle managers of manufacturing company in Banten Province, DKI Jakarta Province and West Java Province. AMOS Software 16 program is used as an additional instrument to resolve the problem in SEM modeling. The study found that interactive control system brought a positive and significant influence on Intended strategy; interactive control system brought a positive and significant influence on implemented strategy; interactive control system brought a positive and significant influence on emergent strategy. The limitation of this study is that our empirical model only used one way relationship between the process of strategy formation and interactive control system.

  10. Interactive Control System, Intended Strategy, Implemented Strategy dan Emergent Strategy

    Tubagus Ismail; Darjat Sudrajat

    2012-01-01

    The purpose of this study was to examine the relationship between management control system (MCS) and strategy formation processes, namely: intended strategy, emergent strategy and impelemented strategy. The focus of MCS in this study was interactive control system. The study was based on Structural Equation Modeling (SEM) as its multivariate analyses instrument. The samples were upper middle managers of manufacturing company in Banten Province, DKI Jakarta Province and West Java Province. AM...

  11. RECENT ADVANCES IN STRATEGIES FOR IMMUNOTHERAPY OF HUMAN PAPILLOMAVIRUS-INDUCED LESIONS

    Kanodia, Shreya; Da Silva, Diane M.; Kast, W. Martin

    2016-01-01

    Human papillomavirus (HPV)-induced lesions are distinct in that they have targetable foreign antigens, the expression of which is necessary to maintain the cancerous phenotype. Hence, they pose as a very attractive target for “proof of concept” studies in the development of therapeutic vaccines. This review will focus on the most recent clinical trials for the immunotherapy of mucosal and cutaneous HPV-induced lesions as well as emerging therapeutic strategies that have been tested in pre-clinical models for HPV-induced lesions. Progress in peptide-based vaccines, DNA-based vaccines, viral/bacterial vector-based vaccines, immune response modifiers, photodynamic therapy and T cell receptor based therapy for HPV will be discussed. PMID:17973257

  12. Analytical strategies for phosphoproteomics

    Thingholm, Tine E; Jensen, Ole N; Larsen, Martin R

    2009-01-01

    sensitive and specific strategies. Today, most phosphoproteomic studies are conducted by mass spectrometric strategies in combination with phospho-specific enrichment methods. This review presents an overview of different analytical strategies for the characterization of phosphoproteins. Emphasis...

  13. Strategy Development in Organisations

    Sørensen, Lene

    1999-01-01

    There exist certain ambiguities with the converging fields of information technology and organisational strategy development. The term "IT strategy" has evolved and reflects in some respects this confusion. This paper discusses some of the ambiguities and difficulties of the term "IT strategy......" as used in practice and literature. Emphasis is put on how the term is related to the problem, the organisation, the strategy process and the practical way of methodologically developing the strategy. Finally, alternative strategy developing perspectives are presented....

  14. Comparison of four support-vector based function approximators

    de Kruif, B.J.; de Vries, Theodorus J.A.

    2004-01-01

    One of the uses of the support vector machine (SVM), as introduced in V.N. Vapnik (2000), is as a function approximator. The SVM and approximators based on it, approximate a relation in data by applying interpolation between so-called support vectors, being a limited number of samples that have been

  15. Development and applications of VSV vectors based on cell tropism

    Hideki eTani

    2012-01-01

    Full Text Available Viral vectors have been available in various fields such as medical and biological research or gene therapy applications. Targeting vectors pseudotyped with distinct viral envelope proteins that influence cell tropism and transfection efficiency is a useful tool not only for examining entry mechanisms or cell tropisms but also for vaccine vector development. Vesicular stomatitis virus (VSV is an excellent candidate for development as a pseudotype vector. A recombinant VSV lacking its own envelope (G gene has been used to produce a pseudotype or recombinant VSV possessing the envelope proteins of heterologous viruses. These viruses possess a reporter gene instead of a VSV G gene in their genome, and therefore it is easy to evaluate their infectivity in the study of viral entry, including identification of viral receptors. Furthermore, advantage can be taken of a property of the pseudotype VSV, which is competence for single-round infection, in handling many different viruses that are either difficult to amplify in cultured cells or animals or that require specialized containment facilities. Here we describe procedures for producing pseudotype or recombinant VSVs and a few of the more prominent examples from among envelope viruses, such as hepatitis C virus, Japanese encephalitis virus, baculovirus, and hemorrhagic fever viruses.

  16. Chikungunya Virus Vaccines: Viral Vector-Based Approaches.

    Ramsauer, Katrin; Tangy, Frédéric

    2016-12-15

    In 2013, a major chikungunya virus (CHIKV) epidemic reached the Americas. In the past 2 years, >1.7 million people have been infected. In light of the current epidemic, with millions of people in North and South America at risk, efforts to rapidly develop effective vaccines have increased. Here, we focus on CHIKV vaccines that use viral-vector technologies. This group of vaccine candidates shares an ability to potently induce humoral and cellular immune responses by use of highly attenuated and safe vaccine backbones. So far, well-described vectors such as modified vaccinia virus Ankara, complex adenovirus, vesicular stomatitis virus, alphavirus-based chimeras, and measles vaccine Schwarz strain (MV/Schw) have been described as potential vaccines. We summarize here the recent data on these experimental vaccines, with a focus on the preclinical and clinical activities on the MV/Schw-based candidate, which is the first CHIKV-vectored vaccine that has completed a clinical trial. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  17. EVE: Explainable Vector Based Embedding Technique Using Wikipedia

    Qureshi, M. Atif; Greene, Derek

    2017-01-01

    We present an unsupervised explainable word embedding technique, called EVE, which is built upon the structure of Wikipedia. The proposed model defines the dimensions of a semantic vector representing a word using human-readable labels, thereby it readily interpretable. Specifically, each vector is constructed using the Wikipedia category graph structure together with the Wikipedia article link structure. To test the effectiveness of the proposed word embedding model, we consider its usefulne...

  18. Space vector-based analysis of overmodulation in triangle ...

    methods such as vector control or field oriented control are used for fast dynamic response .... This average voltage vector falls in sector-I as shown in figure 5 for .... The dwell times T1, T2 and Tz can be derived using volt-second balance.

  19. A measure of association between vectors based on "similarity covariance"

    Pascual-Marqui, Roberto D.; Lehmann, Dietrich; Kochi, Kieko; Kinoshita, Toshihiko; Yamada, Naoto

    2013-01-01

    The "maximum similarity correlation" definition introduced in this study is motivated by the seminal work of Szekely et al on "distance covariance" (Ann. Statist. 2007, 35: 2769-2794; Ann. Appl. Stat. 2009, 3: 1236-1265). Instead of using Euclidean distances "d" as in Szekely et al, we use "similarity", which can be defined as "exp(-d/s)", where the scaling parameter s>0 controls how rapidly the similarity falls off with distance. Scale parameters are chosen by maximizing the similarity corre...

  20. Vaccination with an adenoviral vector encoding the tumor antigen directly linked to invariant chain induces potent CD4(+) T-cell-independent CD8(+) T-cell-mediated tumor control

    Sorensen, Maria R; Holst, Peter J; Pircher, Hanspeter

    2009-01-01

    of the vaccine antigen to invariant chain (Ii). To evaluate this strategy we used a mouse model, in which an immunodominant epitope (GP33) of the LCMV glycoprotein (GP) represents the tumor-associated neoantigen. Prophylactic vaccination of C57BL/6 mice with a replication-deficient human adenovirus 5 vector...... encoding GP linked to Ii (Ad-Ii-GP) resulted in complete protection against GP33-expressing B16.F10 tumors. Therapeutic vaccination with Ad-Ii-GP delayed tumor growth by more than 2 wk compared with sham vaccination. Notably, therapeutic vaccination with the linked vaccine was significantly better than...... the tumor degradation. Finally, Ad-Ii-GP but not Ad-GP vaccination can break the immunological non-reactivity in GP transgenic mice indicating that our vaccine strategy will prove efficient also against endogenous tumor antigens....

  1. Strategy and space

    Jensen, Per Anker

    2011-01-01

    in different periods and how these strategies can be related to the general conditions of the corporation. The strategic uncertainty of the corporation is investigated as a main determining factor for changes in space strategy based on theories of the relations between strategy and place. These theories......The article is based on results from a research project on space strategies and building values, which included a major case study of the development of facilities for the Danish Broadcasting Corporation over time. The focus is to identify, how different space strategies have been implemented...... include that corporations follows one of the three generic space strategies: Incrementalism, standardization, and value-based strategy. Among the conclusion are, that the space strategies mostly changes between incremental and value-based strategies, but one period of standardization was identified...

  2. Getting genetic access to natural adenovirus genomes to explore vector diversity.

    Zhang, Wenli; Ehrhardt, Anja

    2017-10-01

    Recombinant vectors based on the human adenovirus type 5 (HAdV5) have been developed and extensively used in preclinical and clinical studies for over 30 years. However, certain restrictions of HAdV5-based vectors have limited their clinical applications because they are rather inefficient in specifically transducing cells of therapeutic interest that lack the coxsackievirus and adenovirus receptor (CAR). Moreover, enhanced vector-associated toxicity and widespread preexisting immunity have been shown to significantly hamper the effectiveness of HAdV-5-mediated gene transfer. However, evolution of adenoviruses in the natural host is driving the generation of novel types with altered virulence, enhanced transmission, and altered tissue tropism. As a consequence, an increasing number of alternative adenovirus types were identified, which may represent a valuable resource for the development of novel vector types. Thus, researchers are focusing on the other naturally occurring adenovirus types, which are structurally similar but functionally different from HAdV5. To this end, several strategies have been devised for getting genetic access to adenovirus genomes, resulting in a new panel of adenoviral vectors. Importantly, these vectors were shown to have a host range different from HAdV5 and to escape the anti-HAdV5 immune response, thus underlining the great potential of this approach. In summary, this review provides a state-of-the-art overview of one essential step in adenoviral vector development.

  3. De Nederlandse cybersecurity strategie

    Luiijf, H.A.M.

    2011-01-01

    Recent werd de Nederlandse 'Nationale Cybersecurity Strategie: Slagkracht door samenwerking' openbaar gemaakt. Wat zijn de hoofdpunten van deze strategie en wat betekend dat voor de burgers, bedrijven, overheid, afnemers of leveranciers van informatie- en communicatie technologie?

  4. Radioactive Waste Management Strategy

    2002-01-01

    This strategy defines methods and means how collect, transport and bury radioactive waste safely. It includes low level radiation waste and high level radiation waste. In the strategy are foreseen main principles and ways of storage radioactive waste

  5. National Privacy Research Strategy

    Networking and Information Technology Research and Development, Executive Office of the President — On July 1, NITRD released the National Privacy Research Strategy. Research agencies across government participated in the development of the strategy, reviewing...

  6. US Strategy for Cyberspace

    Veazie, Arnold

    2003-01-01

    .... This strategic research paper analyzes the President's National Strategy to Secure Cyberspace to determine whether it effectively provides solutions for securing cyberspace. It concludes by proposing an alternative strategy for securing cyberspace.

  7. POSITIONING STRATEGIES DEVELOPMENT

    Shakhshir Ghassan

    2014-07-01

    Full Text Available The positioning strategy has suffered serious changes in the last few decades, being influenced by the rapid development of competition and the growing focus on specific traits belonging to the market, to the consumer or to the product. The purpose of this paper is to present the developments of theoretical positioning strategies and the orientation from more simple, product oriented strategies, to ones more oriented towards the client and with a briefer period of time. The world is moving in a much faster pace than in the past, thanks to communication development so companies are obliged to adopt more specific strategies in order for them to be effective. This essay represents a literary review presenting a documentary research within the scientific articles and strategy and positioning books. The paper begins with the analysis of company strategies and the marketing strategies in general. The first author to group the product positioning strategies is Porter with his three generic strategies. Following the development of brands and because of the lack of competitiveness in the simple generic positioning strategies, this paper has also presented the newer positioning strategies proposed by Kotler, Treacy & Wiersema, and also more complex ones such as Bowman's Strategy Clock and Blankson and Kalafatis positioning strategy based on the type of the consumer. The fast expansion of local brands in all categories has led to mistakes in positioning strategies, categories also presented in the current essay. The results of this study show that new positioning strategies are more and more based on the consumer and market segments and on the product specification - which have also evolved in the last decades. Adaptability to fast changes in the competitive market will represent the future positioning strategies.

  8. Digital Content Strategies

    Halbheer, Daniel; Stahl, Florian; Koenigsberg, Oded; Lehmann, Donald R

    2013-01-01

    This paper studies content strategies for online publishers of digital information goods. It examines sampling strategies and compares their performance to paid content and free content strategies. A sampling strategy, where some of the content is offered for free and consumers are charged for access to the rest, is known as a "metered model" in the newspaper industry. We analyze optimal decisions concerning the size of the sample and the price of the paid content when sampling serves the dua...

  9. Manufacturing knowledge management strategy

    Shaw , Duncan; Edwards , John

    2006-01-01

    Abstract The study sought to understand the components of knowledge management strategy from the perspective of staff in UK manufacturing organisations. To analyse this topic we took an empirical approach and collaborated with two manufacturing organisations. Our main finding centres on the key components of a knowledge management strategy, and the relationships between it and manufacturing strategy and corporate strategy. Other findings include: the nature of knowledge in manufact...

  10. Strategy Instruction in Mathematics.

    Goldman, Susan R.

    1989-01-01

    Experiments in strategy instruction for mathematics have been conducted using three models (direct instruction, self-instruction, and guided learning) applied to the tasks of computation and word problem solving. Results have implications for effective strategy instruction for learning disabled students. It is recommended that strategy instruction…

  11. Online Strategy Games.

    Dye, Bryan

    2002-01-01

    A strategy game is an online interactive game that requires thinking in order to be played at its best and whose winning strategy is not obvious. Provides information on strategy games that are written in Java or JavaScript and freely available on the web. (KHR)

  12. Backbone amide linker strategy

    Shelton, Anne Pernille Tofteng; Jensen, Knud Jørgen

    2013-01-01

    In the backbone amide linker (BAL) strategy, the peptide is anchored not at the C-terminus but through a backbone amide, which leaves the C-terminal available for various modifications. This is thus a very general strategy for the introduction of C-terminal modifications. The BAL strategy...

  13. Strategies Against Poverty.

    Riessman, Frank

    The major antipoverty strategies of the 1960's are analyzed--the conflict model of Alinsky, the welfare crisis approach of Cloward and Piven, and the new careers viewpoint of Riessman and Pearl. The latter strategy is said to have a greater "multiplier effect" on poverty than other approaches. Discussed are such specific strategies in…

  14. Elevator Control Strategies

    Ceder, Frederick; Nordin, Alexandra

    2013-01-01

    The purpose of this essay is to investigate if it is eective to switch strategies for elevators during one day in an oce building. This essay describes some of the strategies in use today, followed by a comparison and analysis of two of the strategies described. We have also implemented optimizations to one of these strategies. From our test results we can conclude that our optimized strategy worked and produced better results on average waiting time and total traveling time than the two stra...

  15. Contemporary evolution strategies

    Bäck, Thomas; Krause, Peter

    2013-01-01

    Evolution strategies have more than 50 years of history in the field of evolutionary computation. Since the early 1990s, many algorithmic variations of evolution strategies have been developed, characterized by the fact that they use the so-called derandomization concept for strategy parameter adaptation. Most importantly, the covariance matrix adaptation strategy (CMA-ES) and its successors are the key representatives of this group of contemporary evolution strategies. This book provides an overview of the key algorithm developments between 1990 and 2012, including brief descriptions of the a

  16. Creativity and Strategy Development

    Sørensen, Lene Tolstrup; Vidal, Rene Victor Valqui

    This paper focus on how creative thinking, processes and methods can support the strategy development and planning process in organisations. First, several fundamental concepts related to both strategy development and planning are stipulated. In addition, the concept of living organisation...... will be discussed as well as the interaction between strategy and creativity. Then, methodological ideas to support the strategy making process are presented enhancing the use of creative methods and tools. Finally, a case study related to the development of a strategy for organisational development using...... creativity tools is discussed....

  17. Strategies in PRholog

    Besik Dundua

    2010-01-01

    Full Text Available PRholog is an experimental extension of logic programming with strategic conditional transformation rules, combining Prolog with Rholog calculus. The rules perform nondeterministic transformations on hedges. Queries may have several results that can be explored on backtracking. Strategies provide a control on rule applications in a declarative way. With strategy combinators, the user can construct more complex strategies from simpler ones. Matching with four different kinds of variables provides a flexible mechanism of selecting (subterms during execution. We give an overview on programming with strategies in PRholog and demonstrate how rewriting strategies can be expressed.

  18. Strategy as Texts

    Obed Madsen, Søren

    of the strategy into four categories. Second, the managers produce new texts based on the original strategy document by using four different ways of translation models. The study’s findings contribute to three areas. Firstly, it shows that translation is more than a sociological process. It is also...... a craftsmanship that requires knowledge and skills, which unfortunately seems to be overlooked in both the literature and in practice. Secondly, it shows that even though a strategy text is in singular, the translation makes strategy plural. Thirdly, the article proposes a way to open up the black box of what......This article shows empirically how managers translate a strategy plan at an individual level. By analysing how managers in three organizations translate strategies, it identifies that the translation happens in two steps: First, the managers decipher the strategy by coding the different parts...

  19. Pembajakan Produk: Problema, Strategi dan Antisipasi Strategi

    Anas Hidayat

    2009-08-01

    Full Text Available Pemakaian ‘merek’ dalam dunia perdagangan telah dilakukan sejak jaman Yunani kuno. Demikian pula peniruan atau pembajakan terhadap produk bermerek. Di abad pertengahan, ancaman sangsi terhadap pe¬langgaran penggunaan merek juga telah dilakukan, misalnya ancaman hukuman gantung bagi para pelaku pem¬bajakan.Di era bisnis modern, bisnis produk bajakan menjadi semakin merajalela dengan skala internasional. Kerjasama internasional antar Negara telah dilakukan dalam menggalang pemberantasan dengan menghasilkan produk-produk hukum penangkalnya. Demikian pula upaya pemerintah domestik masing-masing negara di dunia di bawah koordinasi WTO, telah dan sebagian masih dalam proses menerapkan hukum perlindungan HKI. Misal¬nya Indonesia mencanangkan pemberlakuan UU HKI sejak tahun 2000.Meskipun penelitian di bidang pembajakan produk sudah mulai mendapatkan apresiasi dari para ahli, namun penelitian yang dikaitkan dengan ilmu pemasaran masih tergolong baru, dan hasilnya masih bersifat spo¬radis, belum menemukan konsep teori yang kuat, baik penelitian pada sisi permintaan maupun sisi penawaran produk. Penelitian sisi penawaran memang lebih dahulu mendapatkan perhatian dari para ahli dengan meng¬indentifikasikan strategi masuk pasar para pembajak dan memformulasikan anti strategi pembajakan produk. Namun anti strategi pembajakan produk belum menunjukkan hasil yang efektif, jika dilihat dari kenyataan di lapa¬ngan bahwa pembajakan masih merajalela, terutama di pasar Asia (Callan 1998.Kata Kunci: Pembajakan produk, strategi pembajakan, strategi anti pembajakan

  20. Discursive strategies of strategy in public organizations

    Lystbæk, Christian Tang; Holmgren, Jens; Friis, Ole Uhrskov

    In the last decades, private sector principles and policies have spread into public management. This has fuelled the growth of strategic practices in public service organizations. Although public service organizations typically do not exist in markets or have directs competitors, they tend...... conceptual structures in discourses of strategy in public management. Based on a focus group interview with six management consultants working in a municipality in Denmark, we identify two dimensions regarding how strategy making in public service organizations is given discursive legitimacy. One dimension...

  1. Intermittent search strategies

    Bénichou, O.; Loverdo, C.; Moreau, M.; Voituriez, R.

    2011-01-01

    This review examines intermittent target search strategies, which combine phases of slow motion, allowing the searcher to detect the target, and phases of fast motion during which targets cannot be detected. It is first shown that intermittent search strategies are actually widely observed at various scales. At the macroscopic scale, this is, for example, the case of animals looking for food; at the microscopic scale, intermittent transport patterns are involved in a reaction pathway of DNA-binding proteins as well as in intracellular transport. Second, generic stochastic models are introduced, which show that intermittent strategies are efficient strategies that enable the minimization of search time. This suggests that the intrinsic efficiency of intermittent search strategies could justify their frequent observation in nature. Last, beyond these modeling aspects, it is proposed that intermittent strategies could also be used in a broader context to design and accelerate search processes.

  2. POSITIONING STRATEGIES DEVELOPMENT

    Shakhshir Ghassan

    2014-01-01

    The positioning strategy has suffered serious changes in the last few decades, being influenced by the rapid development of competition and the growing focus on specific traits belonging to the market, to the consumer or to the product. The purpose of this paper is to present the developments of theoretical positioning strategies and the orientation from more simple, product oriented strategies, to ones more oriented towards the client and with a briefer period of time. The world is moving in...

  3. Interactive Strategy-Making

    Andersen, Torben Juul

    2015-01-01

    This article outlines an interactive strategy-making model that combines central reasoning with ongoing learning from decentralised responses. The management literature often presents strategy as implementing an optimal plan identified through rational analysis and ascribes potential shortcomings...... to failed communication and execution of the planned actions. However, effective strategy-making comprises both central reasoning from forward-looking planning considerations and decentralised responses to emerging events as interacting elements in a dynamic adaptive system. The interaction between...

  4. Tvorba strategie PR

    Novosadová, Petra

    2009-01-01

    This diploma thesis deals with the question of Public Relations strategy planning for a company operating in the field of providing travel services. The objective of this thesis is to create such a strategy based on primary and secondary data we have gathered. When doing so we consider the key areas first on theoretical grounds, and then apply them into practice. The outcome of this work is a tailored propsal of Public Relations strategy for a particular business.

  5. PRICE AND PRICING STRATEGIES

    SUCIU Titus

    2013-01-01

    In individual companies, price is one significant factor in achieving marketing success. In many purchase situations, price can be of great importance to customers. Marketers must establish pricing strategies that are compatible with the rest of the marketing mix. Management should decide whether to charge the same price to all similar buyers of identical quantities of a product (a one-price strategy) or to set different prices (a flexible price strategy). Many organizations, especially retai...

  6. Patterns of strategy development

    Bailey, Andy; Johnson, Gerry

    1996-01-01

    This paper builds on a multidimensional framework of strategy development to more clearly understand the processes by which strategy develops within organisations. It reports on a survey based research project which employs senior executives’ perceptions of the strategy development process in their organisations to examine how context specific configurations of dimensions explaining such processes can advance our understanding of strategic management. Six configurations are ide...

  7. Management strategies for business

    Alexander Sumets

    2018-01-01

    The paper aims to systematize business management strategies and identify their potential opportunities for the development of the competitive business advantages in transition economies. Characteristics of the features of modern business in developing countries (on the example of Ukraine) are given in the article in concise form. The relevance of the study of the relationship between strategy and business management is substantiated. Modern interpretations of the concepts of «strategy», «str...

  8. Usefulness of intra-arterial embolization method using gelfoam particles in effective gene transduction of adenoviral vector for liver-directed gene therapy: an preliminary animal study in dogs

    Lee, Jin Hwa; Park, Byeong Ho; Kim, Chan Sung [Dong-A University College of Medicine, Pusan (Korea, Republic of)

    2003-02-01

    Liver-directed gene therapy is being actively pursued and developed as a method of treating various liver diseases. A number of aspects, including gene intervention, an efficient gene delivery system, and stable transgene expression are key to the success of the chosen strategy, and to overcome problems in these areas, several tactics can be used. In this study, we assess the utility of transarterial embolization using gelfoam particles soaked in an adenovirus vector as a gene-delivery method. Using the angiographic approach, three dogs each weighing 9.5-11kg were superselectively catheterized at the left hepatic artery using a 3-F microcatheter and the coaxial method. Two of the dogs were embolized at the left hepatic artery using 3x2x2-mm and 2x1x1-mm gelfoam particles soaked in 2x10{sup 11} particles/kg of recombinant adv. CMV.LacZ(LacZ-adv). The left hepatic artery of the remaining animal, used as a control, was infused with the same dose of lacZ-adv in the same way as before but without embolization of the left hepatic artery. Three days after embolization or the infusion of LacZ-adv, the dogs were sacrificed prior to harvest of the entire liver for the evaluation of gene transduction. X-gal staining of the liver tissue obtained was positive for hepatocytes, but the pattern and degree of gene transduction differed according to gelfoam particle size. Where this was 3x2x2 mm, gene transduction along the liver hilum varied, but where 2x1x1-mm particles were used, transduction was more even. No pathologic hepatic tissue injury or inflammation was apparent, and control liver tissue was not stained by X-gal. Serum SGOT and SGPT levels were slightly higher one day after the procedure, but had normalized by day 3. Intrahepatic transarterial embolization using gelfoam particles soaked in LacZ-adv appears to be a good method for effective liver-targed gene therapy.

  9. Usefulness of intra-arterial embolization method using gelfoam particles in effective gene transduction of adenoviral vector for liver-directed gene therapy: an preliminary animal study in dogs

    Lee, Jin Hwa; Park, Byeong Ho; Kim, Chan Sung

    2003-01-01

    Liver-directed gene therapy is being actively pursued and developed as a method of treating various liver diseases. A number of aspects, including gene intervention, an efficient gene delivery system, and stable transgene expression are key to the success of the chosen strategy, and to overcome problems in these areas, several tactics can be used. In this study, we assess the utility of transarterial embolization using gelfoam particles soaked in an adenovirus vector as a gene-delivery method. Using the angiographic approach, three dogs each weighing 9.5-11kg were superselectively catheterized at the left hepatic artery using a 3-F microcatheter and the coaxial method. Two of the dogs were embolized at the left hepatic artery using 3x2x2-mm and 2x1x1-mm gelfoam particles soaked in 2x10 11 particles/kg of recombinant adv. CMV.LacZ(LacZ-adv). The left hepatic artery of the remaining animal, used as a control, was infused with the same dose of lacZ-adv in the same way as before but without embolization of the left hepatic artery. Three days after embolization or the infusion of LacZ-adv, the dogs were sacrificed prior to harvest of the entire liver for the evaluation of gene transduction. X-gal staining of the liver tissue obtained was positive for hepatocytes, but the pattern and degree of gene transduction differed according to gelfoam particle size. Where this was 3x2x2 mm, gene transduction along the liver hilum varied, but where 2x1x1-mm particles were used, transduction was more even. No pathologic hepatic tissue injury or inflammation was apparent, and control liver tissue was not stained by X-gal. Serum SGOT and SGPT levels were slightly higher one day after the procedure, but had normalized by day 3. Intrahepatic transarterial embolization using gelfoam particles soaked in LacZ-adv appears to be a good method for effective liver-targed gene therapy

  10. from strategy formulation to strategy formation

    Gerhard Louw;Abel Esterhuyse

    ultimately its weakness in accounting for the external environment in realised ..... implements and then controls a strategy that it deems appropriate to achieve an .... Every social system (such as the SANDF) seems to employ information ..... to favour rational analysis over this type of internal debate – in effect, it would.

  11. Secretary Marshall's Employment Strategies

    Stevenson, Gloria

    1977-01-01

    A review of proposed employment strategies and priorities of Ray Marshall, Secretary of Labor, with regard to training programs, governmental subsidy programs, apprenticeships, private sector jobs, etc. (WL)

  12. Strategy and New Media

    Plesner, Ursula; Gulbrandsen, Ib Tunby

    2015-01-01

    Despite current attention to the materiality of organizations and the performative role of tools, devices, artefacts and objects in processes of strategy-making, the impact of new media has not been thoroughly conceptualized in the strategy literature. We argue that new media challenge core...... assumptions in strategy about control, boundaries and choice. To understand their constitutive effects and the implications for strategy-making, it is necessary to develop a research agenda oriented towards understanding technological affordances – but not only in local practices. Due to vital characteristics...

  13. Processuel strategi i organisationer

    Gylling, Martin

    2014-01-01

    on process theory and strategy, which in these years aims to move focus away from the dominance of designed strategy. I.e. an approach to practice understood as methodological individualism and pragmatic rationality (Chia & Holt 2009; Steyaert 2007; Stacey 2011; Hjorth 2012). Through recent poststructuralist...... currents in the field of processual strategy thinking and organisational entrepreneurship, for example Chia & Holt’s creation philosophical research in strategy without design and Steyaert’s (2007) thinking on the concept of entrepreneuring; the process theoretical thinking of entrepreneurship...

  14. The advertising strategies

    YAKOUBI Mohamed Lamine

    2013-01-01

    We will try to demonstrate, through the display of the various advertising creation strategies and their evolution, how the advertising communication passed from of a vision or a strategy focused on the product, to a vision focused on the brand. The first advertising strategy that was applied by advertising agencies is the"Unique Selling Proposition";it focused only on the product advantages and its philosophy dominated the advertising world, throughout its various evolutions, till the nineties but this is without counting the introduction of the new advertising strategies that brought a more brand oriented philosophy to the ground.

  15. Multiserotype protection elicited by a combinatorial prime-boost vaccination strategy against bluetongue virus.

    Eva Calvo-Pinilla

    Full Text Available Bluetongue virus (BTV belongs to the genus Orbivirus within the family Reoviridae. The development of vector-based vaccines expressing conserved protective antigens results in increased immune activation and could reduce the number of multiserotype vaccinations required, therefore providing a cost-effective product. Recent recombinant DNA technology has allowed the development of novel strategies to develop marker and safe vaccines against BTV. We have now engineered naked DNAs and recombinant modified vaccinia virus Ankara (rMVA expressing VP2, VP7 and NS1 proteins from BTV-4. IFNAR((-/- mice inoculated with DNA/rMVA-VP2,-VP7-NS1 in an heterologous prime boost vaccination strategy generated significant levels of antibodies specific of VP2, VP7, and NS1, including those with neutralizing activity against BTV-4. In addition, vaccination stimulated specific CD8(+ T cell responses against these three BTV proteins. Importantly, the vaccine combination expressing NS1, VP2 and VP7 proteins of BTV-4, elicited sterile protection against a lethal dose of homologous BTV-4 infection. Remarkably, the vaccine induced cross-protection against lethal doses of heterologous BTV-8 and BTV-1 suggesting that the DNA/rMVA-VP2,-VP7,-NS1 marker vaccine is a promising multiserotype vaccine against BTV.

  16. Entrepreneurial Barriers to Strategy

    Elkjær, Jørgen Ravn

    2013-01-01

    En begrænsende faktor for strategisk ledelse er ofte iværksætterens uddannelse og erfaring, som efter en del forskningsbidrag synes at både fremme og hæmme bestemte strategie. Desuden kan der i hierarkier være en tendens til at opretholde de strategier, som blev dannet ved stiftelsen. Organisator...

  17. Geometric leaf placement strategies

    Fenwick, J D; Temple, S W P; Clements, R W; Lawrence, G P; Mayles, H M O; Mayles, W P M

    2004-01-01

    Geometric leaf placement strategies for multileaf collimators (MLCs) typically involve the expansion of the beam's-eye-view contour of a target by a uniform MLC margin, followed by movement of the leaves until some point on each leaf end touches the expanded contour. Film-based dose-distribution measurements have been made to determine appropriate MLC margins-characterized through an index d 90 -for multileaves set using one particular strategy to straight lines lying at various angles to the direction of leaf travel. Simple trigonometric relationships exist between different geometric leaf placement strategies and are used to generalize the results of the film work into d 90 values for several different strategies. Measured d 90 values vary both with angle and leaf placement strategy. A model has been derived that explains and describes quite well the observed variations of d 90 with angle. The d 90 angular variations of the strategies studied differ substantially, and geometric and dosimetric reasoning suggests that the best strategy is the one with the least angular variation. Using this criterion, the best straightforwardly implementable strategy studied is a 'touch circle' approach for which semicircles are imagined to be inscribed within leaf ends, the leaves being moved until the semicircles just touch the expanded target outline

  18. Green product innovation strategy

    Driessen, P.H.

    2005-01-01

    Over the last decades, companies have started to incorporate green issues in product innovation strategies. This dissertation studies green product innovation strategy, its antecedents and its outcomes. A three-stage approach is followed. In the first stage, the topic is explored and a preliminary

  19. Value oriented marketing strategies

    Stanković Ljiljana

    2009-01-01

    Full Text Available The complexity of business environment imposes the need for continuous change and reexamination of business marketing strategies of enterprises. Theory and practice of strategic management and marketing show that the activities of marketing, which are closely connected to corporate strategy, are the key drivers of growth. There is a positive correlation between competition intensity, marketing strategy and business performance of companies. Even though, managers of many companies don't see a clear connection between marketing strategy and business performance, numerous empirical research show that the companies which possess and efficiently use marketing resources and capabilities are more successful. In knowledge-based economics, the development of value oriented marketing strategies for all participants in the chain is a supposition of the survival, growth and development of companies. Competitive advantage is the essence of any strategy. Acquisition and maintenance of competitive advantage is more successful if the potentials for value creation are used efficiently. The paper examines the critical factors that influence alignment and transformation of marketing strategies in accordance with changes in value estimation. Superior value, is created in different network classes. Theory and practice researches create a reliable basis for the development of new concepts, marketing strategy business models that will contribute to competitive advantage of enterprises and the economy.

  20. Multimodal Strategies of Theorization

    Cartel, Melodie; Colombero, Sylvain; Boxenbaum, Eva

    This paper examines the role of multimodal strategies in processes of theorization. Empirically, we investigate the theorization process of a highly disruptive innovation in the history of architecture: reinforced concrete. Relying on archival data from a dominant French architectural journal from...... with well-known rhetorical strategies and develop a process model of theorization....

  1. Listening strategies instruction

    Nogueroles López, Marta

    2017-01-01

    , who presented similar level of Spanish, needs, educational and cultural background, but did not receive such a training. The listening strategies instruction consisted in integrating the development of listening strategies into a regular course of Spanish as a foreign language. Data referring...

  2. Introduction: Experimental Green Strategies

    Peters, Terri

    2011-01-01

    Defining new ways in which archietcts are responding to the challenge of creating sustainable architecture , Experimental Green Strategies present a state of the art in applied ecological architectural research.......Defining new ways in which archietcts are responding to the challenge of creating sustainable architecture , Experimental Green Strategies present a state of the art in applied ecological architectural research....

  3. Strategies for Competitive Volleyball.

    Fraser, Stephen D.

    This book deals with strategies and team tactics involved in the game of volleyball. It is not intended to be an instructional book on how to execute the various skills required to play volleyball but instead endeavors to detail and explain basic tactics and strategies involved in volleyball team play. Each chapter deals with major areas of team…

  4. Strategy as a Virus

    Obed Madsen, Søren

    This article is based on virus theory (Røvik, 2007, 2011), and proposes to develop a framework that defines technology as a virus that penetrates the organism of an organization. The framework develops a new vocabulary, which can help in analyzing technologies and their negative effects on actors...... and organizations. In this paper, the virus theory is used to analyze a strategy process in an organization as an example of a technology. It shows how the strategy over time creates a memory loss, where the managers who are exposed to the virus forget their critique of the new strategy concept. The article also...... shows how resistant can be understood as being immune to a virus, since the strategy concepts bears resemblance to a former strategy concept. The article also argues that there should be more focus on the negative impacts of management tool and especially how organizations and managers are dealing...

  5. Strategies of inducing cooperation

    Deutsch, M.

    1986-01-01

    The results of the four experiments described in this paper are very consistent, and they can be summarized as follows: (1) The ''nonpunitive'' strategy was most effective in eliciting cooperative behavior from the subjects and, overall, resulted in the highest joint outcomes as well as the highest outcomes for the accomplice. (2) The effectiveness of the turn-the-other-cheek strategy was very much influenced by the competitiveness of the situation; the more competitive the incentives of the subjects, the more massively they exploited the accomplice who employed this strategy. (3) The punitive deterrent strategy elicited more agressive and self-protective, as well as less cooperative, behavior from the subjects than did the other strategies

  6. Strategy as simple rules.

    Eisenhardt, K M; Sull, D N

    2001-01-01

    The success of Yahoo!, eBay, Enron, and other companies that have become adept at morphing to meet the demands of changing markets can't be explained using traditional thinking about competitive strategy. These companies have succeeded by pursuing constantly evolving strategies in market spaces that were considered unattractive according to traditional measures. In this article--the third in an HBR series by Kathleen Eisenhardt and Donald Sull on strategy in the new economy--the authors ask, what are the sources of competitive advantage in high-velocity markets? The secret, they say, is strategy as simple rules. The companies know that the greatest opportunities for competitive advantage lie in market confusion, but they recognize the need for a few crucial strategic processes and a few simple rules. In traditional strategy, advantage comes from exploiting resources or stable market positions. In strategy as simple rules, advantage comes from successfully seizing fleeting opportunities. Key strategic processes, such as product innovation, partnering, or spinout creation, place the company where the flow of opportunities is greatest. Simple rules then provide the guidelines within which managers can pursue such opportunities. Simple rules, which grow out of experience, fall into five broad categories: how- to rules, boundary conditions, priority rules, timing rules, and exit rules. Companies with simple-rules strategies must follow the rules religiously and avoid the temptation to change them too frequently. A consistent strategy helps managers sort through opportunities and gain short-term advantage by exploiting the attractive ones. In stable markets, managers rely on complicated strategies built on detailed predictions of the future. But when business is complicated, strategy should be simple.

  7. DOE groundwater protection strategy

    Lichtman, S.

    1988-01-01

    EH is developing a DOE-wide Groundwater Quality Protection Strategy to express DOE's commitment to the protection of groundwater quality at or near its facilities. This strategy responds to a September 1986 recommendation of the General Accounting Office. It builds on EPA's August 1984 Ground-Water Protection Strategy, which establishes a classification system designed to protect groundwater according to its value and vulnerability. The purposes of DOE's strategy are to highlight groundwater protection as part of current DOE programs and future Departmental planning, to guide DOE managers in developing site-specific groundwater protection practices where DOE has discretion, and to guide DOE's approach to negotiations with EPA/states where regulatory processes apply to groundwater protection at Departmental facilities. The strategy calls for the prevention of groundwater contamination and the cleanup of groundwater commensurate with its usefulness. It would require long-term groundwater protection with reliance on physical rather than institutional control methods. The strategy provides guidance on providing long-term protection of groundwater resources; standards for new remedial actions;guidance on establishing points of compliance; requirements for establishing classification review area; and general guidance on obtaining variances, where applicable, from regulatory requirements. It also outlines management tools to implement this strategy

  8. Typhoid fever vaccination strategies.

    Date, Kashmira A; Bentsi-Enchill, Adwoa; Marks, Florian; Fox, Kimberley

    2015-06-19

    Typhoid vaccination is an important component of typhoid fever prevention and control, and is recommended for public health programmatic use in both endemic and outbreak settings. We reviewed experiences with various vaccination strategies using the currently available typhoid vaccines (injectable Vi polysaccharide vaccine [ViPS], oral Ty21a vaccine, and injectable typhoid conjugate vaccine [TCV]). We assessed the rationale, acceptability, effectiveness, impact and implementation lessons of these strategies to inform effective typhoid vaccination strategies for the future. Vaccination strategies were categorized by vaccine disease control strategy (preemptive use for endemic disease or to prevent an outbreak, and reactive use for outbreak control) and vaccine delivery strategy (community-based routine, community-based campaign and school-based). Almost all public health typhoid vaccination programs used ViPS vaccine and have been in countries of Asia, with one example in the Pacific and one experience using the Ty21a vaccine in South America. All vaccination strategies were found to be acceptable, feasible and effective in the settings evaluated; evidence of impact, where available, was strongest in endemic settings and in the short- to medium-term. Vaccination was cost-effective in high-incidence but not low-incidence settings. Experience in disaster and outbreak settings remains limited. TCVs have recently become available and none are WHO-prequalified yet; no program experience with TCVs was found in published literature. Despite the demonstrated success of several typhoid vaccination strategies, typhoid vaccines remain underused. Implementation lessons should be applied to design optimal vaccination strategies using TCVs which have several anticipated advantages, such as potential for use in infant immunization programs and longer duration of protection, over the ViPS and Ty21a vaccines for typhoid prevention and control. Copyright © 2015. Published by

  9. Cooperative strategies European perspectives

    Killing, J Peter

    1997-01-01

    Cooperative Strategies: European Perspectives is one of three geographically targeted volumes in which the contributors present the most current research on topics such as advances in theories of cooperative strategies, the formation of cooperative alliances, the dynamics of partner relationships, and the role of information and knowledge in cooperative alliances. Blending conceptual insights with empirical analyses, the contributors highlight commonalities and differences across national, cultural, and trade zones. The chapters in this volume are anchored in a wide set of theoretical approaches, conceptual frameworks, and models, illustrating how rich the area of cooperative strategies is for scholarly inquiry.

  10. Strategy as Performative Practice

    Kornberger, Martin; Clegg, Stewart

    2011-01-01

    is it based upon? And what are its power effects? Based on a detailed empirical analysis of the strategy-making process, the article charts how strategy rendered the city knowable and how performative effects of strategizing mobilized the public and legitimized outcomes of the process while silencing other...... (traditionally the domain of science) and values (the realm of politics); third, and consequently, that strategy is a sociopolitical practice that aims at mobilizing people, marshalling political will and legitimizing decisions. The article concludes with reflections on five practical implications of the study....

  11. Genesis nature of financial strategy

    O.V. Pashchenko

    2015-01-01

    The article is devoted to the study of the origin and history of the interpretation of the genesis of «strategy», «financial strategy», its elements and composite types. Scientists studied different views on the concept of strategy. Several specific positions founders of different approaches to define the strategy of schools operating strategies involved in the formulation and implementation of the concept of «strategy». Evaluation of different schools of strategies that deepened understandin...

  12. Price strategy and pricing strategy: terms and content identification

    Panasenko Tetyana

    2015-01-01

    The article is devoted to the terminology and content identification of seemingly identical concepts "price strategy" and "pricing strategy". The article contains evidence that the price strategy determines the direction, principles and procedure of implementing the company price policy and pricing strategy creates a set of rules and practical methods of price formation in accordance with the pricing strategy of the company.

  13. The relationship between Business Strategy, IT Strategy and Alignment Capability

    Drs. A.J.G. Silvius

    2009-01-01

    Aligning business and IT strategy is a prominent area of concern. Organizations that successfully align their business strategy and their IT strategy, outperform their non-aligned peers (Chan et al., 1997). This chapter explores the relationship between business strategy, IT strategy and alignment

  14. A New Distribution Strategy : The Omnichannel Strategy

    Mihaela Gabriela Belu

    2014-06-01

    Full Text Available In an increasingly globalized world, dependent on information technology, distribution companies are searching for new marketing models meant to enrich the consumer’s experience. Therefore, the evolution of new technologies, the changes in the consumer’s behaviour are the main factors that determine changes in the business model in the distribution field. The following article presents different forms of distribution, focusing on the omnichannel strategy. In the last part of the paper, the authors analyse the Romanian retail market, namely, the evolution of the market, its key competitors and the new distribution models adopted by retaileres in our country.

  15. Information transmission strategy

    Moreau, A.

    1989-01-01

    The four propositions on which our radiation protection information transmission strategy is based are as follows: 1. Emotion exists. It rules our lives at work as well as at home, particularly when radiation safety is involved. Emotion is therefore the terrain for our strategy. 2. The basic emotion is that of fear. This must be recognized and accepted if we want to transmit objective information. The basis of our strategy is therefore listening. 3. A person cannot be divided into parts. The whole person is concerned about safety. We have to deal with that whole person. 4. To follow a strategy we need strategists. We must look at our own emotions and our own motivation before going into the field

  16. Qualitative Data Analysis Strategies

    Greaves, Kristoffer

    2014-01-01

    A set of concept maps for qualitative data analysis strategies, inspired by Corbin, JM & Strauss, AL 2008, Basics of qualitative research: Techniques and procedures for developing grounded theory, 3rd edn, Sage Publications, Inc, Thousand Oaks, California.

  17. Strategy as Projects

    Lund Pedersen, Carsten; Ritter, Thomas; Andersen, Torben Juul

    This paper proposes the adoption of a project-based view to analyze strategy formation and strategic renewal over time. Projects are resource-committing, empirically-tracable investments, and as such, particularly suitable for the analysis of different manifestations of intended strategies as well...... as post-hoc manifestations of deviant, even rebellious, actions taken in opposition to the initial strategy announcement. The paper presents an analytical framework (a 5x2 matrix) of ten different project categories that together allows researchers to investigate how strategic renewal is realized through...... the enactment of different types of project initiatives throughout the organization. The developed framework is validated by two field studies that outline the robustness of the proposed matrix. In addition to the demonstration of the advantages of the framework, we discuss the limitations of the strategy-as-projects...

  18. Compositional Advantage and Strategy

    Li, Xin

    advantage is redefined as the attractiveness of the composition of the producer’s offering in terms of scope and perceived value/price ratio. I identify five ways or basic compositional strategies to improve the value/price ratio. A firm may have an overall compositional strategy that is composed of some......In this paper, I first critique the composition-based view of Yadong Luo and John Child for understanding how resource-poor firms survive and thrive. To remedy the deficiencies in their perspective, I then propose a dynamic theory of compositional advantage and strategy. Here, the compositional...... or all of the five basic compositional strategies. I argue there are three indispensable key success factors for a composition-based competition, i.e., aspiration (ambition-position asymmetry), attitude (being ALERT), and action (turning asymmetry into advantage). I also discuss the particular relevance...

  19. Combustion strategy : United Kingdom

    Greenhalgh, D. [Heriot-Watt Univ., Edingburgh, Scotland (United Kingdom). School of Engineering and Physical Sciences

    2009-07-01

    The United Kingdom's combustion strategy was briefly presented. Government funding sources for universities were listed. The United Kingdom Research Councils that were listed included the Arts and Humanities Research Council (AHRC) and the Biotechnology and Biological Sciences Research Council (BBSRC); the Engineering and Physical Sciences Research Council (EPSRC); the Economic and Social Research Council; the Medical Research Council; the Natural Environment Research Council; and the Science and Technology Facilities Council. The EPSRC supported 65 grants worth 30.5 million pounds. The combustion industry was noted to be dominated by three main players of which one was by far the largest. The 3 key players were Rolls-Royce; Jaguar Land Rover; and Doosan Babcock. Industry and government involvement was also discussed for the BIS Technology Strategy Board, strategy technology areas, and strategy application areas.

  20. INTEGRATED CORPORATE STRATEGY MODEL

    CATALINA SORIANA SITNIKOV

    2014-02-01

    Full Text Available Corporations are at present operating in demanding and highly unsure periods, facing a mixture of increased macroeconomic need, competitive and capital market dangers, and in many cases, the prospect for significant technical and regulative gap. Throughout these demanding and highly unsure times, the corporations must pay particular attention to corporate strategy. In present times, corporate strategy must be perceived and used as a function of various fields, covers, and characters as well as a highly interactive system. For the corporation's strategy to become a competitive advantage is necessary to understand and also to integrate it in a holistic model to ensure sustainable progress of corporation activities under the optimum conditions of profitability. The model proposed in this paper is aimed at integrating the two strategic models, Hoshin Kanri and Integrated Strategy Model, as well as their consolidation with the principles of sound corporate governance set out by the OECD.

  1. Defeating Saddam Hussein's Strategy

    Millen, Raymond A

    2003-01-01

    Should war break out between Iraq and the United States, Saddam Hussein will likely adopt a strategy designed to undermine the prestige of the United States and turn the Arab World against the West...

  2. US Strategy for Cyberspace

    Veazie, Arnold

    2003-01-01

    .... in conventional warfare. As a result, America's adversaries are adopting asymmetrical warfare approaches, such as cyber attacks, as part of their strategy to disrupt the American infrastructure and economy...

  3. SPORT PROMOTION STRATEGIES

    Alexandru Lucian MIHAI

    2013-10-01

    Full Text Available In sport marketing, the word promotion covers a range of interrelated activities. All of these activities are designed to attract attention, stimulate the interest and awareness of consumers, and of course, encourage them to purchase a sport product. Promotion is about communicating with and educating consumers. The purpose of a sport promotional strategy is to build brand loyalty and product credibility, develop image, and position the brand. A promotional strategy is similar to a marketing strategy, but the promotional strategy seeks short-term objectives, both direct and indirect. Promotional objectives usually include increased sales, stimulate impulse buying, raise customer traffic, and present and reinforce image. It also provides information about products and services, publicizes new stores or websites, and creates and enhances customer satisfaction.

  4. Consolidating Social Media Strategies

    Gyimóthy, Szilvia; Munar, Ana Maria; Larson, Mia

    2014-01-01

    This study revisits and integrates the insights of recent studies on emergent social media strategies deployed by destination and event management organisations. In a comparative analysis Munar (2012) identified four generic approaches pursued by national tourism boards in the Nordic region, while...... Gyimóthy & Larson (2014) portrayed three digital value co-creation strategies deployed by festival social media. Both frameworks provided novel analytical typologies which identified a series of categories (mimetic, analytic, immersion, advertising and insourcing, crowdsourcing and community consolidation......). This paper discusses the complementary nature of these conceptual proposals and advances an integrated conceptual framework of social media strategies. Based on the empirical findings of a case study that revisits evolving digital and social media strategies of European DMOs this paper maps the dynamics...

  5. Enacting Governance through Strategy

    Brandtner, Christof; Höllerer, Markus A.; Meyer, Renate E.

    2017-01-01

    of strategy documents in city administration addresses these challenges. Our central claim is that strategy documents can be understood as a distinct discursive device through which local governments enact aspired governance configurations. We illustrate our argument empirically using two prominent examples...... that, while showing similar features and characteristics, are anchored in different administrative traditions and institutional frameworks: the city administrations of Sydney, Australia, and Vienna, Austria. The contribution of the paper is to show how strategy documents enact governance configurations...... along four core dimensions: the setting in space and time, the definition of the public, the framing of the res publica and legitimacy issues. Moreover, our comparative analysis of Sydney and Vienna gives evidence of differences in governance configurations enacted through strategy documents....

  6. E-commerce strategy

    Qin, Zheng; Li, Shundong; Li, Fengxiang

    2014-01-01

    This book helps deepen understanding of key e-commerce strategies. It brings together theoretical perspectives based on academic research, integrated use of technologies and a large amount of cases, especially those of China.

  7. Forces in strategy formation

    Steensen, Elmer Fly; Sanchez, Ron

    2008-01-01

    This chapter proposes that organizational strategy formation should be characterized theoretically as a process that is subject to several interacting forces, rather than represented by separate discrete decisionmodels or theoretic perspectives, as is commonly done in the strategic management...... literature. Based on an extensive review of relevant theory and empirical work in strategic decision-making, organizational change theory, cognitive and social psychology, and strategy processes, seven kinds of ''forces'' - rational, imposed, teleological, learning, political, heuristic, and social...... - are identified as interacting in and having significant influence on the strategy formation process. It is further argued that by applying a holistic ''forces-view'' of the significant and interacting influences on strategy formation, we can better understand the dynamics and challenges in managing the process...

  8. Resources, Technology, and Strategy

    Resources, Technology and Strategy brings together contributors from Europe, North America and Asia to consider the strategic relationship between technology and other resources, such as production capabilities, marketing prowess, finance and organisational culture. Throughout the book...

  9. Organizing export strategies.

    G. Lojacono; M. Venzin

    2014-01-01

    The article unfolds as follows: after a brief introduction on the relevance of international trade and the characteristics of export strategies, we describe four distinct archetypes: export manager, centralistic export developer, export skimmer, integrated export developer.

  10. Cloud computing strategies

    Chorafas, Dimitris N

    2011-01-01

    A guide to managing cloud projects, Cloud Computing Strategies provides the understanding required to evaluate the technology and determine how it can be best applied to improve business and enhance your overall corporate strategy. Based on extensive research, it examines the opportunities and challenges that loom in the cloud. It explains exactly what cloud computing is, what it has to offer, and calls attention to the important issues management needs to consider before passing the point of no return regarding financial commitments.

  11. Strategi Pembelajaran Tanpa Kekerasan

    Idrus, Muhammad

    2013-01-01

    This paper will discuss learning strategy models which put student as subject of learning. Teacher is expected to take an advantage in using those models to reduce violence in education circumstance. As found in researches and mass media, violence in education circumstances, which is performed by teachers or students, still become high concerns among parents, teachers, and students themselves. One such thing that may cause this violence is learning and teaching approach or strategy by which t...

  12. Hexavalent Chromium Minimization Strategy

    2011-05-01

    Logistics 4 Initiative - DoD Hexavalent Chromium Minimization Non- Chrome Primer IIEXAVAJ ENT CHRO:M I~UMI CHROMIUM (VII Oil CrfVli.J CANCEfl HAnRD CD...Management Office of the Secretary of Defense Hexavalent Chromium Minimization Strategy Report Documentation Page Form ApprovedOMB No. 0704-0188...00-2011 4. TITLE AND SUBTITLE Hexavalent Chromium Minimization Strategy 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6

  13. Management strategies for fibromyalgia

    Le Marshall KF; Littlejohn GO

    2011-01-01

    Kim Francis Le Marshall, Geoffrey Owen LittlejohnDepartments of Rheumatology and Medicine, Monash Medical Centre and Monash University, Victoria, AustraliaDate of preparation: 14 June 2011Clinical question: What are the effective, evidence-based strategies available for the management of fibromyalgia?Conclusion: There are a number of management strategies available with robust evidence to support their use in clinical practice.Definition: Fibromyalgia is a complex pain syndrome characterized ...

  14. Strategies in digital marketing

    Robert DRAGOMIR; Mihai ANDRONIE

    2017-01-01

    The present paper deals with digital marketing. The approach into discussion is the strategies met with the concept mentioned above. Within the actual socio-economic context, the electronic equipments offer on one hand new and innovative methods for products promoting and, on the other hand new challenges for the consumers. Thus, we analysed different and major types of strategies, which have a great impact on the digital marketing.

  15. Marketing Strategy for Kukaneko

    Kämpjärvi, Tiina

    2013-01-01

    The topic of this thesis was to create a realistic marketing strategy for Kukaneko that sells Finnish sustainable fashion in Lahti. The company had no comprehensive marketing strategy in its use which why this thesis was written. Both secondary and primary research was used to carry out the research. The secondary data was gathered from books, scholarly journals and internet sources. Qualitative data was gathered in co-operation with the owner of the case company through an interview...

  16. Social Media Cocreation Strategies

    Gyimóthy, Szilvia; Larson, Mia

    2015-01-01

    This paper explores how social media becomes a part of integrated marketing communications of festival organizations. The purpose of this paper is to conceptualize the co-creation of festival experiences online by comparing managerial strategies and communicative patterns of three large....... Based on the empirical findings, we propose an analytical framework to improve our understanding of the management of social media communications, offering three distinct value co-creation strategies in a festival context....

  17. Human Life History Strategies.

    Chua, Kristine J; Lukaszewski, Aaron W; Grant, DeMond M; Sng, Oliver

    2017-01-01

    Human life history (LH) strategies are theoretically regulated by developmental exposure to environmental cues that ancestrally predicted LH-relevant world states (e.g., risk of morbidity-mortality). Recent modeling work has raised the question of whether the association of childhood family factors with adult LH variation arises via (i) direct sampling of external environmental cues during development and/or (ii) calibration of LH strategies to internal somatic condition (i.e., health), which itself reflects exposure to variably favorable environments. The present research tested between these possibilities through three online surveys involving a total of over 26,000 participants. Participants completed questionnaires assessing components of self-reported environmental harshness (i.e., socioeconomic status, family neglect, and neighborhood crime), health status, and various LH-related psychological and behavioral phenotypes (e.g., mating strategies, paranoia, and anxiety), modeled as a unidimensional latent variable. Structural equation models suggested that exposure to harsh ecologies had direct effects on latent LH strategy as well as indirect effects on latent LH strategy mediated via health status. These findings suggest that human LH strategies may be calibrated to both external and internal cues and that such calibrational effects manifest in a wide range of psychological and behavioral phenotypes.

  18. Human Life History Strategies

    Kristine J. Chua

    2016-12-01

    Full Text Available Human life history (LH strategies are theoretically regulated by developmental exposure to environmental cues that ancestrally predicted LH-relevant world states (e.g., risk of morbidity–mortality. Recent modeling work has raised the question of whether the association of childhood family factors with adult LH variation arises via (i direct sampling of external environmental cues during development and/or (ii calibration of LH strategies to internal somatic condition (i.e., health, which itself reflects exposure to variably favorable environments. The present research tested between these possibilities through three online surveys involving a total of over 26,000 participants. Participants completed questionnaires assessing components of self-reported environmental harshness (i.e., socioeconomic status, family neglect, and neighborhood crime, health status, and various LH-related psychological and behavioral phenotypes (e.g., mating strategies, paranoia, and anxiety, modeled as a unidimensional latent variable. Structural equation models suggested that exposure to harsh ecologies had direct effects on latent LH strategy as well as indirect effects on latent LH strategy mediated via health status. These findings suggest that human LH strategies may be calibrated to both external and internal cues and that such calibrational effects manifest in a wide range of psychological and behavioral phenotypes.

  19. Social strategies that work.

    Piskorski, Mikołaj Jan

    2011-11-01

    Although most companies have collected lots of friends and followers on social platforms such as Facebook, few have succeeded in generating profits there. That's because they merely port their digital strategies into social environments by broadcasting their commercial messages or seeking customer feedback. To succeed on social platforms, says Harvard Business School's Piskorski, businesses need to devise social strategies that are consistent with users' expectations and behavior in these venues--namely, people want to connect with other people, not with companies. The author defines successful social strategies as those that reduce costs or increase customers' willingness to pay by helping people establish or strengthen relationships through doing free work on a company's behalf. Citing successes at Zynga, eBay, American Express, and Yelp, Piskorski shows that social strategies can generate profits by helping people connect in exchange for tasks that benefit the company such as customer acquisition, marketing, and content creation. He lays out a systematic way to build a social strategy and shows how a major credit card company he advised used the method to roll out its own strategy.

  20. Lithuanian Energy Strategy

    Valentukevichius, V.

    1999-01-01

    The First National Energy Strategy, outlining the principal provisions of the Government on the reconstruction and development of energy sector, was approved for a comparatively long period - until the year 2015. The Energy Law envisages that the energy strategy is approved by the Parliament and has to be revised every five year. This National Energy Strategy amended and specified the energy development trends defined in 1994. The recent positive developments and tendencies in Lithuania's economy called for the necessity to revise the strategies for the further development of the infra structural areas, especially the energy sector. The preparation of an updated National Energy Strategy was based on the overall forecasts for the development of the country, and also experience, which was gained by participation in the programmes and studies supported by European Union and PHARE, and also priorities indicated in the National Programme for Adoption of Acquis (NPAA programme). Formulation of the basic goals of the National Energy Strategy included requirements of the European Association Agreement, Energy Charter, and also principles and tendencies in the energy sector development of the member countries

  1. Combined distemper-adenoviral pneumonia in a dog

    Rodriguez-Tovar, Luis E.; Ramírez-Romero, Rafael; Valdez-Nava, Yazel; Nevárez-Garza, Alicia M.; Zárate-Ramos, Juan J.; López, Alfonso

    2007-01-01

    A 3 1/2-month-old pug with oculonasal discharge and seizures was submitted for postmortem examination. Grossly, the lungs had cranioventral consolidation, and microscopically, 2 distinct types of inclusion bodies compatible with Canine distemper virus and Canine adenovirus type 2. Presence of both viruses was confirmed via immunohistochemical staining. PMID:17616064

  2. Coinfections of Multiple Virulent Adenoviral Species in Previously Vaccinated Patients

    Vora, Gary J; Lin, Baochuan; Gratwick, Kevin; Meador, Carolyn; Seto, Donald; Purkayastha, Anjan; Freed, Nikki E; Russell, Kevin; Metzgar, David

    2004-01-01

    .... Despite the general success of the vaccination program, surveillance still detected breakthrough infections cases of acute respiratory disease associated with the adenovirus serotypes (4 and 7...

  3. Decommissioning strategy selection

    Warnecke, E.

    2005-01-01

    At the end of their useful life nuclear facilities have to be decommissioned. The strategy selection on how to decommission a facility is a highly important decision at the very beginning of decommissioning planning. Basically, a facility may be subject to (a) immediate dismantling; (b) deferred dismantling after a period of ''safe enclosure'' or (c) entombment where a facility is turned into a near surface disposal facility. The first two strategies are normally applied. The third one may be accepted in countries without significant nuclear activities and hence without disposal facilities for radioactive waste. A large number of factors has to be taken into account when a decision on the decommissioning strategy is being made. Many of the factors cannot be quantified. They may be qualitative or subject to public opinion which may change with time. At present, a trend can be observed towards immediate dismantling of nuclear facilities, mainly because it is associated with less uncertainty, less local impact, a better public acceptance, and the availability of operational expertise and know how. A detailed evaluation of the various factors relevant to strategy selection and a few examples showing the situation regarding decommissioning strategy in a number of selected countries are presented in the following article. (orig.)

  4. APL: a corporate strategy.

    Fox, J; Nyatanga, L; Ringer, C; Greaves, J

    1992-06-01

    This paper is based on, and summarises, papers read at the second annual international conference of Nurse Education Tomorrow held at the University of Durham (UK) September 1991. To this end this paper will offer: Some Accreditation of Prior Learning (APL) definition and process as reflected in the literature available. A distinction will be made between APL and Accreditation of Prior Experiential Learning (APEL) although the procedures and processes for assessing them will be shown to be the same. A brief outline of corporate strategy, as it applies to APL, will be given to form the basis for logical demonstration of how Derbyshire Institute of Health and Community Studies has employed such a corporate strategy. Insights developed and gained from APL research currently being undertaken through the college of nursing and midwifery will be used to inform the development and nature of corporate strategy. A flowchart of the operationalisation of the corporate strategy is offered as an integrative summary of how all the APL ideas have had a positive cumulative effect. The paper finishes by highlighting the possible strengths and limitations of APL corporate strategy.

  5. Comprehensive national energy strategy

    NONE

    1998-04-01

    This Comprehensive National Energy Strategy sets forth a set of five common sense goals for national energy policy: (1) improve the efficiency of the energy system, (2) ensure against energy disruptions, (3) promote energy production and use in ways that respect health and environmental values, (4) expand future energy choices, and (5) cooperate internationally on global issues. These goals are further elaborated by a series of objectives and strategies to illustrate how the goals will be achieved. Taken together, the goals, objectives, and strategies form a blueprint for the specific programs, projects, initiatives, investments, and other actions that will be developed and undertaken by the Federal Government, with significant emphasis on the importance of the scientific and technological advancements that will allow implementation of this Comprehensive National Energy Strategy. Moreover, the statutory requirement of regular submissions of national energy policy plans ensures that this framework can be modified to reflect evolving conditions, such as better knowledge of our surroundings, changes in energy markets, and advances in technology. This Strategy, then, should be thought of as a living document. Finally, this plan benefited from the comments and suggestions of numerous individuals and organizations, both inside and outside of government. The Summary of Public Comments, located at the end of this document, describes the public participation process and summarizes the comments that were received. 8 figs.

  6. Fault Management Design Strategies

    Day, John C.; Johnson, Stephen B.

    2014-01-01

    Development of dependable systems relies on the ability of the system to determine and respond to off-nominal system behavior. Specification and development of these fault management capabilities must be done in a structured and principled manner to improve our understanding of these systems, and to make significant gains in dependability (safety, reliability and availability). Prior work has described a fundamental taxonomy and theory of System Health Management (SHM), and of its operational subset, Fault Management (FM). This conceptual foundation provides a basis to develop framework to design and implement FM design strategies that protect mission objectives and account for system design limitations. Selection of an SHM strategy has implications for the functions required to perform the strategy, and it places constraints on the set of possible design solutions. The framework developed in this paper provides a rigorous and principled approach to classifying SHM strategies, as well as methods for determination and implementation of SHM strategies. An illustrative example is used to describe the application of the framework and the resulting benefits to system and FM design and dependability.

  7. Genesis nature of financial strategy

    O.V. Pashchenko

    2015-03-01

    Full Text Available The article is devoted to the study of the origin and history of the interpretation of the genesis of «strategy», «financial strategy», its elements and composite types. Scientists studied different views on the concept of strategy. Several specific positions founders of different approaches to define the strategy of schools operating strategies involved in the formulation and implementation of the concept of «strategy». Evaluation of different schools of strategies that deepened understanding of the industry and its strategy in the early stages of formation. Based on the works of various scholars studied by the author actually proposed interpretation of the concept strategy. The general industry and functional strategies which include the following strategies: innovation, resource, financial, production, marketing and human resources. Allocated financial strategy and its significant impact on other strategies. Author developed financial sector strategy and financial strategy of competitive enterprise. The importance of financial strategies under conditions of companies and the industry as a whole, as well as components of development of financial strategy. Deals with the factors that must be considered in the development and implementation of financial strategies. The systems analysis strategies and the impact on financial results, the estimation of their attractiveness and risk. Considered classification on the basis of financial strategies and sectoral orientation of the financial sector strategy based on company size, its form and noted the importance of this trait in systematizing strategies. The expediency of the financial strategy. Defined competitive advantage and efficiency of business and industry through the implementation of various financial strategies.

  8. Teaching Writing Strategies

    Zaououi,Merbouh

    2010-03-01

    Full Text Available Developing learners’ writing skills has been of concern for a long time in education. Students studying English in our educational institutions have been found to face problems mainly in writing, making them unable to cope with the institution’s literacy expectations. However, these students may be able to develop writing skills significantly with positive instructional attitudes towards the errors they make and awareness on the teachers’ part of learner problems. That is why they should improve classroom writing instruction to address the serious problem of students writing difficult. Teaching strategies has shown a dramatic effect on the quality of students’ writing. Strategy instruction involves explicitly and systematically teaching steps necessary to use strategies independently. The following table will explain the above ideas.

  9. Strategies of Human Mating

    David M. Buss

    2006-12-01

    Full Text Available Modern humans have inherited the mating strategies that led to the success of their ancestors. These strategies include long-term mating, short-term mating, extra-pair mating, mate poaching, and mate guarding. This article presents empirical evidence supporting evolution-based hypotheses about the complexities of these mating strategies. Since men and women historically confronted different adaptive problems in the mating domain, the sexes differ profoundly in evolved strategic solutions. These differences include possessing different mate preferences, different desires for short-term mating, and differences in the triggers that evoke sexual jealousy. The study of human mating is one of the “success stories” of evolutionary psychology.

  10. Bulgarian energy strategy

    2002-01-01

    The creation of a competitive energy market in Bulgaria is one of the top priorities in the government policy. To achieve this goal the following conditions are necessary: normalizing of the energy prices; financial healing; well working regulatory institutions and mechanisms; market rules and structures; appropriate legal framework. The main topics discussed in connection with the new energy strategy are: 1) General energy policy - competitive energetics; private investments and privatization; security of the energy supply, environment, energy efficiency; social protection and guarantees; 2) Sector policy - market regulation; licensing; effective use of the available power facilities; nuclear safety; 3) Gasification; 4) Heating; 5) Coal production. According to the strategy framework documents in the following aspects should be developed: integrated long-term plan 'Energetics-Environment'; price policy; market rules and structures; privatization strategies; healing programmes

  11. Compositional Advantage and Strategy

    Li, Xin

    In this paper, I first critique the composition-based view of Yadong Luo and John Child for understanding how resource-poor firms survive and thrive. To remedy the deficiencies in their perspective, I then propose a dynamic theory of compositional advantage and strategy. Here, the compositional...... advantage is redefined as the attractiveness of the composition of the producer’s offering in terms of scope and perceived value/price ratio. I identify five ways or basic compositional strategies to improve the value/price ratio. A firm may have an overall compositional strategy that is composed of some...... of the present theory to understanding Chinese firms. I conclude with managerial implications and suggestions for future research....

  12. Assessment of strategy formulation

    Acur, Nuran; Englyst, Linda

    2006-01-01

    of the success criteria through face-to-face interviews with 46 managers, workshops involving 40 managers, and two in-depth case studies. The success criteria have been slightly modified due to the empirical results, to yield the assessment tool. Findings – The resulting assessment tool integrates three generic...... approaches to strategy assessment, namely the goal-centred, comparative and improvement approaches, as found in the literature. Furthermore, it encompasses three phases of strategy formulation processes: strategic thinking, strategic planning and embedding of strategy. The tool reflects that the different......, but cases and managerial perceptions indicate that the need for accurate and detailed plans might be overrated in the literature, as implementation relies heavily on continuous improvement and empowerment. Concerning embedding, key aspects relate both to the goal-centred and improvement approaches, while...

  13. Operations Strategy in practice

    Rytter, Niels Gorm; Koch, Christian; Boer, Harry

    2005-01-01

    In this paper, we describe and illustrate a new, action-based longitudinal case study approach, which aims at helping scholars narrow the gap between the theory and practice of Operations Strategy (OS). First, we elaborate on the need for new research methods for studying OS in practice. Then, we...... and disadvantages of the method. Finally, we draw conclusions on its potential for operations strategy and operations management studies.......In this paper, we describe and illustrate a new, action-based longitudinal case study approach, which aims at helping scholars narrow the gap between the theory and practice of Operations Strategy (OS). First, we elaborate on the need for new research methods for studying OS in practice. Then, we...

  14. Requirements of modernization strategies

    Heinbuch, R.

    1997-01-01

    Instrumentation and control contributed a major share to the current level of safety, economic efficiency, and availability of the German nuclear power plants. German NPPs occupy a top position in this respect at international level, but novel instrumentation and digital control technology alone will not guarantee further enhancements. Therefore, the owner/operators established carefully devised maintenance and modernization strategies in order to safeguard their NPPs top position in the long run. The German NPPs are the most thoroughly automated plants of the world. In addition to the sweeping modernization strategies recommended by the plant manufacturers, based on computer-supported control, alternative modernization strategies have been considered in the evaluation process. This approach provides for room for maneuvre, for manufacturers as well as managers responsible for risk and cost optimization, which is a major task in view of the changing regulatory framework in the electricity market. (orig./CB) [de

  15. Power Subscription Strategy

    None, None

    1998-12-21

    This document lays out the Bonneville Power Administration`s Power Subscription Strategy, a process that will enable the people of the Pacific Northwest to share the benefits of the Federal Columbia river Power System after 2001 while retaining those benefits within the region for future generations. The strategy also addresses how those who receive the benefits of the region`s low-cost federal power should share a corresponding measure of the risks. This strategy seeks to implement the subscription concept created by the Comprehensive Review in 1996 through contracts for the sale of power and the distribution of federal power benefits in the deregulated wholesale electricity market. The success of the subscription process is fundamental to BPA`s overall business purpose to provide public benefits to the Northwest through commercially successful businesses.

  16. Developing a glocalisation strategy

    Hollensen, Svend; Schimmelpfennig, Christian

    2015-01-01

    while exploiting the benefits of global integration. The challenge is to balance the local knowledge with global reach. In the case of Persil Abaya Shampoo (for the Middle East market) and Persil Black Gel (for the European market), Henkel chose a strategy that successfully benefitted from...... markets and used Persil Abayas’ particular significance in the Arab world to its advantage. The results document that it has been possible for Henkel’s Persil to gain competitive advantages in terms of higher market shares, with the ‘glocalisation strategy’ in the (Middle East) liquid detergent market.......The glocalisation strategy strives to achieve the slogan, ‘think globally but act locally’, through dynamic interdependence between headquarters and subsidiaries and/or local intermediaries around the world. Companies following such a strategy coordinate their efforts, ensuring local flexibility...

  17. Strategy under uncertainty.

    Courtney, H; Kirkland, J; Viguerie, P

    1997-01-01

    At the heart of the traditional approach to strategy lies the assumption that by applying a set of powerful analytic tools, executives can predict the future of any business accurately enough to allow them to choose a clear strategic direction. But what happens when the environment is so uncertain that no amount of analysis will allow us to predict the future? What makes for a good strategy in highly uncertain business environments? The authors, consultants at McKinsey & Company, argue that uncertainty requires a new way of thinking about strategy. All too often, they say, executives take a binary view: either they underestimate uncertainty to come up with the forecasts required by their companies' planning or capital-budging processes, or they overestimate it, abandon all analysis, and go with their gut instinct. The authors outline a new approach that begins by making a crucial distinction among four discrete levels of uncertainty that any company might face. They then explain how a set of generic strategies--shaping the market, adapting to it, or reserving the right to play at a later time--can be used in each of the four levels. And they illustrate how these strategies can be implemented through a combination of three basic types of actions: big bets, options, and no-regrets moves. The framework can help managers determine which analytic tools can inform decision making under uncertainty--and which cannot. At a broader level, it offers executives a discipline for thinking rigorously and systematically about uncertainty and its implications for strategy.

  18. Optimizing decommissioning strategies

    Passant, F.H.

    1993-01-01

    Many different approaches can be considered for achieving satisfactory decommissioning of nuclear installations. These can embrace several different engineering actions at several stages, with time variations between the stages. Multi-attribute analysis can be used to help in the decision making process and to establish the optimum strategy. It has been used in the Usa and the UK to help in selecting preferred sites for radioactive waste repositories, and also in UK to help with the choice of preferred sites for locating PWR stations, and in selecting optimum decommissioning strategies

  19. Reading Comprehension Strategies

    Unal Ulker

    2017-12-01

    Full Text Available The academic success of the university students greatly depends on the mastery of an academic reading skill. However, students as well as teachers, take the learning of this skill for granted, as they tend to presuppose that reading skill is acquired as a part of their secondary education. As a result, most first-year students employ non university strategies to read academic texts, which leads to a surface approach to reading and prevents students from a better understanding of the material. This paper will discuss the strategies that involve students in taking a deep approach to reading academic texts.

  20. Emergency response strategies

    Carrilo, D.; Dias de la Cruz, F.

    1984-01-01

    In the present study is estimated, on the basis of a release category (PWR4) and several accident scenarios previously set up, the emergency response efficacy obtained in the application of different response strategies on each of the above mentioned scenarios. The studied strategies contemplate the following protective measures: evacuation, shelter and relocation. The radiological response has been obtained by means of CRAC2 (Calculation of Reactor Accident Consequences) code, and calculated in terms of absorbed dose equivalent (Whole body and thyroid), as well as early and latent biological effects. (author)

  1. Editorial: Sales Strategy (2010)

    Chris McPhee

    2010-01-01

    The editorial theme for this issue of the OSBR is Sales Strategy. While "marketing" is everything a company does to build interest in its offers, "sales" consists of converting these offers into cash. By "sales strategy," we refer to all sales planning and process development activities leading up to the actual selling of a product or service. In his recent blog post at MaRS Discovery District, Mark Zimmerman answered a question he is frequently asked by the founders of startups: "How do we f...

  2. Strategi i praksis

    Holm, Michael Jessen; Jenster, Per; Junghagen, Sven

    Præsentation af seks danske små og mellemstore virksomheder, som alle har været succesfulde inden for deres metier. Gennem en belysning af hver virksomheds strategiske situation og udviklingsinitiativer skabes et billede af hvorledes strategi praktiseres i disse virksomheder......Præsentation af seks danske små og mellemstore virksomheder, som alle har været succesfulde inden for deres metier. Gennem en belysning af hver virksomheds strategiske situation og udviklingsinitiativer skabes et billede af hvorledes strategi praktiseres i disse virksomheder...

  3. Prodrug Strategies for Paclitaxel

    Ziyuan Meng

    2016-05-01

    Full Text Available Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective.

  4. Dissemination and Exploitation Strategy

    Badger, Merete; Monaco, Lucio; Fransson, Torsten

    of Technology in Sweden, Politecnico di Torino in Italy, and Eindhoven University of Technology in the Netherlands. The project is partially funded by the European Commission under the 7th Framework Programme (project no. RI-283746). This report describes the final dissemination and exploitation strategy...... for project Virtual Campus Hub. A preliminary dissemination and exploitation plan was setup early in the project as described in the deliverable D6.1 Dissemination strategy paper - preliminary version. The plan has been revised on a monthly basis during the project’s lifecycle in connection with the virtual...

  5. Mobile Portal Implementation Strategy

    Gao, Ping; Damsgaard, Jan

    2005-01-01

    Mobile portal plays an important role in mobile commerce market. Current literature focuses on static analysis on the value chain of mobile portals. This article provides a dynamic perspective on mobile portal strategy. Drawing upon network economics, we describe mobile portal implementation...... as a fourphase process. In different phase, a portal provider has various challenges to overcome and adopt diverse strategies, and correspondingly the regulator has different foci. The conceptual framework proposed in this article offers a basis for further analyses on the market dynamics of mobile commerce......, and can be generalized to studying other networked technologies...

  6. Marketing Management and Strategy

    This book gives readers an understanding of the factors that shape the marketing decisions of managers who operate in African economies. It brings together fifteen African cases written by scholars and executives with rich knowledge of business practices in Africa. By combining theoretical insights...... undergraduate and graduate students in marketing, international strategy and international business who require an understanding of African business...... with practical information from the cases, the reader is introduced to issues relating to marketing strategy formulation, managerial actions in designing and implementing marketing decisions, as well as the operational contexts within which these actions are taken. The book is essential reading for both...

  7. Dissemination Strategy Report

    Badger, Merete; Kjems, Jørgen; Farinetti, Laura

    This report describes the dissemination and exploitation strategy for project Virtual Campus Hub (EU FP7 contract RI-283746). The project duration is October 2011-13 and the dissemination and exploitation plan will be revised continuously during the project’s lifecycle.......This report describes the dissemination and exploitation strategy for project Virtual Campus Hub (EU FP7 contract RI-283746). The project duration is October 2011-13 and the dissemination and exploitation plan will be revised continuously during the project’s lifecycle....

  8. Current therapeutic vaccination and immunotherapy strategies for HPV-related diseases.

    Skeate, Joseph G; Woodham, Andrew W; Einstein, Mark H; Da Silva, Diane M; Kast, W Martin

    2016-06-02

    Carcinomas of the anogenital tract, in particular cervical cancer, remains one of the most common cancers in women, and represent the most frequent gynecological malignancies and the fourth leading cause of cancer death in women worldwide. Human papillomavirus (HPV)-induced lesions are immunologically distinct in that they express viral antigens, which are necessary to maintain the cancerous phenotype. The causal relationship between HPV infection and anogenital cancer has prompted substantial interest in the development of therapeutic vaccines against high-risk HPV types targeting the viral oncoproteins E6 and E7. This review will focus on the most recent clinical trials for immunotherapies for mucosal HPV-induced lesions as well as emerging therapeutic strategies that have been tested in pre-clinical models for HPV-induced diseases. Progress in peptide- and protein-based vaccines, DNA-based vaccines, viral/bacterial vector-based vaccines, immune checkpoint inhibition, immune response modifiers, and adoptive cell therapy for HPV will be discussed.

  9. Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients.

    Morse, Michael A; Chaudhry, Arvind; Gabitzsch, Elizabeth S; Hobeika, Amy C; Osada, Takuya; Clay, Timothy M; Amalfitano, Andrea; Burnett, Bruce K; Devi, Gayathri R; Hsu, David S; Xu, Younong; Balcaitis, Stephanie; Dua, Rajesh; Nguyen, Susan; Balint, Joseph P; Jones, Frank R; Lyerly, H Kim

    2013-08-01

    First-generation, E1-deleted adenovirus subtype 5 (Ad5)-based vectors, although promising platforms for use as cancer vaccines, are impeded in activity by naturally occurring or induced Ad-specific neutralizing antibodies. Ad5-based vectors with deletions of the E1 and the E2b regions (Ad5 [E1-, E2b-]), the latter encoding the DNA polymerase and the pre-terminal protein, by virtue of diminished late phase viral protein expression, were hypothesized to avoid immunological clearance and induce more potent immune responses against the encoded tumor antigen transgene in Ad-immune hosts. Indeed, multiple homologous immunizations with Ad5 [E1-, E2b-]-CEA(6D), encoding the tumor antigen carcinoembryonic antigen (CEA), induced CEA-specific cell-mediated immune (CMI) responses with antitumor activity in mice despite the presence of preexisting or induced Ad5-neutralizing antibody. In the present phase I/II study, cohorts of patients with advanced colorectal cancer were immunized with escalating doses of Ad5 [E1-, E2b-]-CEA(6D). CEA-specific CMI responses were observed despite the presence of preexisting Ad5 immunity in a majority (61.3 %) of patients. Importantly, there was minimal toxicity, and overall patient survival (48 % at 12 months) was similar regardless of preexisting Ad5 neutralizing antibody titers. The results demonstrate that, in cancer patients, the novel Ad5 [E1-, E2b-] gene delivery platform generates significant CMI responses to the tumor antigen CEA in the setting of both naturally acquired and immunization-induced Ad5-specific immunity.

  10. Understanding Betting Strategy

    Saha, Kanika; Lahiri, Ananya

    2017-01-01

    In this paper, we present betting strategy of a football game using probability theory. We know all betting houses offer slightly unfair odds towards the player. Here we discuss a simple way to figure out which betting house is offering relatively better odds compared to others for English Premier League. However, this methodology can be adopted for another league football match.

  11. Are Communication Strategies Teachable?

    Lewis, Samantha

    2011-01-01

    This article discusses the teachability of communication strategies in the EFL classroom. As well as reflecting on the nature of speech production in the mother tongue, it looks at some of the difficulties encountered when speaking in a foreign language and the inherent difficulties in "teaching" speaking as a skill. It focuses on different types…

  12. Technology Planning Strategies

    Decker, Kathy

    2004-01-01

    Effective planning strategies drive achievement of an overall technology goal to increase access to electronic information in real time in order to increase efficiency, productivity, and communication across campus. Planning relies on providing access, 'Anytime Anywhere' to student information, calendar, email, course management tools, and the…

  13. CO2-strategier

    Jørgensen, Michael Søgaard

    2008-01-01

    I 2007 henvendte Lyngby-Taarbæk kommunens Agenda 21 koordinator sig til Videnskabsbutikken og spurgte om der var interesse for at samarbejde om CO2-strategier. Da Videnskabsbutikken DTU er en åben dør til DTU for borgerne og deres organisationer, foreslog Videnskabsbutikken DTU at Danmarks...

  14. Terrorism and Investigation Strategies

    Muhammad Mustofa

    2005-01-01

    This paper discussed that, for successful implementation of the strategies in investigating terrorism, besides requiring professional skilled investigators, there are some additional requirements that need to be fulfilled. Effective and long term prevention of terrorism should be directed towards producing good social welfare and to minimize every condition that may be conducive to the emergence of terrorism, such as discrimination and marginalization.

  15. Management strategies for fibromyalgia

    Le Marshall KF

    2011-07-01

    Full Text Available Kim Francis Le Marshall, Geoffrey Owen LittlejohnDepartments of Rheumatology and Medicine, Monash Medical Centre and Monash University, Victoria, AustraliaDate of preparation: 14 June 2011Clinical question: What are the effective, evidence-based strategies available for the management of fibromyalgia?Conclusion: There are a number of management strategies available with robust evidence to support their use in clinical practice.Definition: Fibromyalgia is a complex pain syndrome characterized by widespread, chronic muscular pain and tenderness, disordered sleep, emotional distress, cognitive disturbance, and fatigue. Its prevalence is estimated to be 3%–5% in the population and higher yet in patients with comorbid rheumatic diseases.Level of evidence: Systematic reviews, meta-analyses, randomized controlled trials (RCTs.Search sources: PubMed, Cochrane Library, manual searchConsumer summary: Key messages for patients and clinicians are:1. There are many effective pharmacological management strategies available for fibromyalgia.2. A nonpharmacological, multicomponent approach utilizing education, aerobic exercise, psychological therapy, and other strategies is also effective for fibromyalgia.3. Despite the significant and, at times, disabling physical and psychological symptoms, fibromyalgia can be a manageable condition with a potentially good outcome.Keywords: fibromyalgia, pain, treatment, management, evidence 

  16. Delta hedging strategies comparison

    De Giovanni, Domenico; Ortobelli, S.; Rachev, S.T.

    2008-01-01

    In this paper we implement dynamic delta hedging strategies based on several option pricing models. We analyze different subordinated option pricing models and we examine delta hedging costs using ex-post daily prices of S&P 500. Furthermore, we compare the performance of each subordinated model...

  17. Resilient Grid Operational Strategies

    Pasqualini, Donatella [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-03-01

    Extreme weather-related disturbances, such as hurricanes, are a leading cause of grid outages historically. Although physical asset hardening is perhaps the most common way to mitigate the impacts of severe weather, operational strategies may be deployed to limit the extent of societal and economic losses associated with weather-related physical damage.1 The purpose of this study is to examine bulk power-system operational strategies that can be deployed to mitigate the impact of severe weather disruptions caused by hurricanes, thereby increasing grid resilience to maintain continuity of critical infrastructure during extreme weather. To estimate the impacts of resilient grid operational strategies, Los Alamos National Laboratory (LANL) developed a framework for hurricane probabilistic risk analysis (PRA). The probabilistic nature of this framework allows us to estimate the probability distribution of likely impacts, as opposed to the worst-case impacts. The project scope does not include strategies that are not operations related, such as transmission system hardening (e.g., undergrounding, transmission tower reinforcement and substation flood protection) and solutions in the distribution network.

  18. Evolutionary Stable Strategy

    IAS Admin

    Biologists refer to this as a 'limited war' or conventional (ritualistic) strategy (not ... Now allow us to explain a few things about cat behaviour, which will help .... getting injured, but it also helped save both energy and time, vital .... intelligent and.

  19. Thermal reactor strategy

    1981-01-01

    This statement sets down briefly the CEGB's views on the requirement for nuclear power and outlines current progress in the implementation of the CEGB's thermal reactor strategy. The programme is traced historically, together with statements of Government policy. The place of Magnox, AGR, SGHWR, PWR and fast breeder reactors is discussed. Advantages and problems associated with the various types are outlined. (U.K.)

  20. When Strategy Ends

    Vestenskov, David; Jørgensen, Lars Wille

    2014-01-01

    This chapter deals with the end of strategy, that is, conflict termination and how strategic achievements are measured and evaluated. It claims that the modern intervention of choice by NATO and its allies are transformation wars and challenges the concept of victory in such wars. Through a compa...

  1. Evolutionary Stable Strategy

    Home; Journals; Resonance – Journal of Science Education; Volume 21; Issue 9. Evolutionary Stable Strategy: Application of Nash Equilibrium in Biology. General Article Volume 21 Issue 9 September 2016 pp 803- ... Keywords. Evolutionary game theory, evolutionary stable state, conflict, cooperation, biological games.

  2. Inflation Protected Investment Strategies

    Mirco Mahlstedt

    2016-03-01

    Full Text Available In this paper, a dynamic inflation-protected investment strategy is presented, which is based on traditional asset classes and Markov-switching models. Different stock market, as well as inflation regimes are identified, and within those regimes, the inflation hedging potential of stocks, bonds, real estate, commodities and gold are investigated. Within each regime, we determine optimal investment portfolios driven by the investment idea of protection from losses due to changing inflation if inflation is rising or high, but decoupling the performance from inflation if inflation is low. The results clearly indicate that these asset classes behave differently in different stock market and inflation regimes. Whereas in the long-run, we agree with the general opinion in the literature that stocks and bonds are a suitable hedge against inflation, we observe for short time horizons that the hedging potential of each asset class, especially of real estate and commodities, depend strongly on the state of the current market environment. Thus, our approach provides a possible explanation for different statements in the literature regarding the inflation hedging properties of these asset classes. A dynamic inflation-protected investment strategy is developed, which combines inflation protection and upside potential. This strategy outperforms standard buy-and-hold strategies, as well as the well-known 1 N -portfolio.

  3. The generic strategy trap.

    Miller, D

    1992-01-01

    Management experts claim that for a company to thrive, it must concentrate on a single generic strategy--on one thing it does better than its rivals. But specialization also has its disadvantages. The author suggests that a broader, mixed approach may be preferable.

  4. Comprehension Strategy Gloves.

    Newman, Gayle

    2002-01-01

    Describes the idea of creating a glove for each of the comprehension strategies for use with different text structures. Notes that the gloves serve as a multisensory approach by providing visual clues through icons on each finger and the palm. Discusses three different gloves: the prereading glove, the narrative text structure glove, and the…

  5. The EU's Biofuel Strategy

    2006-01-01

    The EU is supporting biofuels, with the aim of reducing greenhouse-gas emission, encouraging the decarbonisation of fuels used in transportation, diversifying energy procurement, offering new earning opportunities in rural areas, and developing long-term replacements for oil. We publish lengthy excerpts from the recent Communication, COM(2006) 34def. which describes the strategy adopted by the Commission [it

  6. Behavioural strategy: Adaptability context

    Piórkowska Katarzyna

    2016-05-01

    Full Text Available The paper is embedded in the following fields: strategic management in terms of behavioural strategy concept, adaptability construct, and micro-foundations realm as well as organizational theory and psychology. Moreover, the paper concerns to some extent a multi-level approach in strategic management involving individual, team, and organizational level. The aim of the paper is to contribute to extend, on one hand, the ascertainment set in the field of behavioural strategy as behavioural strategy encompasses a mindboggling diversity of topics and methods and its conceptual unity has been hard to achieve (Powell, Lovallo, Fox 2011, p. 1371, and on the other hand, to order mixed approaches to adaptability especially to gain insights on micro-level adapting processes (individual adaptability and adaptive performance in terms of the multi-level approach. The method that has been used is literature studies and the interference is mostly deductive. The structure of the manuscript is four-fold. The first part involves the considerations in the field of adaptability and adaptive performance at the individual level. The issues of adaptability and adaptive performance at the team level have been presented in the second part. The third part encompasses the organizational adaptability assertions. Finally, the conclusion, limitations of the considerations highlighted as well as the future research directions have been emphasized. The overarching key finding is that the behavioural strategy concept may constitute the boundary spanner in exploring and explaining adaptability phenomenon at different levels of analysis.

  7. Towards effective learning strategies

    Bergstra, Anouk Simone

    2015-01-01

    To become self-regulative in learning, students should be able to deploy various learning strategies in a flexible way. For this, they require specific knowledge and skills, referred to as metacognition. Metacognition is a complex concept that is difficult for teachers to teach to their students.

  8. INOVASI DAN STRATEGI PENCAPAIANNYA

    Liem Ferryanto

    2009-01-01

    Full Text Available Innovation is the way of life of any institution to profitably sustain its life. It starts with empathy, the ability to reach outside of ourselves and walk in someone else’s shoes, and optimal implementation of the newly advanced technology. Innovation shows its results through continuously hard working efforts known as "10 Thousand Hours Rule". As world uncertainty creates complexity we, instead of predicting, should therefore anticipate the future by creating and managing real options on contingent projects or elements of alternative optimal strategies. This should reflect into our portfolio strategy. Abstract in Bahasa Indonesia: Inovasi merupakan darah bagi suatu institusi untuk bisa hidup berkelanjutan serta menguntungkan. Inovasi berupa penemuan baru secara sistematis yang berawal dari empati, kemampuan untuk melihat dunia melalui mata orang lain, dan pemanfaatan secara optimal kemajuan teknologi yang ada. Inovasi baru menghasilkan buahnya melalui kerja keras, yaitu dengan mengikuti “Aturan 10 Ribu Jam” secara berkesinambungan. Ketidakpastian, interaksi, keterbatasan dan degradasi menciptakan kompleksitas tentang kebutuhan dan solusi di masa depan. Oleh sebab itu daripada meramalkan risiko yang bakal terjadi, kita sebaiknya memasang strategi berupa skenario untuk mereduksi akibat dari risiko masa depan yang tidak kita mengerti. Skenario ini dapat diperoleh lewat penciptaan dan penanganan beberapa pilihan nyata atas semua proyek antisipatif yang ada. Kata kunci: Inovasi, ketidakpastian dan kompleksitas, aturan 10 ribu jam, paradoks strategi, peta jalan, empati, kerja berkesinambungan.

  9. NASA science communications strategy

    1995-01-01

    In 1994, the Clinton Administration issued a report, 'Science in the National Interest', which identified new national science goals. Two of the five goals are related to science communications: produce the finest scientists and engineers for the 21st century, and raise scientific and technological literacy of all Americans. In addition to the guidance and goals set forth by the Administration, NASA has been mandated by Congress under the 1958 Space Act to 'provide for the widest practicable and appropriate dissemination concerning its activities and the results thereof'. In addition to addressing eight Goals and Plans which resulted from a January 1994 meeting between NASA and members of the broader scientific, education, and communications community on the Public Communication of NASA's Science, the Science Communications Working Group (SCWG) took a comprehensive look at the way the Agency communicates its science to ensure that any changes the Agency made were long-term improvements. The SCWG developed a Science Communications Strategy for NASA and a plan to implement the Strategy. This report outlines a strategy from which effective science communications programs can be developed and implemented across the agency. Guiding principles and strategic themes for the strategy are provided, with numerous recommendations for improvement discussed within the respective themes of leadership, coordination, integration, participation, leveraging, and evaluation.

  10. Modeling and Interrogative Strategies.

    Denney, Douglas R.

    Three studies to determine the effects of adult models on interrogative strategies of children (ages 6-11) are reviewed. Two issues are analyzed: (1) the comparative effectiveness of various types of modeling procedures for changing rule-governed behaviors, and (2) the interaction between observational learning and the developmental level of the…

  11. The Seven Step Strategy

    Schaffer, Connie

    2017-01-01

    Many well-intended instructors use Socratic or leveled questioning to facilitate the discussion of an assigned reading. While this engages a few students, most can opt to remain silent. The seven step strategy described in this article provides an alternative to classroom silence and engages all students. Students discuss a single reading as they…

  12. Gazprom: Russia's strategy

    Lizin, A.M.; Zeisler, N.

    2007-01-01

    Seventeen years after the splitting up of the Soviet empire, Russia is looking again for huge international ambitions. Its main advantage in this power search will is its energy resources. Production area, but also transit area between Asia, central Asia, Caucasus and Europe, Russia is an inevitable partner and wishes to take advantage of this strategic position. Gazprom, the hugest gas company in the world, is totally under the control of the government. Therefore, the Kremlin has made gas its main political and diplomatic weapon. Such an energetic imperialisms has strong economical and political consequences on the rest of Europe as illustrated by the recent Ukrainian crisis. The reconstruction of an energy empire similar to the one of the hottest days of the cold war worries also the USA. This study is a collective work carried out by students of the Sciences Po school of Paris in the framework of the 'international organizations' seminar given by by A.M Lizin, president of the Belgium senate and chairwoman of the human rights commission of the organization for European security and cooperation. Content: Gazprom's international strategy, Gazprom: an omnipotent gas company, Gazprom's international strategy at the service of the Russian foreign policy, Gazprom's energy stake and strategies, Gazprom and Armenia, Gazprom and Azerbaijan, Gazprom and Belgium, Gazprom and Bielorussia, Gazprom and Iberia, French position in energy stakes and in front of Gazprom, Gazprom's difficulties in Hungary, Uzbekistan and Kyrgyzstan in front of Gazprom, Gazprom and the US strategy. (J.S.)

  13. Sensemaking and strategy

    Nielsen, Renate

    of these processes my focus will be on how sensemaking processes are transformed into strategy and policies to be applied in daily routines. This way, I believe, we can learn more about how organisations develop and use this knowledge to gain further competitiveness. I will look at these processes on various...

  14. Price strategy and pricing strategy: terms and content identification

    Panasenko Tetyana

    2015-11-01

    Full Text Available The article is devoted to the terminology and content identification of seemingly identical concepts "price strategy" and "pricing strategy". The article contains evidence that the price strategy determines the direction, principles and procedure of implementing the company price policy and pricing strategy creates a set of rules and practical methods of price formation in accordance with the pricing strategy of the company.

  15. Income generation strategy in the overall hierarchy of business strategy

    S.V. Shastun

    2015-03-01

    Full Text Available To comply with claims of a modern economy significantly increases the role of strategic revenue management in enterprises, and in the first place, strategic management of income generation. The concept of an income generation strategy is not disclosed in the scientific literature, in this connection in article describes and analyzes the main concepts which are similar in content to the category of income generation strategy of enterprises (strategy analysis of income, revenue strategy, development strategy of income. Defines the role and importance of income generation strategy in modern management practices and presented the author's definition of income generation strategy. In article considered income generation strategy a compared to financial strategy of the enterprise and proved the difference between them. Show the position of income generation strategy in the hierarchy of strategies of enterprises and spheres of influence at all levels of the company. Income generation strategy described as interlevel, components of which are elements of all the functional and resource strategies and established a direct and feedback between the income generation strategy and corporate, competitive, functional and resource strategy.

  16. Five types of organizational strategy

    Steensen, Elmer Fly

    2014-01-01

    Models in the strategy field defining the strategy concept emphasize schools of thought or strategy perspectives, but not how to define the idiosyncratic composition of an organization’s strategy content. Based on a literature review in which meanings have been attached to the concept, this paper...... presents a new model including five types of organizational strategy. The model emphasizes that key influencers may make heterogeneous contributions to an organization’s strategy and also that significant effects may result from interaction between types of strategy....

  17. Strategy of technology and innovation

    Kim, Yeon Min

    1998-10-01

    This book introduces strategy of technology and innovation which includes design and development of strategy of technology, performance of strategy of technology and building and practice of strategy of development. The contents of this book are form of industrial innovation, act in strategy, advantage of technical innovation, new perspective of studying and innovation, alliance with competitor, cost of transmission and innovation, learning cycle of new product and power of consistency of product.

  18. Probability matching and strategy availability

    J. Koehler, Derek; Koehler, Derek J.; James, Greta

    2010-01-01

    Findings from two experiments indicate that probability matching in sequential choice arises from an asymmetry in strategy availability: The matching strategy comes readily to mind, whereas a superior alternative strategy, maximizing, does not. First, compared with the minority who spontaneously engage in maximizing, the majority of participants endorse maximizing as superior to matching in a direct comparison when both strategies are described. Second, when the maximizing strategy is brought...

  19. Editorial: Sales Strategy (2010

    Chris McPhee

    2010-09-01

    Full Text Available The editorial theme for this issue of the OSBR is Sales Strategy. While "marketing" is everything a company does to build interest in its offers, "sales" consists of converting these offers into cash. By "sales strategy," we refer to all sales planning and process development activities leading up to the actual selling of a product or service. In his recent blog post at MaRS Discovery District, Mark Zimmerman answered a question he is frequently asked by the founders of startups: "How do we find a good sales person?" In short, his answer is "Don't." This is not meant as a slight to sales professionals, but rather, Zimmerman is advocating that companies should not equate having sales professionals to having a sales strategy. Sales professionals have a critical role to play in a company's success, but they are being given an impossible task if asked to sell something that has not been validated with customers. Zimmerman explains that sales professionals should be hired only once a company has validated that the value proposition resonates with customers and that the sales model will be effective. This lesson also applies to established companies, where existing sales staff require this same foundation to be effective. So how does a company determine whether its value proposition resonates with customers? The answer, of course, is to talk to customers. In the OSBR and elsewhere, the need for early customer input is a dominant theme in recent discussions of product development, marketing, and now sales strategy. By talking to customers, listening to how they describe their needs, and interpreting how their needs could be met, a value proposition can tested and refined. It is far more efficient and effective to iteratively refine a value proposition before attempting to sell than to attempt a salvage operation in response to slumping sales. Customer input is also a critical ingredient in developing an effective sales strategy. In this issue of the

  20. CELEBRITY ENDORSEMENT STRATEGY

    CHIOSA ANA RALUCA

    2012-09-01

    Full Text Available Brands ofen use celebrities to get impact, because they are seen by the public as credible source of informationabout product or company. People aspire to the values and lifestyles of celebrities. Consumers selectively integrateperceived values and behavior of celebrities they admire, to build and communicate their own identity.Celebrity endorser is a person who enjoys high reputation and prestige, beeing known to most people. Celebrityendorsement is a relevant strategy for the product categories which improve the image (such as fashion, perfumes orcosmetics.This paper presents types, techniques and models of analysing celebrities’ efficiency in endorsingbrands/products. Celebrity endorsement has become one of the communication strategies used in marketing to buildcongruence between brand image and consumers. Famous persons exert their influence on consumer throughperceived attributes such as expertise, trustworthiness, attractiveness, familiarty and likeability.

  1. Corporate Climate Strategies

    Bjarnø, Ole-Christian; Maltha, Jonas

    2003-01-01

    at establishing operational guidelines for energy-intensive industries to navigate and gain competitive advantages in a diverse and risky business environment. Based on a literature study of strategic environmental management and carbon management, this article aims to establish such guidelines for corporate......Since the 1997 Kyoto Protocol on Climate Change outlined the first embryonic plans for an emissions market, a significant uncertainty about the value on carbon, in concert with a swift development in energy business, has brought about the concept of carbon management. Carbon management aims...... strategic carbon management for medium to large companies with greenhouse gas intensive activities. The guideline framework is established on the basis of a generic strategy structure in which the factors influencing corporate climate strategies are identified. It is concluded that there is little rationale...

  2. Mechanical ventilation strategies.

    Keszler, Martin

    2017-08-01

    Although only a small proportion of full term and late preterm infants require invasive respiratory support, they are not immune from ventilator-associated lung injury. The process of lung damage from mechanical ventilation is multifactorial and cannot be linked to any single variable. Atelectrauma and volutrauma have been identified as the most important and potentially preventable elements of lung injury. Respiratory support strategies for full term and late preterm infants have not been as thoroughly studied as those for preterm infants; consequently, a strong evidence base on which to make recommendations is lacking. The choice of modalities of support and ventilation strategies should be guided by the specific underlying pathophysiologic considerations and the ventilatory approach must be individualized for each patient based on the predominant pathophysiology at the time. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Hybrid strategies in nanolithography

    Saavedra, Hector M; Mullen, Thomas J; Zhang Pengpeng; Dewey, Daniel C; Claridge, Shelley A; Weiss, Paul S [Department of Chemistry, The Pennsylvania State University, University Park, PA 16802 (United States)], E-mail: psw@cnsi.ucla.edu

    2010-03-15

    Hybrid nanoscale patterning strategies combine the registration and addressability of conventional lithographic techniques with the chemical and physical functionality enabled by intermolecular, electrostatic and/or biological interactions. This review aims to highlight and to provide a comprehensive description of recent developments in hybrid nanoscale patterning strategies that enhance existing lithographic techniques or can be used to fabricate functional chemical patterns that interact with their environment. These functional structures create new capabilities, such as the fabrication of physicochemical surfaces that can recognize and capture analytes from complex liquid or gaseous mixtures. The nanolithographic techniques we describe can be classified into three general areas: traditional lithography, soft lithography and scanning-probe lithography. The strengths and limitations of each hybrid patterning technique will be discussed, along with the current and potential applications of the resulting patterned, functional surfaces.

  4. Canadian hydrogen strategies

    Fairlie, M.; Scepanovic, V.; Dube, J.; Hammerli, M.; Taylor, J.

    2004-01-01

    'Full text:' In May of 2004, industry and government embarked on a process to create a strategic plan for development of the 'hydrogen economy' in Canada. The process was undertaken to determine how the development and commercialization of hydrogen technologies could be accelerated to yield a 'visible' reduction in greenhouse gases within the timeframe of Kyoto, while establishing a direction that addresses the necessity of far greater reductions in the future. Starting with a meeting of twenty seven experts drawn from the hydrogen technology, energy and transportation industries and government, a vision and mission for the planning process was developed. Two months later a second meeting was held with a broader group of stakeholders to develop hydrogen transition strategies that could achieve the mission, and from identifying the barriers and enablers for these strategies, an action plan was created. This paper reviews the results from this consultation process and discusses next steps. (author)

  5. Exit-strategies

    Mørck, Line Lerche; Palm, Anne-Mette; Sys Møller-Andersen, Camilla

    different empirical sources. To develop and extend an "exit-prototype" about conditions of importance for moving beyond a gang/criminal position, we have analyzed documents (from newspapers and books), involved ex-gang members, social workers and experts as co-researchers in interviews, "gang......This paper is about exit-strategies, constructing a theoretical and empirical informed analysis of current societal conditions that influence motor cycle gangs such as Hells Angels or Bandidos and other ‘wild' youth' possibilities and limitations for moving beyond criminal activities. We especially...... focus on the involved communities in the current Danish gang-conflict, which escalated with deadly killings in 2008, and thereby became a so called "gang-war". We will start out presenting different practice notions of exit, and we will extend and discuss understandings of "exit-strategies" by analyzing...

  6. COINCO - Strategy 2025

    Jespersen, Per Homann; Jensen, Anne; Lundgaard, Jacob

    2007-01-01

    InvestitionsBank des Landes Brandenburg   The regions and cities in the COINCO-corridor Oslo-Göteborg-Malmö-Copenhagen-Berlin have worked out a COINCO Strategy 2025 for becoming one of the world's most competitive regions. Behind this strategy is a political will to utilize mutual strengths and together become....... Therefore a number of knowledge institutions have to be ormed organized around the ‘triple helix'-principle - a tight collaboration between business, administration and knowledge producers, especially universities. Also new ways of collaboration have to be explored - ‘network governance' has to be developed......The group of COINCO Partners Københavns Kommune (Lead partner) Bornholms Regionskommune Oslo Kommune Østfold Fylkeskommune Akershus Fylkeskommune Business Region Göteborg AB Region Skåne Malmö Stad Lund Kommune Landskrona Kommune Helsingborg Kommune Region Halland Region Västra Götaland...

  7. Nuclear fuel strategies

    Rippon, S.

    1989-01-01

    The paper reports on two international meetings on nuclear fuel strategies, one organised by the World Nuclear Fuel Market in Seville (Spain) October 1988, and the other organised by the American and European nuclear societies in Washington (U.S.A.) November 1988. At the Washington meeting a description was given of the uranium supply and demand market, whereas free trade in uranium was considered in Seville. Considerable concern was expressed at both meetings on the effect on the uranium and enrichment services market of very low prices for spot deals being offered by China and the Soviet Union. Excess enrichment capacity, the procurement policies of the USA and other countries, and fuel cycle strategies, were also discussed. (U.K.)

  8. Modern Competitive Strategy Firm

    František Bartes

    2010-01-01

    Full Text Available The article deals with problems of an ever increasing number of cases of successful application of old combat strategies in business practice. Nevertheless, the author refuses the so called “direct conflict“ of firms, when it is really fought for victory on the market. His approach is based on the philosophy of “victory without fight“, in other words – of achieving the aim without direct conflict with the rival firm.In the end he comes to the conclusion that combat philosophies are more and more often incorporated into classical approach of strategic firm control and become the integral part of philosophy of management. At the close happens to opinion that the one from basic factors absolutely necessary to creation such strategy at company, is necessary present so-called „creative intelligence“.

  9. SPORT MARKETING MIX STRATEGIES

    Alexandru Lucian MIHAI

    2013-01-01

    This paper presents a brief overview of a significant element of the sport marketing management model called the marketing mix. The marketing mix is crucial because it defines the sport business, and much of the sport marketer’s time is spent on various functions within the marketing mix. The marketing mix is the strategic combination of the product, price, place and promotion elements. These elements are typically called the four Ps of marketing. Decisions and strategies for each are importa...

  10. CELEBRITY ENDORSEMENT STRATEGY

    CHIOSA ANA RALUCA

    2012-01-01

    Brands ofen use celebrities to get impact, because they are seen by the public as credible source of information about product or company. People aspire to the values and lifestyles of celebrities. Consumers selectively integrate perceived values and behavior of celebrities they admire, to build and communicate their own identity. Celebrity endorser is a person who enjoys high reputation and prestige, beeing known to most people. Celebrity endorsement is a relevant strategy for the product ca...

  11. Vaccine strategies: Optimising outcomes.

    Hardt, Karin; Bonanni, Paolo; King, Susan; Santos, Jose Ignacio; El-Hodhod, Mostafa; Zimet, Gregory D; Preiss, Scott

    2016-12-20

    Successful immunisation programmes generally result from high vaccine effectiveness and adequate uptake of vaccines. In the development of new vaccination strategies, the structure and strength of the local healthcare system is a key consideration. In high income countries, existing infrastructures are usually used, while in less developed countries, the capacity for introducing new vaccines may need to be strengthened, particularly for vaccines administered beyond early childhood, such as the measles or human papillomavirus (HPV) vaccine. Reliable immunisation service funding is another important factor and low income countries often need external supplementary sources of finance. Many regions also obtain support in generating an evidence base for vaccination via initiatives created by organisations including World Health Organization (WHO), the Pan American Health Organization (PAHO), the Agence de Médecine Préventive and the Sabin Vaccine Institute. Strong monitoring and surveillance mechanisms are also required. An example is the efficient and low-cost approaches for measuring the impact of the hepatitis B control initiative and evaluating achievement of goals that have been established in the WHO Western Pacific region. A review of implementation strategies reveals differing degrees of success. For example, in the Americas, PAHO advanced a measles-mumps-rubella vaccine strategy, targeting different population groups in mass, catch-up and follow-up vaccination campaigns. This has had much success but coverage data from some parts of the region suggest that children are still not receiving all appropriate vaccines, highlighting problems with local service infrastructures. Stark differences in coverage levels are also observed among high income countries, as is the case with HPV vaccine implementation in the USA versus the UK and Australia, reflecting differences in delivery settings. Experience and research have shown which vaccine strategies work well and the

  12. Hand hygiene strategies

    Yazaji, Eskandar Alex

    2011-01-01

    Hand hygiene is one of the major players in preventing healthcare associated infections. However, healthcare workers compliance with hand hygiene continues to be a challenge. This article will address strategies to help improving hand hygiene compliance. Keywords: hand hygiene; healthcare associated infections; multidisciplinary program; system change; accountability; education; feedback(Published: 18 July 2011)Citation: Journal of Community Hospital Internal Medicine Perspectives 2011, 1: 72...

  13. Competitive strategy : Sorrin Puutarha

    Haaristo, Emilia

    2010-01-01

    The thesis handles the fresh food product industry in Finland and especially one company operating in the industry and its competitive position. Sorrin Puutarha manufactures ready-to-use fresh cut salad bag, which is sold in the grocery stores. The objective of the thesis was to find competitive advantages of the case company. Once the competitive advantages were identified the purpose was to choose a fitting competitive strategy that would strengthen those advantages. The field study was con...

  14. Intelligent National Strategy

    2008-01-01

    China has unveiled a strategic plan aimed at strengthening I PR protection and enhancing the country’s overall competitiveness China’s State Council published the Outline of the National Intellectual Property Strategy in early June, taking on one of the country’s major bugbears. The plan aims to improve the use of intellectual property rights (IPR) by 2020 and consists of a preface, guiding prin- ciples and strategic goals, strategic focuses,

  15. Implementing acquisition strategies

    Montgomery, G. K.

    1997-01-01

    The objective of this paper is to address some of the strategies necessary to effect a successful asset or corporate acquisition. Understanding the corporate objective, the full potential of the asset, the specific strategies to be employed, the value of time, and most importantly the interaction of all these are crucial, for missed steps are likely to result in missed opportunities. The amount of factual information that can be obtained and utilized in a timely fashion is the largest single hurdle to the capture of value in the asset or corporate acquisition. Fact, familiarity and experience are key in this context. The importance of the due diligence process prior to title or data transfer cannot be overemphasized. Some of the most important assets acquired in a merger may be the people. To maximize effectiveness, it is essential to merge both existing staff and those that came with the new acquisition as soon as possible. By thinking together as a unit, knowledge and experience can be applied to realize the potential of the asset. Hence team building is one of the challenges, doing it quickly is usually the most effective. Developing new directions for the new enlarged company by combining the strengths of the old and the new creates more value, as well as a more efficient operation. Equally important to maximizing the potential of the new acquisition is the maintenance of the momentum generated by the need to grow that gave the impetus to acquiring new assets in the first place. In brief, the right mix of vision, facts and perceptions, quick enactment of the post-close strategies and keeping the momentum alive, are the principal ingredients of a focused strategy

  16. Real Time Strategy Language

    Hayes, Roy; Beling, Peter; Scherer, William

    2014-01-01

    Real Time Strategy (RTS) games provide complex domain to test the latest artificial intelligence (AI) research. In much of the literature, AI systems have been limited to playing one game. Although, this specialization has resulted in stronger AI gaming systems it does not address the key concerns of AI researcher. AI researchers seek the development of AI agents that can autonomously interpret learn, and apply new knowledge. To achieve human level performance, current AI systems rely on game...

  17. The Nuclear Strategy Tripod

    Nellemann, Camilla

    in the Saudia Arabia. I find coopetitive behavior; vertical integration; technology; market-political ambidexterity; energy policy; industrial policy; and security policy to be the most important factors. My research extends Peng et al.’s (2009) strategy tripod by adding variables that enable it to analyze...... nuclear reactor manufacturers. In a future study, it is relevant to test my hypotheses using a larger sample size....

  18. Greenhouse gas strategy

    2001-03-01

    Because the overall effects of climate change will likely be more pronounced in the North than in other parts of the country, the Government of the Northwest Territories considers it imperative to support global and local actions to reduce greenhouse gas emissions. Government support is manifested through a coordinating role played by senior government representatives in the development of the NWT Greenhouse Gas Strategy, and by participation on a multi-party working committee to identify and coordinate northern actions and to contribute a northern perspective to Canada's National Climate Change Implementation Strategy. This document outlines the NWT Government's goals and objectives regarding greenhouse gas emission reduction actions. These will include efforts to enhance awareness and understanding; demonstrate leadership by putting the Government's own house in order; encouraging action across sectors; promote technology development and innovation; invest in knowledge and building the foundation for informed future decisions. The strategy also outlines the challenges peculiar to the NWT, such as the high per person carbon dioxide emissions compared to the national average (30 tonnes per person per year as opposed to the national average of 21 tonnes per person per year) and the increasing economic activity in the Territories, most of which are resource-based and therefore energy-intensive. Appendices which form part of the greenhouse gas strategy document, provide details of the potential climate change impact in the NWT, a detailed explanation of the proposed measures, an emission forecast to 2004 from industrial processes, fuel combustion and incineration, and a statement of the official position of the Government of the NWT on climate change

  19. Optimal intermittent search strategies

    Rojo, F; Budde, C E; Wio, H S

    2009-01-01

    We study the search kinetics of a single fixed target by a set of searchers performing an intermittent random walk, jumping between different internal states. Exploiting concepts of multi-state and continuous-time random walks we have calculated the survival probability of a target up to time t, and have 'optimized' (minimized) it with regard to the transition probability among internal states. Our model shows that intermittent strategies always improve target detection, even for simple diffusion states of motion

  20. Pure National Security Strategy

    2011-06-01

    gd1ne997g1lu3p7d&size=largest Berlin, Isaiah . Four Essays on Liberty. New York, NY: Oxford University Press, 1970. Bijker, Wiebe E., Thomas P. Hughes and...of the first scientists to formalize what has long been known to kings and emperors is American economist Thomas C. Schelling. In his influential...Robert Pape simplifies the mechanism where coercion affects 45 Schelling, Thomas C. The Strategy of

  1. Strategi Pengembangan Pariwisata Lokal

    Suryani, Ade Irma

    2016-01-01

    Development of the tourism sector is expected to provide benefits to the community, because the tourism sector is one of the sectors of economic development. Tourism activity is one of the non-oil sector is expected to provide a substantial contribution to the economy Negara.Strategis pengebangan tourism in rural areas, namely by taking into account the advice and the existing infrastructure and the application of the stepping tourism. Tourism facilities can be divided into three parts, namel...

  2. PREPARING A MARKETING STRATEGY

    Grönholm, Eija

    2010-01-01

    The objective of this thesis was to prepare a marketing strategy for Living City Centre of Kotka Association. The work was implemented with the members of the association and the executive director Reijo Saksa. Living City Centre of Kotka Association was founded in spring 2006 for promoting living, enjoyable and safe centers in the City of Kotka. The association has two permanent employees. The main duties are managing the Kotka market places and promoting the stakeholder connections betw...

  3. Hotel Marketing Strategy

    Hykšová, Vendula

    2010-01-01

    The Master's Thesis is focused on the hotel marketing strategy issue. The theoretical section summarizes information about an issue of strategic situation analysis and it also involves marketing tools with focus on the hotel and spa industry. The goal of this paper is to design the situation analysis, evaluate the marketing tools used by the hotel and then summarize the results and include suggestions for the analyzed hotel. For the thesis were used literature sources as well as statistical y...

  4. Strategy of technical innovation

    Lee, Ga Jong

    1990-12-01

    This book deals with policy of scientific technique and technical innovation such as research for development and types of technical innovation, historical development and process of technical innovation, economic growth, technology change and investment for research and development, structure and form of technical transfer with the meaning process, from, structure and theory, economic growth and investment of research and development with experiential analysis and case study on strategy of technical innovation in electron and fine chemical industry.

  5. Opaque Nuclear Strategy

    2017-12-01

    Relationship, 0000271219, 1961. https://www.cia.gov/ library / readingroom/docs/DOC_0000271219.pdf. . Trends in South Africa’s Nuclear Security Policies ...official policy or position of the Department of Defense or the U.S. Government. IRB number ____N/A____. 12a. DISTRIBUTION / AVAILABILITY STATEMENT...how Israel and South Africa shaped those strategies. This research may contribute to better understanding possible policies of potential nuclear

  6. Public relations strategy

    Kukovica, T.; Mele, I.

    1996-01-01

    NIMBY (Not In My Back Yard) syndrome has become a major problem in the field of environmental planning. Also in Slovenia. Agency for Radwaste management was established by the Slovene government in 1991. Our main objective is to provide the final disposal of radioactive waste in Slovenia. Overcoming the NIMBY syndrome is therefore the primary aim of Agency's PR (public relations) strategy. Agency's public relations strategy was prepared in 1993. After very unpleasant experience with NIMBY syndrome in local community where one of the potential locations for low and intermediate level repository was identified the strategy was renewed in 1994. It is divided into two parts: information and education. The first one includes providing information to the media, surveys of press clippings, interviews, press conferences, public opinion polls and publishing articles. Agency's first task in the field of education was to prepare different materials like: leaflets, Agency's newspaper and videos. Materials were distributed to various target publics. There is also a special program of lectures for youngsters. All those activities and projects have been successfully realized within the last year. Plans of PR activities for this year are focused on informing the local community about remediation of temporary storage of radioactive waste near village Zavratec. Other new projects are also under preparation like: new leaflets, presentation on Internet, journalist's guide to rad waste management, most frequently asked questions and answers. (author)

  7. STRATEGI KOMUNIKASI PUBLIC RELATIONS

    Artis Artis

    2011-11-01

    Full Text Available Living man in interrelates society. Relationship among human being done by gets communication so man one by another one mutually understand and influence regard for the benefit, it that always been practiced by Public Relations( liaison in a governance and also firm institute to reach to the effect which ices. The institute of Public Relations declares for,”Public Relations is overall effort which be passed off by design and berkesenambungan in order to creates and pet keenness and mutual understanding among an organization with whole its member “. In this case, Public Relations in give distribution on manajement's strategy there is two: First, Doing task as part of Public Relations's strategy and involvement in comprehensive process and gives benefit for management an organization. Both of, Public Relations gets role in management strategy in bring off activity to reach to the effect good one gets internal character and also external one correspond to that desirable by good institute on level governance and firm.

  8. Marketing strategy of company

    Václavíková, Petra

    2008-01-01

    Diplomová práce se zabývá problematikou návrhu marketingové strategie pro internetový obchod www.babylonshop.cz. Na základě shromážděných teoretických východisek a analýzy současného stavu firmy byla navržena marketingová strategie, která má zajistit vyšší počet uskutečněných objednávek. V praktické části jsou zhodnoceny analýzy a sestaveny návrhy a doporučení, které by měly zajistit nárůst prodeje a stálých zákazníků. The thesis deals with the proposition of marketing strategy for the Int...

  9. Manajemen Strategi Pengembangan Pariwisata dengan Pendekatan Blue Ocean Strategy

    Muzha, Vianda Kushardianti

    2015-01-01

    Persaingan industri pariwisata di Indonesia saat ini sangatlah ketat, setiap daerah berlomba untuk menonjolkan keunikannya tersendiri. Dengan adanya persaingan yang sangat ketat tersebut, Kota Batu berusaha keluar dari persaingan (red ocean) dengan menciptkan inovasi baru melalui konsep Blue Ocean Strategy. Blue Ocean Strategy adalah istilah dalam ilmu manajemen strategi yang merujuk pada siasat untuk menciptakan pasar baru yang belum dipenuhi persaingan yang ketat. Blue Ocean Strategy pada d...

  10. Novel strategy for generation and titration of recombinant adeno-associated virus vectors.

    Shiau, Ai-Li; Liu, Pu-Ste; Wu, Chao-Liang

    2005-01-01

    Recombinant adeno-associated virus (rAAV) vectors have many advantages for gene therapeutic applications compared with other vector systems. Several methods that use plasmids or helper viruses have been reported for the generation of rAAV vectors. Unfortunately, the preparation of large-scale rAAV stocks is labor-intensive. Moreover, the biological titration of rAAV is still difficult, which may limit its preclinical and clinical applications. For this study, we developed a novel strategy to generate and biologically titrate rAAV vectors. A recombinant pseudorabies virus (PrV) with defects in its gD, gE, and thymidine kinase genes was engineered to express the AAV rep and cap genes, yielding PS virus, which served as a packaging and helper virus for the generation of rAAV vectors. PS virus was useful not only for generating high-titer rAAV vectors by cotransfection with an rAAV vector plasmid, but also for amplifying rAAV stocks. Notably, the biological titration of rAAV vectors was also feasible when cells were coinfected with rAAV and PS virus. Based on this strategy, we produced an rAAV that expresses prothymosin alpha (ProT). Expression of the ProT protein in vitro and in vivo mediated by rAAV/ProT gene transfer was detected by immunohistochemistry and a bioassay. Taken together, our results demonstrate that the PrV vector-based system is useful for generating rAAV vectors carrying various transgenes.

  11. Strategies for Teaching Astronomy

    Bennett, J.

    2000-12-01

    No matter whether you are teaching school children, undergraduates, or colleagues, a few key strategies are always useful. I will present and give examples for the following five key strategies for teaching astronomy. 1. Provide a Contextual Framework: It is much easier to learn new facts or concepts if they can be ``binned" into some kind of pre-existing mental framework. Unless your listeners are already familiar with the basic ideas of modern astronomy (such as the hierarchy of structure in the universe, the scale of the universe, and the origin of the universe), you must provide this before going into the details of how we've developed this modern picture through history. 2. Create Conditions for Conceptual Change: Many people hold misconceptions about astronomical ideas. Therefore we cannot teach them the correct ideas unless we first help them unlearn their prior misconceptions. 3. Make the Material Relevant: It's human nature to be more interested in subjects that seem relevant to our lives. Therefore we must always show students the many connections between astronomy and their personal concerns, such as emphasizing how we are ``star stuff" (in the words of Carl Sagan), how studying other planets helps us understand our own, and so on. 4. Limit Use of Jargon: The number of new terms in many introductory astronomy books is larger than the number of words taught in many first courses in foreign language. This means the books are essentially teaching astronomy in a foreign language, which is a clear recipe for failure. We must find ways to replace jargon with plain language. 5. Challenge Your Students: Don't dumb your teaching down; by and large, students will rise to meet your expectations, as long as you follow the other strategies and practice good teaching.

  12. Military Strategy Of India

    M. S. Zaitsev

    2017-01-01

    Full Text Available The article analyzes the evolution of military strategy of the Republic of India and key factors that influences its development. New Delhi keeps an eye on the balance of power in South Asia to create favorable conditions for its economic and social development, yet the remaining threats and new challenges still undermine the security and stability in India. The ambitions of China aspiring to power in Asia-Pacific region, combined with its immense military build-up and territorial disputes, cause disturbance in New Delhi. The remaining tensions between India and Pakistan also cause often border skirmishes and medium-scale conflicts. Close relations between China and Pakistan, labeled as “all-weather friendship”, are a source of major concern for India. The fact that both Beijing and Islamabad wield nuclear weapons means that without effective mechanisms of nuclear deterrence any military conflict may turn into a full-scale nuclear war. Terrorist activities and insurgency in the Indian state of Jammu and Kashmir and in the North-Eastern regions of the country, along with maritime piracy and illicit drug trafficking contribute to the complicated nature of the challenges to the Indian security. Indian military strategy is considered as a combination of the army doctrine, maritime doctrine and nuclear doctrine. The Indian political and military leadership wants to meet the challenges of changing geopolitical environment and thus continuously adapts its strategy. However, there is still a gap between theory and practice: Indian armed forces lack the capacity to implement the declared goals because of bulky bureaucratic system, outdated military equipment and insufficient level of command and control. The government needs to mobilize political will and administrative resources to upgrade its defense sector to counter its security threats and challenges.

  13. All strategy is local.

    Greenwald, Bruce; Kahn, Judd

    2005-09-01

    The aim of strategy is to master a market environment by understanding and anticipating the actions of other economic agents, especially competitors. A firm that has some sort of competitive advantage-privileged access to customers, for instance--will have relatively few competitors to contend with, since potential competitors without an advantage, if they have their wits about them, will stay away. Thus, competitive advantages are actually barriers to entry and vice versa. In markets that are exposed, by contrast, competition is intense. If the incumbents have even brief success in earning greater than normal returns on investments, new entrants will swarm in to grab a share of the profits. Sooner or later, the additional competition will push returns as far down as the firms' costs of capital. For firms operating in such markets, the only choice is to forget about strategy and run the business as efficiently as possible. Barriers to entry are easier to maintain in a competitive arena that is "local", either in the geographic sense or in the sense of being limited to one product or a handful of related ones. The two most powerful competitive advantages-customer captivity and economies of scale-are more achievable and sustainable in circumscribed markets of this kind. Their opposites are the open markets and host of rivals that are features of globalization. Compapies entering such markets risk frittering away the advantages they secured on smaller playing fields.., Ifa company wants to grow but still obtain superior returns, the authors argue, the best strategy is to dominate a series of discrete but preferably contiguous markets and then expand only at their edges. WalMart's diminishing margins over the past 15 years are strong evidence of the danger of proceeding otherwise.

  14. Strategy and the Internet.

    Porter, M E

    2001-03-01

    Many of the pioneers of Internet business, both dot-coms and established companies, have competed in ways that violate nearly every precept of good strategy. Rather than focus on profits, they have chased customers indiscriminately through discounting, channel incentives, and advertising. Rather than concentrate on delivering value that earns an attractive price from customers, they have pursued indirect revenues such as advertising and click-through fees. Rather than make trade-offs, they have rushed to offer every conceivable product or service. It did not have to be this way--and it does not have to be in the future. When it comes to reinforcing a distinctive strategy, Michael Porter argues, the Internet provides a better technological platform than previous generations of IT. Gaining competitive advantage does not require a radically new approach to business; it requires building on the proven principles of effective strategy. Porter argues that, contrary to recent thought, the Internet is not disruptive to most existing industries and established companies. It rarely nullifies important sources of competitive advantage in an industry; it often makes them even more valuable. And as all companies embrace Internet technology, the Internet itself will be neutralized as a source of advantage. Robust competitive advantages will arise instead from traditional strengths such as unique products, proprietary content, and distinctive physical activities. Internet technology may be able to fortify those advantages, but it is unlikely to supplant them. Porter debunks such Internet myths as first-mover advantage, the power of virtual companies, and the multiplying rewards of network effects. He disentangles the distorted signals from the marketplace, explains why the Internet complements rather than cannibalizes existing ways of doing business, and outlines strategic imperatives for dot-coms and traditional companies.

  15. Optimal GENCO bidding strategy

    Gao, Feng

    Electricity industries worldwide are undergoing a period of profound upheaval. The conventional vertically integrated mechanism is being replaced by a competitive market environment. Generation companies have incentives to apply novel technologies to lower production costs, for example: Combined Cycle units. Economic dispatch with Combined Cycle units becomes a non-convex optimization problem, which is difficult if not impossible to solve by conventional methods. Several techniques are proposed here: Mixed Integer Linear Programming, a hybrid method, as well as Evolutionary Algorithms. Evolutionary Algorithms share a common mechanism, stochastic searching per generation. The stochastic property makes evolutionary algorithms robust and adaptive enough to solve a non-convex optimization problem. This research implements GA, EP, and PS algorithms for economic dispatch with Combined Cycle units, and makes a comparison with classical Mixed Integer Linear Programming. The electricity market equilibrium model not only helps Independent System Operator/Regulator analyze market performance and market power, but also provides Market Participants the ability to build optimal bidding strategies based on Microeconomics analysis. Supply Function Equilibrium (SFE) is attractive compared to traditional models. This research identifies a proper SFE model, which can be applied to a multiple period situation. The equilibrium condition using discrete time optimal control is then developed for fuel resource constraints. Finally, the research discusses the issues of multiple equilibria and mixed strategies, which are caused by the transmission network. Additionally, an advantage of the proposed model for merchant transmission planning is discussed. A market simulator is a valuable training and evaluation tool to assist sellers, buyers, and regulators to understand market performance and make better decisions. A traditional optimization model may not be enough to consider the distributed

  16. Optimal coal import strategy

    Chen, C.Y.; Shih, L.H.

    1992-01-01

    Recently, the main power company in Taiwan has shifted the primary energy resource from oil to coal and tried to diversify the coal supply from various sources. The company wants to have the imported coal meet the environmental standards and operation requirements as well as to have high heating value. In order to achieve these objectives, establishment of a coal blending system for Taiwan is necessary. A mathematical model using mixed integer programming technique is used to model the import strategy and the blending system. 6 refs., 1 tab

  17. Analysis of maintenance strategies

    Laakso, K.; Simola, K.

    1998-01-01

    The main topics of the presentation include: (1) an analysis model and methods to evaluate maintenance action programs and the support decision to make changes in them and (2) to understand the maintenance strategies in a systems perspective as a basis for future developments. The subproject showed how systematic models for maintenance analysis and decision support, utilising computerised and statistical tool packages, can be taken into use for evaluation and optimisation of maintenance of active systems from the safety and economic point of view

  18. Projektlederen ogvirksomhedens strategi

    Mikkelsen, Hans; Riis, Jens Ove

    2008-01-01

    Ledere af udviklingsprojekter må i stigende grad bruge tid og kræfter på udadvendt ledelse. For udviklingsprojekter skal gennemføres i komplekse og dynamiske omgivelser, hvor formulerede strategier og handlingsplaner ikke entydigt definerer mål og rammer for udviklingsprojekter. Projekterne under...... bevågenhed, mange, mindre forbedringstiltag i dagligdagen udført af Kaizen-grupper og kvalitetsscirkler - og en midtergruppe af enkeltstående udviklingsprojekter, som er afdelingsskabte og konkurrerer om ressourcer og opmærksomhed. Udgivelsesdato: Februar...

  19. Natural hazards science strategy

    Holmes, Robert R.; Jones, Lucile M.; Eidenshink, Jeffery C.; Godt, Jonathan W.; Kirby, Stephen H.; Love, Jeffrey J.; Neal, Christina A.; Plant, Nathaniel G.; Plunkett, Michael L.; Weaver, Craig S.; Wein, Anne; Perry, Suzanne C.

    2012-01-01

    The mission of the U.S. Geological Survey (USGS) in natural hazards is to develop and apply hazard science to help protect the safety, security, and economic well-being of the Nation. The costs and consequences of natural hazards can be enormous, and each year more people and infrastructure are at risk. USGS scientific research—founded on detailed observations and improved understanding of the responsible physical processes—can help to understand and reduce natural hazard risks and to make and effectively communicate reliable statements about hazard characteristics, such as frequency, magnitude, extent, onset, consequences, and where possible, the time of future events.To accomplish its broad hazard mission, the USGS maintains an expert workforce of scientists and technicians in the earth sciences, hydrology, biology, geography, social and behavioral sciences, and other fields, and engages cooperatively with numerous agencies, research institutions, and organizations in the public and private sectors, across the Nation and around the world. The scientific expertise required to accomplish the USGS mission in natural hazards includes a wide range of disciplines that this report refers to, in aggregate, as hazard science.In October 2010, the Natural Hazards Science Strategy Planning Team (H–SSPT) was charged with developing a long-term (10-year) Science Strategy for the USGS mission in natural hazards. This report fulfills that charge, with a document hereinafter referred to as the Strategy, to provide scientific observations, analyses, and research that are critical for the Nation to become more resilient to natural hazards. Science provides the information that decisionmakers need to determine whether risk management activities are worthwhile. Moreover, as the agency with the perspective of geologic time, the USGS is uniquely positioned to extend the collective experience of society to prepare for events outside current memory. The USGS has critical statutory

  20. Conceptualizing operations strategy processes

    Rytter, Niels Gorm; Boer, Harry; Koch, Christian

    2007-01-01

    Purpose - The purpose of this paper is to present insights into operations strategy (OS) in practice. It outlines a conceptualization and model of OS processes and, based on findings from an in-depth and longitudinal case study, contributes to further development of extant OS models and methods......; taking place in five dimensions of change - technical-rational, cultural, political, project management, and facilitation; and typically unfolding as a sequential and parallel, ordered and disordered, planned and emergent as well as top-down and bottom-up process. The proposed OS conceptualization...

  1. Optimal intermittent search strategies

    Rojo, F; Budde, C E [FaMAF, Universidad Nacional de Cordoba, Ciudad Universitaria, X5000HUA Cordoba (Argentina); Wio, H S [Instituto de Fisica de Cantabria, Universidad de Cantabria and CSIC E-39005 Santander (Spain)

    2009-03-27

    We study the search kinetics of a single fixed target by a set of searchers performing an intermittent random walk, jumping between different internal states. Exploiting concepts of multi-state and continuous-time random walks we have calculated the survival probability of a target up to time t, and have 'optimized' (minimized) it with regard to the transition probability among internal states. Our model shows that intermittent strategies always improve target detection, even for simple diffusion states of motion.

  2. Town Centre Redevelopment Strategies

    Vagnby, Bo Hellisen

    After many years of urban growth Danish downtowns are facing some important choices. Shall the stake one-sidedly be on the town centres as driving forces for growth and 'city marketing', or do they still have a role to play in a broader socio-economic context? In the paper we look back on eight...... as slum clearence and urban renewal. To a certain extent parallels are drawn to international experiences, especially where these are of such a nature that they can be assumed transferred to Danish connctions. Conclusively, the strategies are discussed in the light of the turn of Danish urban planning...

  3. Pricing strategies for information goods

    Pricing strategies; information goods; bundling and versioning strategies; ... variety of industries including books, music, entertainment, gaming and education. ... Decision and Information Technologies Department, Robert H Smith School of ...

  4. National Strategies for Technological Innovation

    Rossini, Frederick; Bozeman, Barry

    1977-01-01

    Considers the implications of the technological innovation literature for possible national strategies for innovation. Sketches highly generalized innovation strategies for nations at various levels of technological development. (Author/IRT)

  5. Strategies for Sustainable Energy Development

    Meyer, Niels I

    2009-01-01

    The paper analyses international strategies for establishing a sustainable energy development. Proposals are given for mitigation of global warming.......The paper analyses international strategies for establishing a sustainable energy development. Proposals are given for mitigation of global warming....

  6. INL Vision and Strategy 2015

    Pillai, Rekha Sukamar

    2015-01-01

    This Laboratory vision and strategy presents INL's vision and strategy for the Laboratory and is our introduction to a special place dedicated to improving our nation's energy security future.

  7. China's Maritime Strategy Peaceful Rise

    Horrell, Steven L

    2008-01-01

    .... As a result the global maritime environment will be key to this continental power's continued growth As a subset of maritime strategy China's naval strategy and accompanying People's Liberation Army...

  8. National Strategy to Secure Cyberspace

    Schwalm, Keith T

    2006-01-01

    ... of a national strategy for securing cyberspace. The approach explored the development of cyber technology strategies and programs related to the mission and roles of Homeland Security Advanced Research Projects Agency...

  9. Market strategies for climate change

    Kolk, A.; Pinkse, J.M.

    2004-01-01

    The issue of climate change has attracted increasing business attention in the past decade. Whereas companies initially aimed primarily at influencing the policy debate, corporate strategies increasingly include economic responses. Existing classifications for climate change strategies however still

  10. Inspection Strategies for Concrete Bridges

    Sørensen, John Dalsgaard; Thoft-Christensen, Palle

    1989-01-01

    In this paper an optimal inspection strategy for concrete bridges based on periodic routine and detailed inspections is presented. The failure mode considered is corrosion of the reinforcement due to chlorides. A simple modelling of the corrosion and of the inspection strategy is presented....... The optimal inspection strategy is determined from an optimization problem, where the design variables are time intervals between detailed inspections and the concrete cover. The strategy is illustrated on a simple structure, namely a reinforced concrete beam....

  11. Non-oblivious Strategy Improvement

    Fearnley, John

    2010-01-01

    We study strategy improvement algorithms for mean-payoff and parity games. We describe a structural property of these games, and we show that these structures can affect the behaviour of strategy improvement. We show how awareness of these structures can be used to accelerate strategy improvement algorithms. We call our algorithms non-oblivious because they remember properties of the game that they have discovered in previous iterations. We show that non-oblivious strategy improvement algorit...

  12. A responsible remediation strategy

    Knowles, C.R.

    1992-01-01

    This paper deals with an approach to cleaning up the residue of 150 years of intense urban and industrial development in the United States. The discussion focuses on several choices and strategies that business can adopt given the existing environmental laws and the socio-economic trends of the 1990's. The thesis of this paper is that the best business strategy for dealing with environmental liabilities is to act affirmatively and aggressively. An aggressive, pro-active approach to environmental remediation liabilities makes good business sense. It allows a company to learn the true size of the problem early. Early assessment and prioritization allows one to control the course and conduct of the cleanup. Early voluntary action is always viewed favorably by agencies. It gives one control over spending patterns which has value in and of itself. Voluntary cleanups are certainly faster and invariably more efficient. And they attain clearly acceptable standards. The volunteering company that takes the lead in a multi-party site finds that the courts are supportive in helping the volunteer collect from recalcitrant polluters. All of these pluses have a direct and positive impact on the bottom line and that means that the aggressive approach is the right thing to do for both stockholders and the communities where a business exists

  13. Patent protection strategies

    Himanshu Gupta

    2010-01-01

    Full Text Available It is widely recognized that the pharmaceutical industry faces serious financial challenges. Large numbers of blockbuster drugs are losing patent protection and going generic. The pipeline of new drugs is too sparse to fill the gap and generate a platform for future growth. Moreover, many of the new products are biologics with much narrower target patient populations and comparatively higher prices relative to traditional pharmaceuticals. So now the time has come for pharmaceutical scientists to have a better understanding of patent fundamentals. This need is illustrated by analyses of key scientific and legal issues that arose during recent patent infringement cases involving Prozac, Prilosec, and Buspar. Facing this scenario, the pharmaceutical industry has moved to accelerate drug development process and to adopt at the same time different strategies to extend the life time of the patent monopoly to provide the economic incentives and utilizing it for drug discovery and development. This review covers the need of patent protection and various strategies to extend the patent.

  14. Strategies for stroke rehabilitation.

    Dobkin, Bruce H

    2004-09-01

    Rehabilitation after hemiplegic stroke has typically relied on the training of patients in compensatory strategies. The translation of neuroscientific research into care has led to new approaches and renewed promise for better outcomes. Improved motor control can progress with task-specific training incorporating increased use of proximal and distal movements during intensive practice of real-world activities. Functional gains are incorrectly said to plateau by 3-6 months. Many patients retain latent sensorimotor function that can be realised any time after stroke with a pulse of goal-directed therapy. The amount of practice probably best determines gains for a given level of residual movement ability. Clinicians should encourage patients to build greater strength, speed, endurance, and precision of multijoint movements on tasks that increase independence and enrich daily activity. Imaging tools may help clinicians determine the capacity of residual networks to respond to a therapeutic approach and help establish optimal dose-response curves for training. Promising adjunct approaches include practice with robotic devices or in a virtual environment, electrical stimulation to increase cortical excitability during training, and drugs to optimise molecular mechanisms for learning. Biological strategies for neural repair may augment rehabilitation in the next decade.

  15. CMS multicore scheduling strategy

    Yzquierdo, Antonio Pérez-Calero; Hernández, Jose; Holzman, Burt; Majewski, Krista; McCrea, Alison

    2014-01-01

    In the next years, processor architectures based on much larger numbers of cores will be most likely the model to continue 'Moore's Law' style throughput gains. This not only results in many more jobs in parallel running the LHC Run 1 era monolithic applications, but also the memory requirements of these processes push the workernode architectures to the limit. One solution is parallelizing the application itself, through forking and memory sharing or through threaded frameworks. CMS is following all of these approaches and has a comprehensive strategy to schedule multicore jobs on the GRID based on the glideinWMS submission infrastructure. The main component of the scheduling strategy, a pilot-based model with dynamic partitioning of resources that allows the transition to multicore or whole-node scheduling without disallowing the use of single-core jobs, is described. This contribution also presents the experiences made with the proposed multicore scheduling schema and gives an outlook of further developments working towards the restart of the LHC in 2015.

  16. Anorexia: A "losing" strategy?

    Mealey, L

    2000-03-01

    Several theorists have tried to model anorexia on Wasser and Barash's (1983) "reproductive suppression model" (RSM). According to the RSM, individual females adaptively suppress their reproductive functioning under conditions of social or physiological stress. From this perspective, mild anorexia is viewed as an adaptive response to modern conditions; more severe anorexia is viewed as an adaptation gone awry. Previous models have not, however, examined the full richness of the RSM. Specifically, Wasser and Barash documented not only self-imposed reproductive suppression, but also manipulative reproductive suppression of subordinate females by dominants. I propose that the modern "epidemic" of anorexia is explained neither by adaptive self-suppression nor by environmental mismatch (an adaptation gone awry); I propose that the "epidemic" levels of anorexia seen in modern western society are a direct consequence of intrasexual competition, the scope of which has been enhanced by the power and reach of modern communications media. According to this perspective, anorexia, even in its mild forms, is a manipulative strategy imposed on subordinates by dominants. Anorexia is, in both senses, a "losing" strategy.

  17. Strategies in the HSCM

    Hung-Chang Liao

    2015-01-01

    Full Text Available The purpose of this study was to establish a hospital supply chain management (HSCM model in which three kinds of drugs in the same class and with the same indications were used in creating an optimal robust design and adjustable ordering strategies to deal with a drug shortage. The main assumption was that although each doctor has his/her own prescription pattern, when there is a shortage of a particular drug, the doctor may choose a similar drug with the same indications as a replacement. Four steps were used to construct and analyze the HSCM model. The computation technology used included a simulation, a neural network (NN, and a genetic algorithm (GA. The mathematical methods of the simulation and the NN were used to construct a relationship between the factor levels and performance, while the GA was used to obtain the optimal combination of factor levels from the NN. A sensitivity analysis was also used to assess the change in the optimal factor levels. Adjustable ordering strategies were also developed to prevent drug shortages.

  18. Ruslands strategi i Arktis

    Staun, Jørgen Meedom

    Russia’s strategy in the Arctic is dominated by two overriding discourses – and foreign policy directions – which at first glance may look like opposites. On the one hand, an IR realism/geopolitical discourse that often has a clear patriotic character, dealing with “capturing”, “winning” or “conq......Russia’s strategy in the Arctic is dominated by two overriding discourses – and foreign policy directions – which at first glance may look like opposites. On the one hand, an IR realism/geopolitical discourse that often has a clear patriotic character, dealing with “capturing”, “winning......-focused discourse, which is characterized by words such as “negotiation”, “cooperation” and “joint ventures” and which has as an axiom that the companies and countries operating in the Arctic all benefit the most if they collaborate in peace and friendliness. So far, the IR liberalism discourse has set the trend...... into the projects is uncertain. The hard-pressed Russian economy, with the prospects of recession, increasing inflation, increasing flight of capital, rising interest rates and a continuously low oil price, provides a market economic incentive for suspending the projects until further notice. Whether the Kremlin...

  19. Public information strategies

    Waldahl, R.

    1995-01-01

    The Chernobyl accident in 1986 uncovered serious information problems in many Western countries, and started a debate on crisis communication and information strategies in relation to radiation danger in society. The information problem focuses on four main perspectives. The first is related to information as a persuasion process in which an efficient strategy would influence both the public's knowledge of radiation danger, their attitude towards it and their behaviour. The second perspective calls attention to the importance of the different elements of the information process. How important are different characteristics of the information source; the message itself, and the receiver? The third perspective concentrates on different types of information. What is this issue all about, why is the situation as it is, and how should people behave to protect themselves? The fourth perspective points to the various phases of a crisis. The information needed is obviously not the same in the period before a crisis emerges when no one knows what is going to happen, in the warning period when one knows that something may happen, and during the crisis itself. (Author)

  20. The HGF strategy project

    Knebel, J.U.; Fellmoser, F.; Lefhalm, C.; Mack, K.; Pettan, C.; Piecha, H.; Konys, J.; Adelhelm, C.; Glasbrenner, H.; Muscher, H.; Novotny, J.; Voss, Z.; Wedemeyer, O.; Mueller, G.; Heinzel, A.; Schumacher, G.; Huber, R.; Zimmermann, F.; Groetzbach, G.; Dorr, B.; Carteciano, L.N.

    2000-01-01

    Within the Hermann von Helmholtz-Gemeinschaft Deutscher Forschungszentren (HGF) an HGF-Strategy Fund Project entitled 'Innovative Technologies to Reduce Radiotoxicity' is funded since October 1999. The objectives of this HGF-Strategy Fund Project is the development of new methods and technologies to design and manufacture thin-walled and highly thermally-loaded surfaces which are cooled by a corrosive heavy liquid metal (lead-bismuth eutectic). The result of this project will be the basic scientific-technical tool which allows the conception and the design of a European Demonstrator of an ADS system (cf. 32.23.05). The work performed at Forschungszentrum Karlsruhe is embedded in a broad European research and development programme on ADS systems. The project is divided in three sub-projects: Sub-Project 1: Thermalhydraulic Investigations, Sub-Project 2: Material Specific Investigations, Sub-Project 3: Oxygen Control System. This progress report gives a general description of the project and its envisaged objectives. As a selection of the results achieved, first, FLUTAN calculations for the COULI beam window design and, second, the oxygen control system for the KArlsruhe Lead LAboratory KALLA are described in detail. Finally, the design and status of KALLA is given. (orig.)

  1. A strategy model for management

    Friis, Ole Uhrskov; Holmgren, Jens; Eskildsen, Jacob Kjær

    2016-01-01

    Purpose: Developing a strategy model which explains what organisations should focus on in their strategy work, both in terms of the environment as well as how the strategy is implemented. In addition, the purpose is to demonstrate how this can influence and improve the organisations’ performance....

  2. Operations Strategy with Paper Boats

    Sumukadas, Narendar

    2010-01-01

    When participants in introductory business courses encounter the term "operations strategy," it is not easy for them to appreciate what operations strategy is about, or how it fits with overall business strategy. This game breaks down highfalutin jargon into experiences that participants can readily relate to. While working in teams to make paper…

  3. Strategy development marketing commercial enterprise

    Shatalov D. S.; Hamidova O. M.

    2016-01-01

    in the scientific article the necessity of development and implementation of marketing strategies in the activity of any commercial enterprise, we give a meaningful description of the concept of «marketing strategy» and develop requirements for the selection strategy of trade enterprise.

  4. Decision Strategy Research

    Hardeman, F

    2001-04-01

    The objective of SCK-CEN's R and D programme on decision strategies is: (1) to study the decision-making process in a nuclear context with particular emphasis on emergency preparedness; (2) to disseminate knowledge on nuclear emergency preparedness including courses in the field of off-site emergency response to nuclear accidents; (3) to co-ordinate efforts within SCK-CEN in the field of medical applications of radiation; (4) to support projects and reflexion groups related to interdisciplinary research on the no-technical aspects of radiation protection or nuclear apllications; (5) to give advice and support to authorities and the industry on any topic related to radiation protection and to make expertise and infrastructure available. Main focus of the programme is on the surveillance of the territory and emergency preparedness. Principal achievements in 2000 are described.

  5. SPORT MARKETING MIX STRATEGIES

    Alexandru Lucian MIHAI

    2013-06-01

    Full Text Available This paper presents a brief overview of a significant element of the sport marketing management model called the marketing mix. The marketing mix is crucial because it defines the sport business, and much of the sport marketer’s time is spent on various functions within the marketing mix. The marketing mix is the strategic combination of the product, price, place and promotion elements. These elements are typically called the four Ps of marketing. Decisions and strategies for each are important for the marketer. Information for making educated decisions involving the four Ps comes from the marketing research involving primarily the four Cs - consumer, competitor, company and climate. A critical decision and one of the greatest challenges for the sport business is how to strategically combine the four Ps to best satisfy the consumer, meet company objectives, enhance market position, and enhance competitive advantages.

  6. SAGD operating strategies

    Nasr, T. N.; Golbeck, H.; Korpany, G.; Pierce, G. [Alberta Research Council, Edmonton, AB (Canada)

    1998-12-31

    Steam-assisted gravity drainage (SAGD) has become one of the most effective means of recovering oil from oil sands deposits that are too deeply buried for surface mining. In general terms, the process involves drilling paired horizontal wells, one well above the other, and separated by a distance, near the bottom of the oil-bearing formation. The top well is used to inject the steam, heating up the oil and allowing it to drain under the action of gravity, into the bottom well. This paper reviews advances in SAGD operating strategies, based on work at the Underground Test Facility (UTF) in Alberta. Problems that continue to challenge researchers and operators, and concepts to overcome these challenges are discussed in terms of laboratory studies at UTF, designed to improve SAGD oil-to-steam ratios and to reduce water requirements for the process. 8 refs., 20 figs.

  7. Product Architecture Modularity Strategies

    Mikkola, Juliana Hsuan

    2003-01-01

    The focus of this paper is to integrate various perspectives on product architecture modularity into a general framework, and also to propose a way to measure the degree of modularization embedded in product architectures. Various trade-offs between modular and integral product architectures...... and how components and interfaces influence the degree of modularization are considered. In order to gain a better understanding of product architecture modularity as a strategy, a theoretical framework and propositions are drawn from various academic literature sources. Based on the literature review......, the following key elements of product architecture are identified: components (standard and new-to-the-firm), interfaces (standardization and specification), degree of coupling, and substitutability. A mathematical function, termed modularization function, is introduced to measure the degree of modularization...

  8. LHCb software strategy

    Van Herwijnen, Eric

    1998-01-01

    This document describes the software strategy of the LHCb experiment. The main objective is to reuse designs and code wherever possible; We will implement an architecturally driven design process; This architectural process will be implemented using Object Technology; We aim for platform indepence; try to take advantage of distributed computing and will use industry standards, commercial software and profit from HEP developments; We will implement a common software process and development environment. One of the major problems that we are immediately faced with is the conversion of our current code from Fortran into an Object Oriented language and the conversion of our current developers to Object technology. Some technical terms related to OO programming are defined in Annex A.1

  9. Nuclear reactor strategies

    Konno, H.; Srinivasan, T.N.

    1975-01-01

    Reference is made to a linear programming model considered by Hafele and Manne ('Strategies for a Transition from Fossil to Nuclear Fuels'. 11ASA Research Report RR-74-7) in which the sum of discounted costs of meeting demand for electrical and non-electrical energy over a horizon of 75 years divided into 25 periods of 3 years is minimised subject to constraints, inter alia, on the total availability of fossil fuel and low cost ($15/lb) natural uranium. The sensitivity of the Hafele-Manne results are explored with respect to changes in some crucial parameters and assumptions namely; variation in discount rate, variation in current costs of operation of HTRB, variation in costs and availability of natural uranium, market penetration constraints, changing capital costs, price responsive demands, petroleum prices, and minimisation of PETG consumption with constraints on the sum of discounted costs. (U.K.)

  10. Business strategies for climate

    Duchene, Patrice-Henry; Colas, Julien; Boulharouf, Zoubeida; Chalendar, Pierre-Andre de; Baecher, Cedric; Fonta, Philippe; Gay, Guillaume; Timbaud, Xavier; Rivallain, Mathieu; Salomon, Thierry

    2015-03-01

    Studies published in 2014, whether by IPCC scientists or New Climate Economy economists, showed that it is still possible to combat climate change without having to give up on economic growth and human development. This applies both to emerging countries which do not want to give up on their promised growth and to developed countries that fear having to surrender their lifestyles. Positioning ourselves on a greenhouse gas emission trajectory enabling us to limit global warming to 2 deg. C by the end of this century nonetheless requires a far-reaching and immediate response coordinated by all economic and political stakeholders. Companies know that they have a major role to play in dealing with the climate challenge. They are ready to change direction, as the United Nations Secretary-General Ban Kimoon urged them to do in September 2014. Companies of all sizes engaged in this process innovate and develop technological, organisational and financial solutions to reduce greenhouse gas emissions and adapt to the consequences of climate change. They are adjusting their strategies and economic models in response to these new challenges. It is these solutions that are presented in this publication 'Business strategies for climate'. All sectors of the economy are concerned; companies in all sectors can take a forward-looking approach to the changes caused by climate change and mobilise their resources to provide effective responses in line with the issues at stake. Global economic growth is resulting in a huge increase in the demand for mobility and transport. Companies are working on ways to improve vehicles, develop engines that are less fossil-fuel dependent, and on finding new ways for people to move around and to transport goods. The challenge is considerable: it will involve working with the growing need for transport while at the same time massively reducing the sector's greenhouse gas emissions. Cities are home to an ever-increasing number of people

  11. Inventory control strategies

    Primrose, D.

    1998-01-01

    Finning International Inc. is in the business of selling, financing and servicing Caterpillar and complementary equipment. Its main markets are in western Canada, Britain and Chile. This paper discusses the parts inventory strategies system for Finning (Canada). The company's territory covers British Columbia, Alberta, the Yukon and the Northwest Territories. Finning's parts inventory consists of 80,000 component units valued at more than $150 M. Distribution centres are located in Langley, British Columbia and Edmonton, Alberta. To make inventory and orders easier to control, Finning has designed a computer-based system, with software written exclusively for Caterpillar dealers. The system makes use of a real time electronic interface with all Finning locations, plus all Caterpillar facilities and other dealers in North America. Details of the system are discussed, including territorial stocking procedures, addition to stock, exhaustion of stock, automatic/suggest order controls, surplus inventory management, and procedures for jointly managed inventory. 3 tabs., 1 fig

  12. Decision Strategy Research

    Hardeman, F.

    2001-01-01

    The objective of SCK-CEN's R and D programme on decision strategies is: (1) to study the decision-making process in a nuclear context with particular emphasis on emergency preparedness; (2) to disseminate knowledge on nuclear emergency preparedness including courses in the field of off-site emergency response to nuclear accidents; (3) to co-ordinate efforts within SCK-CEN in the field of medical applications of radiation; (4) to support projects and reflexion groups related to interdisciplinary research on the no-technical aspects of radiation protection or nuclear apllications; (5) to give advice and support to authorities and the industry on any topic related to radiation protection and to make expertise and infrastructure available. Main focus of the programme is on the surveillance of the territory and emergency preparedness. Principal achievements in 2000 are described

  13. Designing concepts and strategies

    Kiib, Hans

    2012-01-01

    , that new developments often employ very modest research on the subject and often very little has been done in order to challenge traditional concepts and to invent new sustainable concepts for redevelopment. In order to avoid mistakes in urban redevelopment we need to learn from research and evaluation...... of the best planning practice. But what might be just as important is to learn from concept development practice, which can give us a comprehensive understanding of our complex cities and make us develop a way of experiencing the unique qualities of the architectural typologies at the site. Finally...... and strategies are briefly described in the article, and the adaption by city planners and developers has been critical reviewed....

  14. SURF Model Calibration Strategy

    Menikoff, Ralph [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-03-10

    SURF and SURFplus are high explosive reactive burn models for shock initiation and propagation of detonation waves. They are engineering models motivated by the ignition & growth concept of high spots and for SURFplus a second slow reaction for the energy release from carbon clustering. A key feature of the SURF model is that there is a partial decoupling between model parameters and detonation properties. This enables reduced sets of independent parameters to be calibrated sequentially for the initiation and propagation regimes. Here we focus on a methodology for tting the initiation parameters to Pop plot data based on 1-D simulations to compute a numerical Pop plot. In addition, the strategy for tting the remaining parameters for the propagation regime and failure diameter is discussed.

  15. Hospital turnaround strategies.

    Langabeer, James

    2008-01-01

    Despite reports of higher profitability in recent years, hospitals are failing at a faster rate than ever before. Although many hospitals leave decisions regarding revenues and costs to chief financial officers and their staff, this is a recipe for disaster. From research conducted over the last 4 years on hospital bankruptcies and turnarounds, the author found that a common series of actions will help organizations evade collapse. The author explored these turnaround strategies through research and analysis of a variety of hospitals and health systems that had a high probability of immediate financial crisis or collapse. His continued observation and analysis of these hospitals in subsequent years showed that most hospitals never emerge from their bleak financial conditions. However, a few hospital administrations have successfully turned around their organizations.

  16. Tax Strategy Control

    Rossing, Christian Plesner

    2013-01-01

    This paper examines how a functional tax strategy impacts the management control system (MCS) in a multinational enterprise (MNE) facing transfer pricing tax risks. Based on case study findings it is argued that the MCS in a multinational setting is contingent upon the MNE's response to its tax...... environment. Moreover, the paper extends existing contingency-based theory on MCS by illustrating the role of inter-organisational network collaboration across MNE transfer pricing tax experts. This collaboration, caused by a widely dispersed tax knowledge base, fuels the formal interactive control system...... and reduces tax uncertainty. The paper adopts an interdisciplinary approach for explaining findings, using contingency-based theory and network theory at the inter-organisational level....

  17. Optimal fuel inventory strategies

    Caspary, P.J.; Hollibaugh, J.B.; Licklider, P.L.; Patel, K.P.

    1990-01-01

    In an effort to maintain their competitive edge, most utilities are reevaluating many of their conventional practices and policies in an effort to further minimize customer revenue requirements without sacrificing system reliability. Over the past several years, Illinois Power has been rethinking its traditional fuel inventory strategies, recognizing that coal supplies are competitive and plentiful and that carrying charges on inventory are expensive. To help the Company achieve one of its strategic corporate goals, an optimal fuel inventory study was performed for its five major coal-fired generating stations. The purpose of this paper is to briefly describe Illinois Power's system and past practices concerning coal inventories, highlight the analytical process behind the optimal fuel inventory study, and discuss some of the recent experiences affecting coal deliveries and economic dispatch

  18. Divestiture: strategy's missing link.

    Dranikoff, Lee; Koller, Tim; Schneider, Antoon

    2002-05-01

    Although most companies dedicate considerable time and attention to acquiring and creating businesses, few devote much effort to divestitures. But regularly divesting businesses--even good, healthy ones--ensures that remaining units reach their potential and that the overall company grows stronger. Drawing on extensive research into corporate performance over the last decade, McKinsey consultants Lee Dranikoff, Tim Koller, and Antoon Schneider show that an active divestiture strategy is essential to a corporation's long-term health and profitability. In particular, they say that companies that actively manage their businesses through acquisitions and divestitures create substantially more shareholder value than those that passively hold on to their businesses. Therefore, companies should avoid making divestitures only in response to pressure and instead make them part of a well-thought-out strategy. This article presents a five-step process for doing just that: prepare the organization, identify the best candidates for divestiture, execute the best deal, communicate the decision, and create new businesses. As the fifth step suggests, divestiture is not an end in itself. Rather, it is a means to a larger end: building a company that can grow and prosper over the long haul. Wise executives divest so that they can create new businesses and expand existing ones. All of the funds, management time, and support-function capacity that a divestiture frees up should therefore be reinvested in creating shareholder value. In some cases, this will mean returning money to shareholders. But more likely than not, it will mean investing in attractive growth opportunities. In companies as in the marketplace, creation and destruction go hand in hand; neither flourishes without the other.

  19. Diversity as strategy.

    Thomas, David A

    2004-09-01

    IBM's turnaround in the last decade is an impressive and well-documented business story. But behind that success is a less told people story, which explains how the corporation dramatically altered its already diverse composition and created millions of dollars in new business. By the time Lou Gerstner took the helm in 1993, IBM had a long history of progressive management when it came to civil rights and equal-opportunity employment. But Gerstner felt IBM wasn't taking full advantage of a diverse market for talent, nor was it maximizing the potential of its diverse customer and employee base. So in 1995, he launched a diversity task force initiative to uncover and understand differences among people within the organization and find ways to appeal to an even broader set of employees and customers. Gerstner established a task force for each of eight constituencies: Asians; blacks; the gay, lesbian, bisexual, transgendered community; Hispanics; white men; Native Americans; people with disabilities; and women. He asked the task forces to research four questions: What does your constituency need to feel welcome and valued at IBM? What can the corporation do, in partnership with your group, to maximize your constituency's productivity? What can the corporation do to influence your constituency's buying decisions so that IBM is seen as a preferred solution provider? And with which external organizations should IBM form relationships to better understand the needs of your constituency? The answers to these questions became the basis for IBM's diversity strategy. Thomas stresses that four factors are key to implementing any major change initiative: strong support from company leaders, an employee base that is fully engaged with the initiative, management practices that are integrated and aligned with the effort, and a strong and well-articulated business case for action. All four elements have helped IBM make diversity a key corporate strategy tied to real growth.

  20. Newer antiatherosclerosis treatment strategies.

    Aggarwal, Amitesh; Singh, Safal

    2011-01-01

    Atherosclerosis has been a target of much clinical and molecular research. As a result of this extensive research, it is amply clear that atherogenesis is a multifactorial process involving an interplay of metabolic, immune and inflammatory mechanisms. Antiatherosclerotic strategies are today aiming for a multipronged approach targeting each arm of this multifactorial process. The newer agents under development can be divided into three broad categories: anti-inflammatory agents, modulators of intermediary metabolism and antiatherosclerosis vaccines. Potential targets for anti-inflammatory agents include inhibition of conversion of low-density lipoprotein (LDL) to oxidised LDL, blocking or downregulation of cell adhesion molecules, chemokine modulation and macrophage receptor blockade. Beyond inhibition of plaque formation, efforts are also ongoing to develop agents which stabilise the plaque by increasing its fibrous content and inhibiting its disruption. So far as research in the sphere of intermediary metabolism is concerned, the focus is now primarily on raising high-density lipoprotein and promoting reverse cholesterol transport; potential targets include cholesteryl ester transfer protein, liver X-receptor, lecithin cholesterol acyltransferase and high-density lipoprotein mimetics. Acyl-coenzymeA: cholesterol acyltransferase is another enzyme whose selective and differential inhibition is under active investigation. The concept of immunisation against a non-communicable disease such as atherosclerosis is still in its nascent stages. However, with increasing evidence to suggest the role of antigen-specific T-cell-mediated immunity in atherogenesis, this approach is potentially promising. Possible antigens under evaluation include oxidised LDL and its subparticles, heat-shock proteins and cholesteryl ester transfer protein. With cardiovascular disease being the single leading cause of death worldwide, the development of a safe and successful antiatherosclerosis

  1. Supervisory Control Strategy Development

    Gary D Storrick; Bojan Petrovic

    2007-01-01

    Task 4 of this collaborative effort between ORNL, Brazil, and Westinghouse for the International Nuclear Energy Research Initiative entitled 'Development of Advanced Instrumentation and Control for an Integrated Primary System Reactor' focused on the design of the hierarchical supervisory control for multiple-module units. The state of the IRIS plant design--specifically, the lack of a detailed secondary system design--made developing a detailed hierarchical control difficult at this time. However, other simultaneous and ongoing efforts have contributed to providing the needed information. This report summarizes the results achieved under Task 4 of this Financial Assistance Award. Section 1.2 describes the scope of this effort. Section 2 discusses the IRIS control functions. Next, it briefly reviews the current control concepts, and then reviews the maneuvering requirements for the IRIS plant. It closes by noting the benefits that automated sequences have in reducing operator workload. Section 3 examines reactor loading in the frequency domain to establish some guidelines for module operation, paying particular attention to strategies for using process steam for desalination and/or district heating. The final subsection discusses the implications for reactor control, and argues that using the envisioned percentage (up to 10%) of the NSSS thermal output for these purposes should not significantly affect the NSSS control strategies. Section 4 uses some very general economic assumptions to suggest how one should approach multi-module operation. It concludes that the well-known algorithms used for economic dispatching could be used to help manage a multi-unit IRIS site. Section 5 addresses the human performance factors of multi-module operation. Section 6 summarizes our conclusions

  2. WHEN BUSINESS STRATEGY MEETS CREATIVITY

    Sorin-George TOMA

    2013-12-01

    Full Text Available Purpose – Our paper aims to present in short the theoretical foundation of the concepts of business strategy and creativity, and to highlight the relationship between them. Design/methodology/approach – Using the literature review, the study examined the conceptual framework of the notions of strategy, business strategy, and creativity. Also, it analysed the relationship between business strategy and creativity. Findings – The results confirm previous studies related to the beneficial impact of creativity on the business strategy of a company. As creativity has become an important input for a successful business strategy, companies are making significant efforts in order to bring creativity into play. Practical implications/originality/value – Business strategy and creativity are two interconnected concepts not only in theory, but also in practice. Also, creativity represents a fundamental asset of a successful company in turbulent times.

  3. Employment strategy of the Russians

    Vladimir Borisovich Toreev

    2015-05-01

    Full Text Available During the crisis it is especially important to choose a correct employment strategy. Every employee uses an employment strategy, as he/she selects the direction of long-term employment consciously or intuitively. The choice of strategy is determined by a number of factors shaping the person’s attitudes: health, character, upbringing, education, social environment, institutional environment. The employment strategies of the young people newly entering the labor market differ from lab our strategies of workers. Young people do not have such experience and can plan their life “from scratch”. The Soviet specialists, people who started their career in the planned economy, have their own features of employment strategies. The article describes employment strategies of the Russians

  4. Probability matching and strategy availability.

    Koehler, Derek J; James, Greta

    2010-09-01

    Findings from two experiments indicate that probability matching in sequential choice arises from an asymmetry in strategy availability: The matching strategy comes readily to mind, whereas a superior alternative strategy, maximizing, does not. First, compared with the minority who spontaneously engage in maximizing, the majority of participants endorse maximizing as superior to matching in a direct comparison when both strategies are described. Second, when the maximizing strategy is brought to their attention, more participants subsequently engage in maximizing. Third, matchers are more likely than maximizers to base decisions in other tasks on their initial intuitions, suggesting that they are more inclined to use a choice strategy that comes to mind quickly. These results indicate that a substantial subset of probability matchers are victims of "underthinking" rather than "overthinking": They fail to engage in sufficient deliberation to generate a superior alternative to the matching strategy that comes so readily to mind.

  5. Strategy Innovation with Employee Involvement

    Friis, Ole Uhrskov; Koch, Christian

    2015-01-01

    The purpose of this article is to investigate how employees can be involved in strategy innovation processes and how new strategy practices (new tools and procedures) are used to change strategy praxis in order to sustain value creation. In the strategizing actions, we found that even...... if the managers still dominate, some processes of direct involvement of employees occur, in particular when employees are asked to supplement overall strategic goals and when they directly shape several sub-strategies. Strategy practices found include strategy planning, an open space workshop and organised...... strategy projects. Especially the latter two are important in facilitating the employee involvement. The case, however, also exhibits enterprise-situated praxises related to unplanned events, like the mitigation of taboos....

  6. Immunosuppressive strategies and management

    Shi-hui PAN

    2008-01-01

    Advances in immunosuppressive therapy have significantly improved short-term allograft and patient survival.However,chronic allograft failure,antibody mediated rejection,recurrent diseases and immunosuppressive drug associated adverse effects remain serious barriers to long-term survival and quality of life.New immunosuppressive agents and protocols are being evaluated to combat these problems.Importantly,clinicians must work to manage post-transplant complications and avoid complex medication regimens,which will potentiate drug interactions and non.compliance.Different organs have different immunogenicities and each recipient has a unique clinical and immunologic profile.The clinician must recognize these variations and customize the immunosuppressive regimens and treatment protocols based on the individual condition.The general principles of an individualized immunosuppressive protocol should take the following factors into account:organ type,donor and recipient characteristics,quality of the donor organ,recipienVs medical history,recipient's undedying disease,immunologic risk for acute rejection,potential co-morbidity related to immunosuppression,significant druginteractions,medication costs and patient compliance.In addition,the combination of immunosuppressive drugs must have a pharmacologic rationale to achieve the desired goal of suppressing the individual's immune system to render the patient tolerant to the allograft while minimizing co-morbidities.For the past few years,many clinical strategies have been applied in an attempt to improve graft survival or to reduce immunsuppressants induced side-effects.Specific protocols include steroid or CNI avoidance,minimization or withdraw,desensitization,and treatment for antibody mediated rejection,disease specific,and pediatric specific.The short-term outcomes from these different strategies are promising but the long-term results remain to be determined.Unfortunately,current immunosuppressive agents or strategies

  7. Novel Strategies to Enhance Vaccine Immunity against Coccidioidomycosis

    2013-12-19

    Mexico and Central and South America [1]. Coccidioides is a dimorphic ascomycetous fungus with distinct saprobic and parasitic phases and is classified in...lethal spore inoculum. However, sterile immunity was not achieved and pulmonary tissue damage associated with a persistent host inflammatory response...observation will translate to humans. A recent vector-based vaccine against tuberculosis intended to protect by eliciting strong CMI failed in humans despite

  8. Uncertainty Analyses and Strategy

    Kevin Coppersmith

    2001-01-01

    performance difficult. Likewise, a demonstration of the magnitude of conservatisms in the dose estimates that result from conservative inputs is difficult to determine. To respond to these issues, the DOE explored the significance of uncertainties and the magnitude of conservatisms in the SSPA Volumes 1 and 2 (BSC 2001 [DIRS 155950]; BSC 2001 [DIRS 154659]). The three main goals of this report are: (1) To briefly summarize and consolidate the discussion of much of the work that has been done over the past few years to evaluate, clarify, and improve the representation of uncertainties in the TSPA and performance projections for a potential repository. This report does not contain any new analyses of those uncertainties, but it summarizes in one place the main findings of that work. (2) To develop a strategy for how uncertainties may be handled in the TSPA and supporting analyses and models to support a License Application, should the site be recommended. It should be noted that the strategy outlined in this report is based on current information available to DOE. The strategy may be modified pending receipt of additional pertinent information, such as the Yucca Mountain Review Plan. (3) To discuss issues related to communication about uncertainties, and propose some approaches the DOE may use in the future to improve how it communicates uncertainty in its models and performance assessments to decision-makers and to technical audiences

  9. Targeting of non-dominant antigens as a vaccine strategy to broaden T-cell responses during chronic viral infection

    Holst, Peter Johannes; Jensen, Benjamin Anderschou Holbech; Ragonnaud, Emeline

    2015-01-01

    In this study, we compared adenoviral vaccine vectors with the capacity to induce equally potent immune responses against non-dominant and immunodominant epitopes of murine lymphocytic choriomeningitis virus (LCMV). Our results demonstrate that vaccination targeting non-dominant epitopes facilita......In this study, we compared adenoviral vaccine vectors with the capacity to induce equally potent immune responses against non-dominant and immunodominant epitopes of murine lymphocytic choriomeningitis virus (LCMV). Our results demonstrate that vaccination targeting non-dominant epitopes...... was lost over time in T cells specific for the dominant T cell epitopes, and these cells were fully capable of expanding in response to a new viral challenge. Overall, our data suggests a potential for broadening of the antiviral CD8+ T-cell response by selecting non-dominant antigens to be targeted...

  10. The Social Strategy Game

    Gurven, Michael; Kaplan, Hillard; Winking, Jeffrey

    2010-01-01

    This paper examines social determinants of resource competition among Tsimane Amerindian women of Bolivia. We introduce a semi-anonymous experiment (the Social Strategy Game) designed to simulate resource competition among women. Information concerning dyadic social relationships and demographic data were collected to identify variables influencing resource competition intensity, as measured by the number of beads one woman took from another. Relationship variables are used to test how the affiliative or competitive aspects of dyads affect the extent of prosociality in the game. Using a mixed-modeling procedure, we find that women compete with those with whom they are quarreling over accusations of meat theft, mate competition, and rumor spreading. They also compete with members of their social network and with those who were designated as cooperative helpers or as close kin. Women take fewer beads from desired friends, neighbors, and from those viewed as enemies. We interpret favoritism toward enemies as resulting from fear of retribution. Our results suggest that social relations among women are multifaceted and often cannot be simplified by exclusive focus on genetic relatedness, physical proximity, or reciprocity. We argue that a complex understanding of cooperation and competition among women may require important contextual information concerning relationship history in addition to typical features of resource ecology. PMID:20526460

  11. LIMS strategy review

    Ibsen, T.G.

    1995-01-01

    The evaluation team found that the LABCORE program has a viable Laboratory Information Management System (LIMS) that will handle the sample tracking and reporting necessary to accomplish the requirements established by the system specifications. The team also found that the LABCORE program has made real accomplishments and that it has been moving in the right direction, for example the phased implementation at the 222-S laboratory. The LABCORE program has many strengths but it also has short comings that need to be addressed. The strengths are that the hardware, software, staff, and the computer and training facilities are all first rate. The shortcomings are that it is missing a strategy outlining the goals which would clearly define when the project implementation has been successfully completed. It also had excessive cost during its acquisition. Specific recommendations are made. As a whole, the evaluation team believes that LABCORE is the system that was specified and will meet the needs of both laboratories, 222-S and the Waste Sampling and Characterization Facility. LABCORE has experienced all the challenges of a new computer system but with continued effort on the part of the LABCORE team and laboratory personnel the system will operate as needed

  12. Lymphoma: Immune Evasion Strategies

    Upadhyay, Ranjan; Hammerich, Linda; Peng, Paul; Brown, Brian; Merad, Miriam; Brody, Joshua D.

    2015-01-01

    While the cellular origin of lymphoma is often characterized by chromosomal translocations and other genetic aberrations, its growth and development into a malignant neoplasm is highly dependent upon its ability to escape natural host defenses. Neoplastic cells interact with a variety of non-malignant cells in the tumor milieu to create an immunosuppressive microenvironment. The resulting functional impairment and dysregulation of tumor-associated immune cells not only allows for passive growth of the malignancy but may even provide active growth signals upon which the tumor subsequently becomes dependent. In the past decade, the success of immune checkpoint blockade and adoptive cell transfer for relapsed or refractory lymphomas has validated immunotherapy as a possible treatment cornerstone. Here, we review the mechanisms by which lymphomas have been found to evade and even reprogram the immune system, including alterations in surface molecules, recruitment of immunosuppressive subpopulations, and secretion of anti-inflammatory factors. A fundamental understanding of the immune evasion strategies utilized by lymphomas may lead to better prognostic markers and guide the development of targeted interventions that are both safer and more effective than current standards of care

  13. Gas strategies in Europe

    Le Floch-Prigent, L.

    1992-01-01

    The different factors affecting gas supply and demand in Europe are examined and the strategies considered necessary to ensure a successful European gas market in the 21st century are outlined. A number of conclusions are drawn. Even though a significant rise in the total demand for gas in Europe is forecast, there are enough sources to cover this demand. However, to think that this gas will be available at cheap conditions is an illusion. These sources are located further and further away which means that their costs will increase. Given the risks inherent in exploring, producing, transporting and marketing these reserves, all the concerned parties must be allowed an acceptable rate of return on their investment. The environmental positive assets inherent in natural gas will guarantee the industry a bright future if they can be fully exploited. New regulations must not hinder the development of new markets or the construction of new infrastructures. The transit directive already permits the softening of the rules regarding transportation; but in order for it to come into real effect there must be gas available on the market. (author)

  14. Management strategy of enterprise

    Osovskiy O.A.

    2017-03-01

    Full Text Available The development of market relations, increasing competition result in the accelerated necessity in strategic management as one of the most efficient and progressive means of organization management. The article deals with such researching methods as SWOT analysis (studying strength and weak points, manufacturing feasibilities of an enterprise and threats caused by environment, BCG matrix (while determining marketing roles of output, Mack Kinsey (determining branch attraction, the tree of aims (looking for perspective directions of development, and also other well-known tools of strategic management. SE «Zhytomyr distillery» is the enterprise with over century traditions of production quality of its output. The results of the SWOT analysis has allowed to determine the lines of behavior due to favorable and unfavorable factors of environment. At present, the enterprise has much strength and manufacturing feasibilities, therefore, the principal directions of its activity have to become the improvement of its technological base, the expansion of output range and sale at the expense of free financial resources. The calculations made by the authors allowed them to develop the main strategies for development of an enterprise. The practical value of the calculations lies in keeping competitive lines both on the domestic market of Ukraine and on the foreign international market.

  15. Marketing Strategy and Implementation

    None

    2010-05-31

    This report documents the marketing campaign that has been designed for middle and high school students in New Mexico to increase interest in participation in national security careers at the National Nuclear Security Administration. This marketing campaign builds on the research that was previously conducted, as well as the focus groups that were conducted. This work is a part of the National Nuclear Security Preparedness Project (NSPP) being performed under a Department of Energy (DOE) / National Nuclear Security Administration (NNSA) grant. Outcome analysis was performed to determine appropriate marketing strategies. The analysis was based upon focus groups with middle school and high school students, student interactions, and surveys completed by students to understand and gauge student interest in Science, Technology, Engineering, and Math (STEM) subjects, interest in careers at NNSA, future job considerations, and student desire to pursue post-secondary education. Further, through the focus groups, students were asked to attend a presentation on NNSA job opportunities and employee requirements. The feedback received from the students was utilized to develop the focus and components of the marketing campaign.

  16. Local strategies for decontamination

    Hubert, P [Institut de Protection et de Surete Nucleaire, Fontenay-aux-Roses cedex (France); Ramzaev, V [Branch of Institute of Radiation Hygiene, Novozybkov, Bryansk region (Russian Federation); Antsypov, G [Chernnobyl State Committee of the Republic of Belarus, Minsk (Belarus); Sobotovich, E [Institute of Geochemistry, Mineralogy and Ore formation, Kiev (Ukraine); Anisimova, L [EMERCOM, Moscow (Russian Federation)

    1996-07-01

    The efficiencies of a great number of techniques for decontamination or dose reduction in contaminated areas have been investigated by several teams of E.C. and CIS scientists (ECP4 project). Modelling, laboratory and field experiments, t and return from experience allowed to assess radiological efficiencies (e.g. 'decontamination factor') and requirements for the operation of numerous practical solutions. Then, those data were supplemented with data on cost and waste generation in order to elaborate all the information for the optimization of decontamination strategies. Results will be presented for about 70 techniques. However, a technique cannot be compared to another from a generic point of view. Rather it is designed for a specific target and the best technology depends on the objectives. It has been decided to implement decision analyses on case studies, and the local conditions and objectives have been investigated. Individual doses ranged from 1 to 5 mSv, with contrasted contributions of internal and external doses. The desire to restore a normal activity in a partially depopulated settlement, and concerns about the recent increase in internal doses were typical incentives for action. The decision aiding analysis illustrated that actions can be usually recommended. Results are outlined here.

  17. Empathic design: Research strategies

    Joyce Thomas

    2013-01-01

    Full Text Available This paper explores the role of empathy within new product development from the perspective of human-centred design. The authors have developed a range of empathic design tools and strategies that help to identify authentic human needs.For products and services to be effective, they need to satisfy both functional and emotional needs of individuals. In addition, the individual user needs to feel that the product and/or service has been designed ‘just for them’, otherwise they may misuse, underuse or abandon the product/service. This becomes critical with a product such as a Zimmer frame (walker, when it fails to resonate with the patient due to any stigma the patient may perceive, and thus remains unused.When training young designers to consider the wider community (people unlike themselves during the design process, it has proven extremely valuable to take them outside their comfort zones, by seeking to develop empathy with the end user for whom they are designing. Empathic modelling offers designers the opportunity to develop greater insight and understanding, in order to support more effective design outcomes. Sensitising designers to the different ways that individuals complete daily tasks has helped to diminish the gap between themselves and others (e.g. people with disabilities.The authors intend for this paper to resonate with health care providers. Human-centred design can help to refocus the designer, by placing the individual end user’s needs at the heart of their decision-making.

  18. Empathic design: Research strategies.

    Thomas, Joyce; McDonagh, Deana

    2013-01-01

    This paper explores the role of empathy within new product development from the perspective of human-centred design. The authors have developed a range of empathic design tools and strategies that help to identify authentic human needs.For products and services to be effective, they need to satisfy both functional and emotional needs of individuals. In addition, the individual user needs to feel that the product and/or service has been designed 'just for them', otherwise they may misuse, underuse or abandon the product/service. This becomes critical with a product such as a Zimmer frame (walker), when it fails to resonate with the patient due to any stigma the patient may perceive, and thus remains unused.When training young designers to consider the wider community (people unlike themselves) during the design process, it has proven extremely valuable to take them outside their comfort zones, by seeking to develop empathy with the end user for whom they are designing. Empathic modelling offers designers the opportunity to develop greater insight and understanding, in order to support more effective design outcomes. Sensitising designers to the different ways that individuals complete daily tasks has helped to diminish the gap between themselves and others (e.g. people with disabilities).The authors intend for this paper to resonate with health care providers. Human-centred design can help to refocus the designer, by placing the individual end user's needs at the heart of their decision-making.

  19. Tenable world strategies

    Meadows, D.L. (New Hampshire Univ. (USA). Inst. for Policy and Social Science Research)

    1991-10-01

    The Author presents several arguments explaining and backing the mechanics of a world strategy of zero growth. First, attention is brought to Aurelio Peccei's concerns regarding the short-sightedness of the energy and economic policies of industrialized nations. In his book (entitled 'Verso l'Abisso'), written almost 25 years ago, he correctly predicted the severity and timing of current global environmental problems such as the greenhouse effect and acid rain. Urgent and concerted action by world governments is recommended to contain and and remedy damage being caused by a diverse mix of integrated factors - over-population, uncontrolled food production, pollution, over-production by industry, and the improper use of energy and other natural resources. The Author sets guidelines for the creation of a world of steady-state growth in which an equilibrium is reached between overall standards of living and population dynamics. To meet this goal of global man/environment peaceful coexistence, he strongly urges the creation and instillation of a new set of values through the placing of emphasis on the research and development of cultural, psychological, institutional and moral philosophies which, in the last century, have been almost entirely supplanted world-wide by growing materialistic ideals and the pursuit of technological perfection.

  20. PA strategies in Korea

    Chung, J.K.

    1998-01-01

    The main purpose of promoting nuclear public acceptance in Korea is to secure necessary sites for construction of large nuclear facilities in a timely manner. Another important purpose is to maintain a good neighbor relationship between the operator of nuclear facilities and local population. To promote better understanding about the nation's peaceful nuclear programs to the general public is another facet of nuclear information activities. However, opposition by the local population living around the nuclear facilities has always been aggressive. The primary concern of the local population is basically focused on the financial issues. Professional nationwide anti-nuclear groups are abetting the local population directly but with fabricated information in order to increase psychological fears. In an effort to compensate for the psychological and sociological burdens of the local population, the Korean government arranged legal provisions. To this end, beginning in 1990, community support programs have been implemented. As the nation's nuclear power program expanded, anti-nuclear activities also became very active. Public information programs should be expanded. Some highlights of public acceptance programs of the nuclear industries are 'Go and Meet' rather than 'Come and See', 'Act rather than react', 'Proper messages to proper target groups', 'Maximum use of the third party communicators', and so on. An orchestrated effort among the nation's nuclear industries is essential to the successful implementation of the PA strategies. (author)

  1. Lymphoma: Immune Evasion Strategies

    Upadhyay, Ranjan; Hammerich, Linda; Peng, Paul [Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 (United States); Brown, Brian [Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 (United States); Merad, Miriam [Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 (United States); Brody, Joshua D., E-mail: joshua.brody@mssm.edu [Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 (United States)

    2015-04-30

    While the cellular origin of lymphoma is often characterized by chromosomal translocations and other genetic aberrations, its growth and development into a malignant neoplasm is highly dependent upon its ability to escape natural host defenses. Neoplastic cells interact with a variety of non-malignant cells in the tumor milieu to create an immunosuppressive microenvironment. The resulting functional impairment and dysregulation of tumor-associated immune cells not only allows for passive growth of the malignancy but may even provide active growth signals upon which the tumor subsequently becomes dependent. In the past decade, the success of immune checkpoint blockade and adoptive cell transfer for relapsed or refractory lymphomas has validated immunotherapy as a possible treatment cornerstone. Here, we review the mechanisms by which lymphomas have been found to evade and even reprogram the immune system, including alterations in surface molecules, recruitment of immunosuppressive subpopulations, and secretion of anti-inflammatory factors. A fundamental understanding of the immune evasion strategies utilized by lymphomas may lead to better prognostic markers and guide the development of targeted interventions that are both safer and more effective than current standards of care.

  2. Local strategies for decontamination

    Hubert, P.; Ramzaev, V.; Antsypov, G.; Sobotovich, E.; Anisimova, L.

    1996-01-01

    The efficiencies of a great number of techniques for decontamination or dose reduction in contaminated areas have been investigated by several teams of E.C. and CIS scientists (ECP4 project). Modelling, laboratory and field experiments, t and return from experience allowed to assess radiological efficiencies (e.g. 'decontamination factor') and requirements for the operation of numerous practical solutions. Then, those data were supplemented with data on cost and waste generation in order to elaborate all the information for the optimization of decontamination strategies. Results will be presented for about 70 techniques. However, a technique cannot be compared to another from a generic point of view. Rather it is designed for a specific target and the best technology depends on the objectives. It has been decided to implement decision analyses on case studies, and the local conditions and objectives have been investigated. Individual doses ranged from 1 to 5 mSv, with contrasted contributions of internal and external doses. The desire to restore a normal activity in a partially depopulated settlement, and concerns about the recent increase in internal doses were typical incentives for action. The decision aiding analysis illustrated that actions can be usually recommended. Results are outlined here

  3. Non-oblivious Strategy Improvement

    Fearnley, John

    We study strategy improvement algorithms for mean-payoff and parity games. We describe a structural property of these games, and we show that these structures can affect the behaviour of strategy improvement. We show how awareness of these structures can be used to accelerate strategy improvement algorithms. We call our algorithms non-oblivious because they remember properties of the game that they have discovered in previous iterations. We show that non-oblivious strategy improvement algorithms perform well on examples that are known to be hard for oblivious strategy improvement. Hence, we argue that previous strategy improvement algorithms fail because they ignore the structural properties of the game that they are solving.

  4. Strategic Audit and Ownership Strategy

    Mike Franz Wahl

    2015-10-01

    Full Text Available In the new global economy, ownership has become a central issue for organizational performance. Ownership strategy is where corporate governance meets strategic management. Highlighting a knowledge gap in the field of corporate governance, the author is asking the central research question: “how to develop an ownership strategy?” The main purpose of this paper is to answer this original question and develop a better understanding about ownership strategies. Theoretically there is evidence to indicate that there is a link between strategic audit and ownership strategy. Analyzing firm cases from Estonia allows concluding that the strategic audit is useful for developing systemically ownership strategies, which in turn could be a realistic alternative for complete contracts. The use of strategic audits gives the business owner an opportunity to analyze his own actions and behavior, learning, managing knowledge, and finally clearly expressing his will in the form of an ownership strategy.

  5. The office of strategy management.

    Kaplan, Robert S; Norton, David P

    2005-10-01

    There is a disconnect in most companies between strategy formulation and strategy execution. On average, 95% of a company's employees are unaware of, or do not understand, its strategy. If employees are unaware of the strategy, they surely cannot help the organization implement it effectively. It doesn't have to be like this. For the past 15 years, the authors have studied companies that achieved performance breakthroughs by adopting the Balanced Scorecard and its associated tools to help them better communicate strategy to their employees and to guide and monitor the execution of that strategy. Some companies, of course, have achieved better, longer-lasting improvements than others. The organizations that have managed to sustain their strategic focus have typically established a new corporate-level unit to oversee all activities related to strategy: an office of strategy management (OS M). The OSM, in effect, acts as the CEO's chief of staff. It coordinates an array of tasks: communicating corporate strategy; ensuring that enterprise-level plans are translated into the plans of the various units and departments; executing strategic initiatives to deliver on the grand design; aligning employees' plans for competency development with strategic objectives; and testing and adapting the strategy to stay abreast of the competition. The OSM does not do all the work, but it facilitates the processes so that strategy is executed in an integrated fashion across the enterprise. Although the companies that Kaplan and Norton studied use the Balanced Scorecard as the framework for their strategy management systems, the authors say the lessons of the OSM are applicable even to companies that do not use it.

  6. Communication: essential strategies for success.

    O'Connor, Mary

    2013-06-01

    This department highlights change management strategies that may be successful in strategically planning and executing organizational change initiatives. With the goal of presenting practical approaches helpful to nurse leaders advance organizational change, content includes evidence-based projects, tool, and resources that mobilize and sustain organizational change initiatives. In this article, the author discusses strategies for communication for change processes, whether large or small. Intentional planning and development of a communication strategy alongside, not as an afterthought, to change initiatives are essential.

  7. Formasi Strategi Di Organisasi Profesional

    Jane, Orpha

    2011-01-01

    Strategy formation within every organization has a unique characteristics. Profes-sional organizations are an organization that contains number of individuals with aspecific competency and capability. Also its have a structure with a team of expertrather than technostructure. This type of organization, all the member of the organi-zations are involved in formulating the strategy. Top leader has a role as coordinatorin formulating and executing the strategy.

  8. Marketing Strategy for Merchant Shipbuilders

    1995-01-01

    1995 Ship Production Symposium Paper No. 26: Marketing Strategy for Merchant Shipbuilders U.S. DEPARTMENT OF THE NAVY CARDEROCK DIVISION, NAVAL...Production Symposium Paper No. 26: Marketing Strategy for Merchant Shipbuilders 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6... Marketing Strategy for Merchant Shipbuilders Paul W. Stott (V), A&P Appledore international, U.K. ABSTRACT Much has been published over the years about

  9. A Taxonomy of Manufacturing Strategies

    Jeffrey G. Miller; Aleda V. Roth

    1994-01-01

    This paper describes the development and analysis of a numerical taxonomy of manufacturing strategies. The taxonomy was developed with standard methods of cluster analysis, and is based on the relative importance attached to eleven competitive capabilities defining the manufacturing task of 164 large American manufacturing business units. Three distinct clusters of manufacturing strategy groups were observed. Though there is an industry effect, all three manufacturing strategy types are obser...

  10. Determinants of contractor pricing strategy

    Moses, O. Douglas

    1988-01-01

    This paper investigates pricing strategies used by major defense contractors. Two pricing strategies are identified and discussed: penetration, which calls for a relatively low initial price followed by little reduction in price over time, and skimming, which calls for a relatively high initial price coupled with greater reduction in price over time. It is argued that contractor pricing strategy will depend on features of the defense program under consideration and featur...

  11. Energy policy, strategies for uncertainty

    Cook, P.L.; Surrey, A.J.

    1977-01-01

    The subject is dealt with in chapters, entitled: energy policy-objectives, strategies and policies; the 1967 fuel policy; problems of the optimising approach; the uncertain outlook; oil; coal; gas; electricity; the interdependence of the four fuel industries; energy policy for the future - the need for a long-term strategy; medium-term strategies and short-term policies; the organisational decisions of energy policy. Nuclear power is included in the subject matter. (U.K.)

  12. The processes of strategy development

    Bailey, Andy; Johnson, Gerry

    1995-01-01

    This paper is concerned with the processes by which strategy is developed within organisations. It builds on research into the nature of strategy development being undertaken within the Centre for Strategic Management and Organisational Change at Cranfield School of Management. Initially the process of strategy development is discussed, a number of explanations of the process are presented and an integrated framework is developed. This framework is subsequently used to illustra...

  13. Niche-specific cognitive strategies

    Hulgard, K.; Ratcliffe, J. M.

    2014-01-01

    Related species with different diets are predicted to rely on different cognitive strategies: those best suited for locating available and appropriate foods. Here we tested two predictions of the niche-specific cognitive strategies hypothesis in bats, which suggests that predatory species should...... the niche-specific cognitive strategies hypothesis and suggest that for gleaning and clutter-resistant aerial hawking bats, learning to associate shape with food interferes with subsequent spatial memory learning....

  14. Implementing marketing strategy (Part four).

    Dodson, D C; Dotson, M; McIlwain, T F; Young, D

    1993-01-01

    Every organization must monitor and evaluate the performance of its marketing strategies. The health care marketer must continually develop effective measures related to outcomes so that marketing efforts can be justified and garnish the support and resources they deserve. A major task for the marketing executive for the next decade is to develop marketing strategies and prove that those strategies are being met and that they help the health care organization carry out its objective to meet its mission.

  15. STRATEGIES FOR ACHIEVING COMPETITIVE ADVANTAGE

    Jusuf ZEKIRI; Alexandru NEDELEA

    2011-01-01

    This paper is organized in three parts. A brief overview of the importance of strategies within companies, as well as literature review is presented along with traditional approaches on strategies for achieving competitive advantage, and new approaches for gaining a competitive advantage. The main objective of the paper is to outline and discuss the relevant issues and challenges from a theoretical viewpoint related with the possible strategy formulation of companies in order to achieve a com...

  16. Strategy Assessment of Company ECOPOSTES

    Cortazar Sanabria, Javier Mauricio

    2015-01-01

    This thesis focuses on developing a research on the different types of strategies a company can implement depending on their situation and the various analyses that must be completed before making the strategy decision. External and internal environment methods are described together with the various forms of corporate restructure methods a company can use if needed. The whole process is followed step by step to provide a strategy assessment to company Ecopostes, a Colombian company focused o...

  17. Clarkesville Green Infrastructure Implementation Strategy

    The report outlines the 2012 technical assistance for Clarkesville, GA to develop a Green Infrastructure Implementation Strategy, which provides the basic building blocks for a green infrastructure plan:

  18. Involving Employees in Strategy innovation

    Friis, Ole Uhrskov; Koch, Christian

    2011-01-01

    Strategy as a practice and continuous innovation approaches are combined to conceptualise dilemmas of short versus long term and to analyse a case of employee participation as a particular example of strategy innovation. The case is a medium size textile company developing its strategy involving ...... and Balanced Score Card consultancy, an ‘open space’ workshop and organized strategy projects. Especially the latter two are important in facilitating the employee involvement. The case however also exhibit enterprise situated praxis’s like mitigation of taboos....

  19. STRATEGI PROMOSI EVENT NAMASTE FESTIVAL

    Arie Wibowo

    2015-11-01

    Full Text Available Promotion Strategy is the method that you use to promote the product. If we use the wrong promotion strategy, it will bring the disadvantage for the product and company. And on the contrary, if we are using the right promotion strategy, then it will bring the benefit for the product selling as did by Namaste Festival Event. This research was conducted in order to discover how promotion strategy of Namaste Festival Event to attract Yoga market by using promotion strategy theory. This research was guided by a qualitative approach with descriptive research in particular. The method being used was case study by conducting in-depth interviews. This research enabled the writer to discuss about the promotion strategy that being used by Namaste Festival event to increase the number of visitor. Therefore the researcher will able to get view on how PT Namaste Jaya Aditi as the organizer could run the promotion to get high number of visitor. After conducting an analysis, the main conclusion of this research is that the promotion strategy that been used by Namaste Festival organize is integrated several promotion activities such as online marketing, pre event road show, selling promotion, advertising (television and media printing & publicity. The result of this research is also said that promotion strategy that been use has an important role to attract visitor to participate in the event. Strategi Promosi adalah metode yang Anda gunakan untuk mempromosikan produk. Jika kita menggunakan strategi promosi yang salah, maka akan membawa kerugian bagi produk dan perusahaan. Dan sebaliknya, jika kita menggunakan strategi promosi yang tepat, maka akan membawa keuntungan bagi penjualan produk seperti yang dilakukan oleh Namaste Festival Event. Penelitian ini dilakukan untuk mengetahui bagaimana strategi promosi Namaste Festival Event untuk menarik pasar Yoga dengan menggunakan teori strategi promosi. Penelitian ini dipandu oleh pendekatan kualitatif dengan

  20. Strategi Permintaan dalam Bahasa Jepang

    Timur Sri Astami

    2015-01-01

    Full Text Available Request strategy in Japanese serves to present desires to hearer and speaker gets benefit from the request. Request strategy consists of bald on record, on record with positive politeness, on record with negative politeness, and off record. Research used qualitative descriptive approach. Data were gathered from Maya Koikeda’s Tokimeki Makkun comic book. Research, in the corpus of data, found bald on record strategy was a strategy without any strings attached. Then, on record with positive politeness was showed by the closeness and solidarity relationship. While on record with negative politeness was showed by minimizing load demand and apology, and off record with a vague ellipsis sentence. 

  1. Strategy Use and Strategy Choice in Fraction Magnitude Comparison

    Fazio, Lisa K.; DeWolf, Melissa; Siegler, Robert S.

    2016-01-01

    We examined, on a trial-by-trial basis, fraction magnitude comparison strategies of adults with more and less mathematical knowledge. College students with high mathematical proficiency used a large variety of strategies that were well tailored to the characteristics of the problems and that were guaranteed to yield correct performance if executed…

  2. Mapping your innovation strategy.

    Anthony, Scott D; Eyring, Matt; Gibson, Lib

    2006-05-01

    In the complex sport of American football, teams rely on playbooks as thick as the Manhattan phone directory. But when it comes to creating innovative growth businesses-which is at least as complicated as professional football--most companies have not developed detailed game plans. Indeed, many managers have concluded that a fog enshrouds the world of innovation, obscuring high-potential opportunities. The authors believe that companies can penetrate that fog by developing growth strategies based on disruptive innovations, as defined by Clayton Christensen. Such innovations conform to a pattern: They offer an entirely new solution; they perform adequately along traditional dimensions and much better along other dimensions that matter more to target customers; and they are not initially appealing to powerful incumbents. Companies can develop customized checklists, or playbooks, by combining this basic pattern with analysis of major innovations in their markets. The key early on is to focus not on detailed financial estimates--which will always guide companies toward the markets most hostile to disruptive innovations--but on how well the innovation fits the pattern of success. It's also crucial to encourage flexibility: Companies must be willing to kill projects that are going nowhere, exempt innovations from standard development processes, and avoid burdening project teams with extra financing, which can keep them heading in the wrong direction. Companies can create competitive advantage by becoming champions at defining the pattern of successful innovations and executing against it. But as that pattern becomes obvious--and others emerge-building a sustainable advantage on innovation competencies will again prove elusive.

  3. Marketing Strategy and Implementation

    None, None

    2010-09-30

    This report documents the preparation of materials for the marketing campaign that has been designed for middle and high school students in New Mexico to increase interest in participation in national security careers at the National Nuclear Security Administration. The materials and the marketing campaign build on the research that was previously completed, as well as the focus groups that were conducted. This work is a part of the National Nuclear Security Preparedness Project (NSPP). Previous research included outcome analysis to determine appropriate marketing strategies. The analysis was based upon focus groups with middle school and high school students, student interactions, and surveys completed by students to understand and gauge student interest in Science, Technology, Engineering, and Math (STEM) subjects, interest in careers at NNSA, future job considerations, and student desire to pursue post-secondary education. Further, through the focus groups, students were asked to attend a presentation on NNSA job opportunities and employee requirements. The feedback received from the students was utilized to develop the focus and components of a marketing campaign divided into DISCO (Discovering Intelligence and Security Career Opportunities) for the middle school age group and DISCO…..Your Way! for high school age groups. Both campaigns have an intertwined message that focuses on the education of students in the various national security career opportunities at NNSA using the STEM concepts and the notion that almost any career they can think of has a fit within NNSA. Further, a special emphasis has been placed on the importance of obtaining a national security clearance when working at NNSA and the steps that will need to be taken during middle school, high school, and college to be allowed this opportunity.

  4. Blue ocean strategy.

    Kim, W Chan; Mauborgne, Renée

    2004-10-01

    Despite a long-term decline in the circus industry, Cirque du Soleil profitably increased revenue 22-fold over the last ten years by reinventing the circus. Rather than competing within the confines of the existing industry or trying to steal customers from rivals, Cirque developed uncontested market space that made the competition irrelevant. Cirque created what the authors call a blue ocean, a previously unknown market space. In blue oceans, demand is created rather than fought over. There is ample opportunity for growth that is both profitable and rapid. In red oceans--that is, in all the industries already existing--companies compete by grabbing for a greater share of limited demand. As the market space gets more crowded, prospects for profits and growth decline. Products turn into commodities, and increasing competition turns the water bloody. There are two ways to create blue oceans. One is to launch completely new industries, as eBay did with online auctions. But it's much more common for a blue ocean to be created from within a red ocean when a company expands the boundaries of an existing industry. In studying more than 150 blue ocean creations in over 30 industries, the authors observed that the traditional units of strategic analysis--company and industry--are of limited use in explaining how and why blue oceans are created. The most appropriate unit of analysis is the strategic move, the set of managerial actions and decisions involved in making a major market-creating business offering. Creating blue oceans builds brands. So powerful is blue ocean strategy, in fact, that a blue ocean strategic move can create brand equity that lasts for decades.

  5. Vaccine strategies against schistosomiasis

    A. Capron

    1992-01-01

    Full Text Available Schistosomiasis, the second major parasitic disease in the world after malaria affects at least 200 million people, 500 million being exposed to the risk of infection. It is widely agreed that a vaccine strategy wich could lead to the induction of effector mechanisms reducing the level of reinfection and ideally parasite fecundity would deeply affect the incidence of pathological manifestations as well as the parasite transmission potentialities. Extensive studies performed in the rat model have allowed the identification of novel effector mechanisms involving IgE antibodies and various inflammatory cell populations (eosinophils, macrophages and platelets whereas regulation of immune response by blocking antibodies has been evidencial. Recent epidemiological studies have now entirely confirmed in human populations the the role of IgE antibodies in the acquisition of resistance and the association of IgG4 blocking antibodies with increased susceptibility. On the basis of these concepts, several schistosome glutathion S-transferase (Sm 28 GST appears as a pronising vaccine candidate. Immunization experiments have shown that two complementary goals can be achieved: (a a partial but significant reduction of the worm population (up to 60//in rats; (b a significant reduction of parasite fecundity (up in the mice and 85//in cattle and egg viability (up to 80//. At least two distinct immunological mechanisms account for these two effects. IgE antibodies appear as a major humoral component of acquired resistance whereas IgA antibodies appear as a major humoral factor affecting parasite fecundity. These studies seem to represent a parasite diseases through the identification of potentially protective antigens and of the components of the immune response which vaccination should aim at inducing.

  6. Strategies for safe motherhood.

    Chatterjee, A

    1995-02-01

    The Safe Motherhood Initiative was launched in 1988 as a global effort to halve maternal mortality and morbidity by the year 2000. The program uses a combination of health and nonhealth strategies to emphasize the need for maternal health services, extend family planning services, and improve the status of women. The maternal mortality rate (per 100,000 live births) is 390 for the world, 20-30 for developed countries, 450 for developing countries, and 420 for Asia. This translates into 308,000 maternal deaths in Asia, of which 100,000 occur in India. The direct causes of maternal mortality include sepsis, hemorrhage, eclampsia, and ruptured uterus. Indirect causes occur when associated medical conditions, such as anemia and jaundice, are exacerbated by pregnancy. Underlying causes are ineffective health services, inadequate obstetric care, unregulated fertility, infections, illiteracy, early marriage, poverty, malnutrition, and ignorance. India's Child Survival and Safe Motherhood Program seeks to achieve immediate improvements by improving health care. Longterm improvements will occur as nutrition, income, education, and the status of women improve. Improvements in health care will occur in through the provision of 1) essential obstetric care for all women (which will be essentially designed for low-risk women), 2) early detection of complications during pregnancy and labor, and 3) emergency services. Services will be provided to pregnant women at their door by field staff, at a first referral hospital, perhaps at maternity villages where high risk cases can be housed in the latter part of their pregnancies, and through the continual accessibility of government vehicles. In addition, family planning services will be improved so that fertility regulation can have its expected beneficial effect on the maternal mortality rate. The professional health organizations in India will also play a vital role in the success of this effort to reduce maternal mortality.

  7. Strategy as active waiting.

    Sull, Donald N

    2005-09-01

    Successful executives who cut their teeth in stable industries or in developed countries often stumble when they face more volatile markets. They falter, in part, because they assume they can gaze deep into the future and develop a long-term strategy that will confer a sustainable competitive advantage. But visibility into the future of volatile markets is sharply limited because so many different variables are in play. Factors such as technological innovation, customers' evolving needs, government policy, and changes in the capital markets interact with one another to create unexpected outcomes. Over the past six years, Donald Sull, an associate professor at London Business School, has led a research project examining some of the world's most volatile markets, from national markets like China and Brazil to industries like enterprise software, telecommunications, and airlines. One of the most striking findings from this research is the importance of taking action during comparative lulls in the storm. Huge business opportunities are relatively rare; they come along only once or twice in a decade. And, for the most part, companies can't manufacture those opportunities; changes in the external environment converge to make them happen. What managers can do is prepare for these golden opportunities by managing smart during the comparative calm of business as usual. During these periods of active waiting, leaders must probe the future and remain alert to anomalies that signal potential threats or opportunities; exercise restraint to preserve their war chests; and maintain discipline to keep the troops battle ready. When a golden opportunity or"sudden death"threat emerges, managers must have the courage to declare the main effort and concentrate resources to seize the moment.

  8. STRATEGI PENGEMBANGAN INDUSTRI KECIL CARICA

    Adi Permadi

    2015-03-01

    Full Text Available Tujuan penelitian ini untuk mengetahui bagaimana profil industri kecil carica di Kabupaten Wonosobo serta untuk mengetahui strategi pengembangan apa yang bisa digunakan. Variabel yang diteliti adalah profil industri yang meliputi sumber daya manusia, permodalan, teknologi, dan pemasaran. Metode analisis data yang digunakan adalah metode analisis deskriptif dan analisis SWOT. Berdasarkan hasil penelitian menunjukkan bahwa profil industri kecil carica di Kabupaten Wonosobo pada tahun 2014 ada 15 unit usaha. Ada beberapa prioritas strategi pengembangan yaang dilakukaan yaitu strategi SO dengan meningkatkan kualitas SDM, memanfaatkan tenaga kerja dari daerah sekitar, dan mengoptimalkan lokasi industri yang strategis. Strategi WO menyiapkan stok produk carica, mengoptimalkan produk carica, dan mengoptimalkan pelatihan dari dinas terkait. Strategi ST dengan meningkatkan kualitas ciri khas produk carica,peranan pemerintah dalam hal mengantisipasi bencana longsor di Dieng, dan melakukan inovasi produk carica. Strategi WT dengan meningkatkan kemampuan manajerial pengusaha, menaikkan harga jual produk carica, dan pada musim kemarau diganti dengan produk makanan komoditas Kabupaten Wonosobo. Berdasarkan hasil penelitian, strategi yang diterapkan dalam kondisi ini adalah mendukung kebijakan yang agresif, yaitu industri kecil carica di Kabupaten Wonosobo dapat bersaing dengan produk olahan makanan jenis lainnya dari berbagai daerah dengan cara menjaga dan meningkatkan kualitas produk carica yang dihasilkan.The purpose of this study to find out the profiles of carica industries in Wonosobo regency and to determine what is the development strategy can be used. The variables in this research belongs to human resources, capital, technology, and marketing. Data analysis method used is descriptive analysis method and SWOT analysis. Based on the results of this study showed that small industrial profiles carica in Wonosobo regency in 2014 there were 15 business

  9. Making strategy: learning by doing.

    Christensen, C M

    1997-01-01

    Companies find it difficult to change strategy for many reasons, but one stands out: strategic thinking is not a core managerial competence at most companies. Executives hone their capabilities by tackling problems over and over again. Changing strategy, however, is not usually a task that they face repeatedly. Once companies have found a strategy that works, they want to use it, not change it. Consequently, most managers do not develop a competence in strategic thinking. This Manager's Tool Kit presents a three-stage method executives can use to conceive and implement a creative and coherent strategy themselves. The first stage is to identify and map the driving forces that the company needs to address. The process of mapping provides strategy-making teams with visual representations of team members' assumptions, those pictures, in turn, enable managers to achieve consensus in determining the driving forces. Once a senior management team has formulated a new strategy, it must align the strategy with the company's resource-allocation process to make implementation possible. Senior management teams can translate their strategy into action by using aggregate project planning. And management teams that link strategy and innovation through that planning process will develop a competence in implementing strategic change. The author guides the reader through the three stages of strategy making by examining the case of a manufacturing company that was losing ground to competitors. After mapping the driving forces, the company's senior managers were able to devise a new strategy that allowed the business to maintain a competitive advantage in its industry.

  10. Learning Strategy Instruction Innovation Configuration

    Schumaker, Jean B.

    2011-01-01

    One way of helping students with learning disabilities and other struggling students to be independent life-long learners is to teach them how to use learning strategies in efficient ways. Learning strategy instruction can provide students the opportunity to succeed in today's schools and meet rigorous standards, transforming ineffective learners…

  11. Teaching Strategies for Specialized Ensembles.

    Teaching Music, 1999

    1999-01-01

    Provides a strategy, from the book "Strategies for Teaching Specialized Ensembles," that addresses Standard 9A of the National Standards for Music Education. Explains that students will identify and describe the musical and historical characteristics of the classical era in music they perform and in audio examples. (CMK)

  12. National Drug Control Strategy, 2011

    Office of National Drug Control Policy, 2011

    2011-01-01

    In May of 2010, President Obama released the Administration's inaugural "National Drug Control Strategy". Based on the premise that drug use and its consequences pose a threat not just to public safety, but also to public health, the 2010 "Strategy" represented the first comprehensive rebalancing of Federal drug control policy in the nearly 40…

  13. Strategy Formation in an Adhocracy.

    Mintzberg, Henry; McHugh, Alexandra

    1985-01-01

    This paper identifies and tracks the strategies pursued by a single-project organization, the National Film Board, across almost four decades of its history. Findings focus on three themes: the emergent nature of the organization's strategies, its cycles of behavior, and the organization's quest for "adhocracy." (TE)

  14. National Drug Control Strategy. Update.

    Office of National Drug Control Policy, Washington, DC.

    President Bush's new National Drug Control Strategy for 2003 focuses on three core priorities: stopping drug use before it starts; healing America's drug users; and disrupting the market. The 2003 strategy reports progress toward meeting the President's goals of reducing drug use by 10 percent over 2 years, and 25 percent over 5 years. With regard…

  15. On American Cultural Exportation Strategy

    李德俊

    2015-01-01

    American government has been attaching great importance to the role that cultural values plays in international relationships and Culture Exportation has gradually become one of the important parts of American diplomatic strategy. This strategy,which is propelled by a variety of impetuses and conducted by different approaches,is mainly aimed to serve the overall national interests of the United States.

  16. On American Cultural Exportation Strategy

    李德俊

    2015-01-01

    American government has been attaching great importance to the role that cultural values plays in international relationships and Culture Exportation has gradually become one of the important parts of American diplomatic strategy.This strategy,which is propelled by a variety of impetuses and conducted by different approaches,is mainly aimed to serve the overall national interests of the United States.

  17. Hemodialysis: stressors and coping strategies.

    Ahmad, Muayyad M; Al Nazly, Eman K

    2015-01-01

    End-stage renal disease (ESRD) is an irreversible and life-threatening condition. In Jordan, the number of ESRD patients treated with hemodialysis is on the rise. Identifying stressors and coping strategies used by patients with ESRD may help nurses and health care providers to gain a clearer understanding of the condition of these patients and thus institute effective care planning. The purpose of this study was to identify stressors perceived by Jordanian patients on hemodialysis, and the coping strategies used by them. A convenience sample of 131 Jordanian men and women was recruited from outpatients' dialysis units in four hospitals. Stressors perceived by participants on hemodialysis and the coping strategies were measured using Hemodialysis Stressor Scale, and Ways of Coping Scale-Revised. Findings showed that patients on hemodialysis psychosocial stressors scores mean was higher than the physiological stressors mean. Positive reappraisal coping strategy had the highest mean among the coping strategies and the lowest mean was accepting responsibility. Attention should be focused towards the psychosocial stressors of patients on hemodialysis and also helping patients utilize the coping strategies that help to alleviate the stressors. The most used coping strategy was positive reappraisal strategy which includes faith and prayer.

  18. MUET Preparation Language Learning Strategies

    Kuen, Yoong Li; Embi, Mohamed Amin

    2012-01-01

    The main objective of the study was to examine the English language learning strategies (LLS) used by Lower Six students in secondary schools who are sitting for their MUET test. It analyzed the language learning strategies that students use in order to prepare for the MUET test. Data were collected using a survey questionnaire with 300 students.…

  19. Math Fact Strategies Research Project

    Boso, Annie

    2011-01-01

    An action research project was conducted in order to determine effective math fact strategies for first graders. The traditional way of teaching math facts included using timed tests and flashcards, with most students counting on their fingers or a number line. Six new research-based strategies were taught and analyzed to decide which methods…

  20. Aligning with New Digital Strategy

    Yeow, Adrian; Soh, Christina; Hansen, Rina

    2018-01-01

    Prior IS research has not fully addressed the aligning process in the highly dynamic context of digital strategy. To address this gap, we conduct a longitudinal analysis of a B2B company's journey to enact its B2C digital strategy, using the dynamic capabilities approach. We found...... that as an organization shifts towards a digital strategy, misalignments between the emergent strategy and resources give rise to tension. Our study resulted in the development of an aligning process model that is comprised of three phases (exploratory, building, and extending) and generalizable organizational aligning...... actions that form the organization's sensing, seizing, and transforming capacities. These aligning actions iteratively reconfigured organizational resources and refined strategy in order to respond to both changes in the environment and internal tensions. We also recognized that there are challenges...

  1. Trophic strategies of unicellular plankton

    Chakraborty, Subhendu; Nielsen, Lasse Tor; Andersen, Ken Haste

    2017-01-01

    . To this end, we develop and calibrate a trait-based model for unicellular planktonic organisms characterized by four traits: cell size and investments in phototrophy, nutrient uptake, and phagotrophy. We use the model to predict how optimal trophic strategies depend on cell size under various environmental...... unicellulars are colimited by organic carbon and nutrients, and only large photoautotrophs and smaller mixotrophs are nutrient limited; (2) trophic strategy is bottom-up selected by the environment, while optimal size is top-down selected by predation. The focus on cell size and trophic strategies facilitates......Unicellular plankton employ trophic strategies ranging from pure photoautotrophs over mixotrophy to obligate heterotrophs (phagotrophs), with cell sizes from 10-8 to 1 μg C. A full understanding of how trophic strategy and cell size depend on resource environment and predation is lacking...

  2. Abnormal Returns and Contrarian Strategies

    Ivana Dall'Agnol

    2003-12-01

    Full Text Available We test the hypothesis that strategies which are long on portfolios of looser stocks and short on portfolios of winner stocks generate abnormal returns in Brazil. This type of evidence for the US stock market was interpreted by The Bondt and Thaler (1985 as reflecting systematic evaluation mistakes caused by investors overreaction to news related to the firm performance. We found evidence of contrarian strategies profitability for horizons from 3 months to 3 years in a sample of stock returns from BOVESPA and SOMA from 1986 to 2000. The strategies are more profitable for shorter horizons. Therefore, there was no trace of the momentum effect found by Jagadeesh and Titman (1993 for the same horizons with US data. There are remaing unexplained positive returns for contrarian strategies after accounting for risk, size, and liquidity. We also found that the strategy profitability is reduced after the Real Plan, which suggests that the Brazilian stock market became more efficient after inflation stabilization.

  3. Measurable Strategies in Differential Games

    Ivanov, R. P.

    1990-02-01

    Nonlinear approach-evasion differential games are considered in which the initial data depend on the time. These games are investigated in the class of strategies that are functions of three variables, namely, the time, the phase variable, and the current value of the other player's control, and are measurable jointly with respect to the time and the phase variable. The ideas of the Pontryagin methods in differential games and Krasovskiĭ's ideas on extremal aiming are developed, and it is shown that measurable strategies have broad applicability. It is proved that measurable strategies are compatible with differential equations with discontinuous right-hand side, and general theorems on the existence of solving measurable strategies in approach-evasion problems are proved, along with some auxiliary assertions. It is shown that the saddle point condition in the small game ensures the existence of solving measurable strategies. An example is given. Bibliography: 14 titles.

  4. PROMOTION STRATEGIES IN WINE MARKETING

    Ştefan MATEI

    2014-06-01

    Full Text Available Marketing has proven to be very useful instrument in the wine industry, in fostering comprehensive, cohesive and effective strategies which wineries require to effectively compete in today’s almost saturated wine market. But within wine marketing, the promotion strategy, from our point of view, is the most important component of the winery that can ensure the success in the market or can shorten the life cycle of the product. This being said, the aim of the paper is twofold. Firstly, to determine and analyze the steps that are required to create a promotion strategy in the wine industry, by comparing different approaches. Secondly, to identify the instruments of the promotional mix that helps a winery to implement its promotional strategy. Bearing that in mind, the paper starts with some theoretical aspects regarding the promotion strategy and ends by providing a brief overview of the main findings.

  5. Human capital strategy: talent management.

    Nagra, Michael

    2011-01-01

    Large organizations, including the US Army Medical Department and the Army Nurse Corps, are people-based organizations. Consequently, effective and efficient management of the human capital within these organizations is a strategic goal for the leadership. Over time, the Department of Defense has used many different systems and strategies to manage people throughout their service life-cycle. The current system in use is called Human Capital Management. In the near future, the Army's human capital will be managed based on skills, knowledge, and behaviors through various measurement tools. This article elaborates the human capital management strategy within the Army Nurse Corps, which identifies, develops, and implements key talent management strategies under the umbrella of the Corps' human capital goals. The talent management strategy solutions are aligned under the Nurse Corps business strategy captured by the 2008 Army Nurse Corps Campaign Plan, and are implemented within the context of the culture and core values of the organization.

  6. The Relationship Between The Brand Strategy And Business Strategy

    Karaömer, Ahmed

    2013-01-01

    In this study the relationship between three companies brand strategies and business strategies were investigated based on Aaker’s view on brand architecture. The concept and its strategies are characterized by the driving roles brands possess. At the top of the spectrum, “House of Brands” allows the brands to have the entire driver role which decreases moving downwards on the spectrum, first comes “Endorsed Brands” where the master brand has a little driver role, followed by “Subbrands” wher...

  7. Diagnostic Strategy in APR1400

    Kim, Dongyoung; Kim, Jonghyun [KEPCO International Nuclear Graduate School, Ulsan (Korea, Republic of)

    2013-05-15

    These features may bring out changes in operator tasks, changing the characteristics of tasks, or creating new tasks. Diagnostic strategy for identifying anomaly may be different especially in APR1400 from that in the analog control room due to the change of human-system interface, i.e. alarm system and display system. Since the first plant of APR1400 is being built at this moment, it is not known what strategies the operators will adopt in diagnosis tasks in the new operating environment. In this light, this paper aims at investigating operator's diagnostic strategies which are appropriate for APR1400. In order to collect data, several different approaches which are complementary are used to identify diagnostic strategies in the digital control room: analysis on audio/video recording of operation, observation in the simulator, and interview with the operators. The result shows that the digital control room introduces new strategies in the diagnosis, compared with the analog control room, and also changed the characteristics of strategies, mostly, by getting more support from the computerized system. This paper investigated how the digitalized control room may influence operator's diagnostic strategies. Several different approaches, i. e., audio/video record, observation of training, and the interview with operators, were used to gather information about the operator's behaviors. As a conclusion, this paper figured out that the digital control room introduces new strategies in the diagnosis, compared with the analog control room, and also changed the characteristics of the strategies, mostly, by getting more support from the computerized system. The operators interviewed also commented that the diagnosis in the APR1400 is quicker, more correct, and easier, compared with the analog control room.

  8. Diagnostic Strategy in APR1400

    Kim, Dongyoung; Kim, Jonghyun

    2013-01-01

    These features may bring out changes in operator tasks, changing the characteristics of tasks, or creating new tasks. Diagnostic strategy for identifying anomaly may be different especially in APR1400 from that in the analog control room due to the change of human-system interface, i.e. alarm system and display system. Since the first plant of APR1400 is being built at this moment, it is not known what strategies the operators will adopt in diagnosis tasks in the new operating environment. In this light, this paper aims at investigating operator's diagnostic strategies which are appropriate for APR1400. In order to collect data, several different approaches which are complementary are used to identify diagnostic strategies in the digital control room: analysis on audio/video recording of operation, observation in the simulator, and interview with the operators. The result shows that the digital control room introduces new strategies in the diagnosis, compared with the analog control room, and also changed the characteristics of strategies, mostly, by getting more support from the computerized system. This paper investigated how the digitalized control room may influence operator's diagnostic strategies. Several different approaches, i. e., audio/video record, observation of training, and the interview with operators, were used to gather information about the operator's behaviors. As a conclusion, this paper figured out that the digital control room introduces new strategies in the diagnosis, compared with the analog control room, and also changed the characteristics of the strategies, mostly, by getting more support from the computerized system. The operators interviewed also commented that the diagnosis in the APR1400 is quicker, more correct, and easier, compared with the analog control room

  9. Social network marketing strategy and SME strategy benefits

    Nobre, Helena; Silva, Daniela

    2014-01-01

    The study explored what benefits to small or medium-sized firms (SMEs) could be derived from the development of a social media marketing strategy. Results indicated that Facebook can facilitate communications between SME companies and customers, and can also be an important tool in creating brand recognition and broadening awareness. The importance of developing a thoughtfully designed strategy was cited, as SMEs often lack sophisticated marketing or business plans. The positive study results...

  10. The power of strategy metaphors

    Lystbæk, Christian Tang; Holmgren, Jens

    2016-01-01

    and post-structuralism. The paper reports on an action research study of a strategy workshop with the strategic team of a Human Resource Management Department in a Danish Municipality. It identifies two structural dimensions and four generic spatial metaphors were identified. Thus, the paper shows......This paper explores the power of spatial metaphors in strategy making. I seek to unfold a conception of the power of spatial metaphors in strategy making that stresses their creative and critical capacity as well as their constraints on strategic thinking. In order to identify the power of spatial...

  11. Spent nuclear fuel sampling strategy

    Bergmann, D.W.

    1995-01-01

    This report proposes a strategy for sampling the spent nuclear fuel (SNF) stored in the 105-K Basins (105-K East and 105-K West). This strategy will support decisions concerning the path forward SNF disposition efforts in the following areas: (1) SNF isolation activities such as repackaging/overpacking to a newly constructed staging facility; (2) conditioning processes for fuel stabilization; and (3) interim storage options. This strategy was developed without following the Data Quality Objective (DQO) methodology. It is, however, intended to augment the SNF project DQOS. The SNF sampling is derived by evaluating the current storage condition of the SNF and the factors that effected SNF corrosion/degradation

  12. STRATEGI PENGEMBANGAN ASURANSI TERNAK SAPI

    Nina Sari An-nisa

    2015-03-01

    Full Text Available Livestock is one of the agricultural Subsectors, which has a strategic role in economic matters in Indonesia. However, livestock faces a lot of risks, which often cause loss for the livestock business agents, especially the breeders. This research aimed to analyze a development strategy on livestock insurance pilot project. The development of the strategy is important for a company in achieving its objectives. This research also aimed to analyze external and internal factors affecting the cattle insurance pilot project implementation and to analyze the company position so that the objectives of the company on cattle insurance pilot project implementation could be determined. Furthermore, this research aimed to design a strategy on the implementation of livestock insurance pilot project, and a case study was used as the research method. The result showed that there were some external and internal factors affecting the development of livestock insurance such as brand image and company performance. The position of the company in the development of livestock insurance is to hold and maintain its position by using the strategic recommendations i.e. market penetration and product development strategy. There are 8 alternative strategies for the development of cow insurance obtained based on the strategy analysis, and there is one suitable alternative strategy obtained by SWOT analysis. The priority strategy obtained in this research by QSPM analysis is given to companies as a recommendation to establish cooperation between companies and the ministry of agriculture to socialize the implementation of livestock insurance and good breeding practice. Keyword: development strategy, cow insurance, pilot project, PT Asuransi Jasa Indonesia, QSPMABSTRAKPeternakan merupakan salah satu subsektor pertanian yang mempunyai peran strategis dalam perekonomian di Indonesia. Namun dalam pelaksanaannya subsektor peternakan menghadapi berbagai risiko yang tidak jarang

  13. Theoretical Aspects of Enterprise Business Strategy Formation

    Valentinavičius, Stasys

    2009-01-01

    The paper presents interpretations of business strategy concept and analyses strategy planning and formation, models. The concept of business strategy is revised and formulated considering various authors approaches. Analysis of business strategy formation process – steps of development and management, selection of strategy type – is based on presented strategy planning models. The aspects of enterprise business and investment strategy formation, coordination and valuation are analysed. The s...

  14. STRATEGI PENINGKATAN MUTU PENDIDIKAN ISLAM

    M. Asep Fathur Rozi

    2016-11-01

    Pengembangan sumberdaya manusia dipengaruhi kualitas lembaga pendidikan. Kualitas lembaga pendidikan dipengaruhi oleh visi dan misi lembaga tersebut. Perumusan visi dan misi lembaga melibatkan stakeholder yang sudah di tentukan oleh lembaga. Faktor yang meny ebabkan mutu pendidikan kurang berhasil antara lain, strategi pendidikan yang bersifat input oriented dan pengelolaan pendidikan selama ini lebih bersifat macro-oriented. Setelah penyusunan visi dan misi, lembaga merumuskan rencana strategis. Strategi merupakan kebijakan penting dari lembaga sebagai patokan dalam pembuatan program kelembagaan. Usaha yang bisa dilakukan oleh lembaga pendidikan untuk meningkatkan mutu institusi, antara lain: menyiapkan pemimpin yang berkualitas, merumuskan visi dan misi dengan ciri khas yang hanya dimiliki oleh intitusi, merumuskan strategi dalam rangka mewujudkan tujuan institusi, meningkatkan kemampuan sumberdaya manusia, melakukan survei pasar, melengkapi sarana dan prasarana, manajemen keuangan, menjalin kerjasama dengan stakeholder, merawat konsistensi mutu.

  15. Industrial strategy for nondestructive control

    Martin, P.; Michaut, J.P.

    1994-01-01

    For Electricite de France, the nondestructive control strategy passes by a responsibility of services, a competition between companies, a clarification of the market access and a dialogue with the companies

  16. Voyager 2 Uranus targeting strategy

    Cesarone, R. J.; Gray, D. L.; Potts, C. L.; Francis, K.

    1986-01-01

    One of the major challenges involved in the Voyager 2 Uranus flyby is to deliver the spacecraft to an appropriate aimpoint at the optimum time, so as to maximize the science return of the mission, while yet keeping propellant expenditure low. An unusual targeting strategy has been devised to satisfy these requirements. Its complexity arises from the great distance of the planet Uranus and the limited performance capabilities of Voyager. This selected strategy is developed in relation to a set of candidate strategies, mission requirements and shifting science objectives. The analysis of these candidates is conducted via a Monte Carlo simulation, the results of which yield data for the comparative evaluation and eventual and selection of the actual targeting strategy to be employed.

  17. Strategy against hazardous environmental events

    Estefan, S.F.

    1992-01-01

    The major sources of waterways pollution in egypt have been assessed compact strategy is committed to promote sustainable development of our natural resources and to secure the safety of our environmental capital

  18. Environmental Economics Research Strategy (2005)

    This 2005 Environmental Economics Research Strategy outlines EPA’s research effort to provide the necessary behavioral science foundation for making decisions and designing environmental policies at the least cost to American businesses and consumers.

  19. Strategies for Mentoring Pedagogical Knowledge

    Hudson, Peter

    2013-01-01

    Fundamental for mentoring a preservice teacher is the mentor's articulation of pedagogical knowledge, which in this research draws upon specific practices, viz.: planning, timetabling lessons, preparation, teaching strategies, content knowledge, problem solving, questioning, classroom management, implementation, assessment and viewpoints for…

  20. 2007 National Money Laundering Strategy

    2007-01-01

    ... them. The National Money Laundering Strategy for 2007 identifies areas in which the U.S. government will work to revise, enhance, or renew efforts to enforce existing Federal laws and regulations...

  1. Strategies for online test security.

    Hart, Leigh; Morgan, Lesley

    2009-01-01

    As online courses continue to increase, maintaining academic integrity in student evaluation is a challenge. The authors review several strategies, with varying degrees of cost and technology, to improve test security in the online classroom.

  2. Competitive Strategy in Continuing Education.

    Baden, Clifford

    1987-01-01

    Reviews strategic variables available to those planning continuing education marketing programs. Discusses generic competitive strategies: (1) overall cost leadership, (2) differentiation, and (3) specialization. Mentions several potential problems. (CH)

  3. Strategies for healthcare information systems

    Stegwee, R.A.; Spil, Antonius A.M.

    2001-01-01

    Information technologies of the past two decades have created significant fundamental changes in the delivery of healthcare services by healthcare provider organizations. Many healthcare organizations have been in search of ways and strategies to keep up with continuously emerging information

  4. United States Strategy for Mexico

    Centner, Robert C

    2005-01-01

    The security and stability of Mexico is of national interest to the United States, and a strong, effective alliance between the two countries is pivotal to our national defense strategy and economic prosperity...

  5. Military Strategy of Global Jihad

    Zabel, Sarah E

    2007-01-01

    .... The 9/11 attacks set this plan in motion. In the years leading up to and following the 9/11 attacks, global jihadis have written copiously on their military strategy for creating an Islamic state...

  6. Strategy: A Philosophy of Doctrine.

    1983-06-01

    Strategy is a complex subject. It has no answers; only- informed opinion and judgment, based on a study of history. In an era of positivism ...materialism, and quantitative analy- sis, such indeterminacy is discomforting. Yet, because of the uncertain environment of strategy, planners and decision...has been applied. One such fault is the ability to "lie" with statistics, which largely defeats the purpose of rigorous quantitative analysis

  7. Can NATO Practice Grand Strategy?

    Barfoed, Jacob

    2014-01-01

    In its intervention in Libya, not only did NATO fail to produce a military strategy and a campaign plan before commencing military operations, what is more worrisome was the lack of political guidance to and control of the Joint Task Force.......In its intervention in Libya, not only did NATO fail to produce a military strategy and a campaign plan before commencing military operations, what is more worrisome was the lack of political guidance to and control of the Joint Task Force....

  8. Marketingová strategie penzionu

    Fišerová, Markéta

    2015-01-01

    This bachelor thesis deals with suggestion of marketing strategy for particular business subject. First part concentrates on marketing strategy, marketing of services, marketing mix and tourism together with accommodation sector. In the second part of thesis is effected description of the pension and its marketing mix, internal and external analysis and resulting SWOT analysis. Marketing research is another source for creation suggestion. Final part summarises all pieces of knowledge and pres...

  9. Switching strategies to optimize search

    Shlesinger, Michael F

    2016-01-01

    Search strategies are explored when the search time is fixed, success is probabilistic and the estimate for success can diminish with time if there is not a successful result. Under the time constraint the problem is to find the optimal time to switch a search strategy or search location. Several variables are taken into account, including cost, gain, rate of success if a target is present and the probability that a target is present. (paper: interdisciplinary statistical mechanics)

  10. Organizational strategy, structure, and process.

    Miles, R E; Snow, C C; Meyer, A D; Coleman, H J

    1978-07-01

    Organizational adaptation is a topic that has received only limited and fragmented theoretical treatment. Any attempt to examine organizational adaptation is difficult, since the process is highly complex and changeable. The proposed theoretical framework deals with alternative ways in which organizations define their product-market domains (strategy) and construct mechanisms (structures and processes) to pursue these strategies. The framework is based on interpretation of existing literature and continuing studies in four industries (college textbook publishing, electronics, food processing, and health care).

  11. Recycling - Danish Waste Management Strategy

    Romann, Anne Funch; Thøgersen, John; Husmer, Lis

    The report challanges recycling as the only waste handling strategy. The tonnes of recycled materials should not be the only goal - it is essential to minimize the waste production and focus on eliminating hazardous materials.......The report challanges recycling as the only waste handling strategy. The tonnes of recycled materials should not be the only goal - it is essential to minimize the waste production and focus on eliminating hazardous materials....

  12. Evaluation strategies in CT scanning

    In this talk, dimensional measurement results using different measuring strategies applied in different inspection software packages for volume and surface data analysis are presented. The influence of the strategy on the dimensional measurement is determined by calculating the measurement...... uncertainty. This investigation includes measurements of two industrial items, an aluminum pipe connector and a plastic toggle, a hearing aid component. These are measured using a commercial CT scanner. Traceability is transferred using tactile and optical coordinate measuring machines, which are used...

  13. Strategi Komunikasi Membangun Kemandirian Pangan

    Rangkuti, Parlaungan Adil

    2009-01-01

    Communication strategy in developing food independencyRole of agricultural development communication is important to build food self-suffiency and diversification as the main base of food independency and food security. Food independency will be accomplished if its development comes from people initiative as an awareness to build modern farm industry with effective and efficient communication strategy support. Adoption of innovation technology by means of communication will boost productivity...

  14. Vietnam; Poverty Reduction Strategy Paper

    International Monetary Fund

    2004-01-01

    This paper assesses the Poverty Reduction Strategy Paper of Vietnam, known as the Comprehensive Poverty Reduction and Growth Strategy (CPRGS). It is an action program to achieve economic growth and poverty reduction objectives. This paper reviews the objectives and tasks of socio-economic development and poverty reduction. The government of Vietnam takes poverty reduction as a cutting-through objective in the process of country socio-economic development and declares its commitment to impleme...

  15. Tax planning strategies for physicians.

    Pope, Thomas R; Schwartz, Richard W

    2002-07-01

    The development of tax reduction strategies is a critical aspect of both corporate and personal financial planning because taxes represent the largest annual expenditure for the majority of Americans. The categories of tax reduction strategies discussed include charitable-giving techniques, ways to maximize business deductions, shifting income to family members, education tax incentives, retirement planning, and small business tax considerations. One use for these tax savings is the enhancement of a corporation's capabilities to provide services to patients.

  16. Optimal Strategy and Business Models

    Johnson, Peter; Foss, Nicolai Juul

    2016-01-01

    This study picks up on earlier suggestions that control theory may further the study of strategy. Strategy can be formally interpreted as an idealized path optimizing heterogeneous resource deployment to produce maximum financial gain. Using standard matrix methods to describe the firm Hamiltonia...... variable of firm path, suggesting in turn that the firm's business model is the codification of the application of investment resources used to control the strategic path of value realization....

  17. Strategi Public Relations Pariwisata Bali

    Cahaya Putra, Kadek Dwi

    2008-01-01

    Abstract: Bali has to maintain its image and reputation as the world leading class tourist destination. Tourism in fact is a vulnerable industry easily ruined by related issues and crises. Therefore, Public Relations (PR) with its communication strategy is highly required to maintain good relationships with related parties. This study is aimed at identifying Bali’s Public Relations positioning and setting up its PR strategies. Data and information are gained by means of questionnaire distri...

  18. Trends in Corporate Communication Strategies

    Constantin Milosteanu; Ionel Scaunasu; Alina Cornescu; Nicolae Popovic

    2011-01-01

    When business strategy is correlated with corporate communication strategy, this is reflected in the position and image of the organization on the market, leading to higher sales and increased profitability. The major changes caused by globalization, coupled with the new dynamic of the markets where consumers have access to more information in less time, require new forms of corporate communication. The new corporate communication concept involves major challenges for managers and can help de...

  19. Military Strategy vs. Military Doctrine

    Barfoed, Jacob

    2015-01-01

    The article argues that while doctrine represents the more scientific side of warfare, strategy represents the artistic side. Existing doctrine will almost never meet the requirements for winning the next war; it is through the artistic application of generic peacetime doctrine to the specific st...... strategic and operational context, using doctrine as building blocks for a context specific military strategy, that the military commander outwits and defeats or coerces the adversary and achieves the military objectives....

  20. Putting leadership back into strategy.

    Montgomery, Cynthia A

    2008-01-01

    In recent decades an infusion of economics has lent the study of strategy much needed theory and empirical evidence. Strategy consultants, armed with frameworks and techniques, have stepped forward to help managers analyze their industries and position their companies for strategic advantage. Strategy has come to be seen as an analytical problem to be solved. But, says Montgomery, the Timken Professor of Business Administration at Harvard Business School, the benefits of this rigorous approach have attendant costs: Strategy has become a competitive game plan, separate from the company's larger sense of purpose. The CEO's unique role as arbiter and steward of strategy has been eclipsed. And an overemphasis on sustainable competitive advantage has obscured the importance of making strategy a dynamic tool for guiding the company's development over time. For any company, intelligent guidance requires a clear sense of purpose, of what makes the organization truly distinctive. Purpose, Montgomery says, serves as both a constraint on activity and a guide to behavior. Creativity and insight are key to forging a compelling organizational purpose; analysis alone will never suffice. As the CEO--properly a company's chief strategist--translates purpose into practice, he or she must remain open to the possibility that the purpose itself may need to change. Lou Gerstner did this in the 1990s, when he decided that IBM would evolve to focus on applying technology rather than on inventing it. So did Steve Jobs, when he rescued Apple from a poorly performing strategy and expanded the company into attractive new businesses. Watching over strategy day in and day out is the CEO's greatest opportunity to shape the firm as well as outwit the competition.